NZ719737B2 - Aerosol pirfenidone and pyridone analog compounds and uses thereof - Google Patents
Aerosol pirfenidone and pyridone analog compounds and uses thereof Download PDFInfo
- Publication number
- NZ719737B2 NZ719737B2 NZ719737A NZ71973712A NZ719737B2 NZ 719737 B2 NZ719737 B2 NZ 719737B2 NZ 719737 A NZ719737 A NZ 719737A NZ 71973712 A NZ71973712 A NZ 71973712A NZ 719737 B2 NZ719737 B2 NZ 719737B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- pirfenidone
- pyridone analog
- aqueous solution
- dose
- mosmol
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Abstract
Disclosed are formulations of pirfenidone or pyridone analog compounds for nebulised inhlalation adminsitration. Also disclosed is the use of such formulations for the prevention or treatment of various fibrotic and inflammatory diseases, including disease associated with the lung, heart, kidney, liver, eye and central nervous system. ver, eye and central nervous system.
Description
AEROSOL PIRFENIDONE AND PYRIDONE ANALOG
COMPOUNDS AND USES THEREOF
PRIORITY CLAIM
This application claims benefit of U.S. Provisional Application No. 61/438,203,
entitled “AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND
USES THEREOF” filed on January 31, 2011; U.S. Provisional Application No. 61/508,542,
entitled “AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND
USES THEREOF” filed on July 15, 2011; U.S. Provisional Application No. 61/559,670,
entitled “AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND
USES THEREOF” filed on November 14, 2011; U.S. Provisional Application No.
61/584,119, entitled “AEROSOL PIRFENIDONE AND PYRIDONE ANALOG
COMPOUNDS AND USES THEREOF” filed on January 06 2012; all of which are herein
incorporated by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates generally in its several embodiments to liquid, dry
powder and metered-dose formulations for therapeutic inhaled delivery of pyridone
compositions such as pirfenidone to desired anatomical sites, for treatment and/or
prophylaxis of a variety of pulmonary, neurologic, cardiovascular and solid organ disease
conditions.
BACKGROUND OF THE INVENTION
A number of undesirable pulmonary diseases such as interstitial lung disease (ILD;
and sub-class diseases therein), chronic obstructive pulmonary disease (COPD; and sub-class
diseases therein), asthma, and fibrotic indications of the kidney, heart and eye, the diseases
are initiated from an external challenge. By non-limiting example, these effectors can
include infection, cigarette smoking, environmental exposure, radiation exposure, surgical
procedures and transplant rejection. However, other causes related to genetic disposition and
the effects of aging may also be attributed. Described herein are compositions of pirfenidone
or a pyridone analog compound that are suitable for inhalation delivery to the lungs and/or
systemic compartment and methods of using such compositions.
2
SUMMARY
Described herein is a pirfenidone or pyridone analog compound formulation
composition for oral pulmonary or intranasal inhalation delivery, comprising formulations for
aerosol administration of pirfenidone or pyridone analog compounds for the prevention or
treatment of various fibrotic and inflammatory diseases, including disease associated with the
lung, heart, kidney, liver, eye and central nervous system.
In one aspect, the present invention relates to an aqueous solution for nebulized
inhalation administration comprising: water; pirfenidone at a concentration from about 5.0 to
about 19.0 mg/mL; a sodium or magnesium salt, or a combination thereof, in an amount
sufficient to provide a permeant ion concentration of between about 25 and 200 mM, wherein
the permeant ions are chloride ions, bromide ions, or a combination thereof, a taste masking
agent at a concentration of between 0.1 and 2.0 mM, wherein the osmolality of the aqueous
solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg.
In another aspect the invention relates to a unit dosage adapted for use in a liquid
nebulizer comprising from about 0.5 mL to about 6 mL of an aqueous solution of
pirfenidone, a sodium or magnesium salt, or a combination thereof, in an amount sufficient to
provide a permeant ion concentration of between about 25 and 200 mM, wherein the
permeant ions are chloride ions, bromide ions, or a combination thereof, and a taste masking
agent at a concentration of between 0.1 and 2.0 mM, wherein the osmolality of the aqueous
solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg.
In another aspect the invention relates to a kit comprising a unit dosage of the
invention in a container that is adapted for use in a liquid nebulizer.
In another aspect the invention relates to an aqueous aerosol comprising a plurality of
aqueous droplets of pirfenidone, wherein the plurality of aqueous droplets have a volumetric
mean diameter (VMD), mass median aerodynamic diameter (MMAD), and/or mass median
diameter (MMD) of less than about 5.0 μm.
In another aspect the invention relates to an inhalation system for administration of
pirfenidone compound to the respiratory tract of a mammal, the system comprising: (a) about
0.5 mL to about 6 mL of an aqueous solution of pirfenidone at a concentration from about 5.0
to about 19.0 mg/mL; and a sodium or magnesium salt, or a combination thereof, in an
amount sufficient to provide a permeant ion concentration of between about 25 and 200 mM,
3
wherein the permeant ions are chloride ions, bromide ions, or a combination thereof, one or
more co-solvents, and a taste masking agent at a concentration of between 0.1 and 2.0 mM,
wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 6000
mOsmol/kg; and (b) a liquid nebulizer having a vibrating mesh membrane and a reservoir in
fluid communication therewith containing the aqueous solution of pirfenidone.
Certain statements that appear below are broader than what appears in the statements
of the invention above. These statements are provided in the interests of providing the reader
with a better understanding of the invention and its practice. The reader is directed to the
accompanying claim set which defines the scope of the invention.
Also described herein is an aqueous solution for nebulized inhalation administration
comprising: water; pirfenidone, or a pyridone analog compound, at a concentration from
about 10 mg/mL to about 50 mg/mL; and one or more co-solvents. In another aspect,
described herein is an aqueous solution for nebulized inhalation administration comprising:
water; pirfenidone, or a pyridone analog compound, at a concentration from about 10 mg/mL
to about 50 mg/mL; optionally one or more buffers to maintain the pH between about pH 4.0
to about pH 8.0; and one or more co-solvents. In some embodiments, the pH of the aqueous
solution if from about pH 4.0 to about pH 8.0. In some embodiments, the pH of the aqueous
solution if from about pH 6.0 to about pH 8.0. In some embodiments, described herein is an
aqueous solution for nebulized inhalation administration comprising: water; pirfenidone, or a
pyridone analog compound, at a concentration from about 0.1 mg/mL to about 60 mg/mL;
and one or more co-solvents, wherein the osmolality of the aqueous solution is from about 50
mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, pirfenidone, or a pyridone
analog compound, is at a concentration from about 10 mg/mL to about 60 mg/mL. In some
embodiments, pirfenidone, or a pyridone analog compound, is at a concentration from about
10 mg/mL to about 50 mg/mL. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 15 mg/mL to about 50 mg/mL. In some
embodiments, pirfenidone, or a pyridone analog compound, is at a concentration from about
mg/mL to about 50 mg/mL. In some embodiments, pirfenidone, or a pyridone analog
compound, is at a concentration from about 25 mg/mL to about 50 mg/mL. In some
embodiments, pirfenidone, or a pyridone analog compound, is at a concentration from about
mg/mL to about 50 mg/mL. In some embodiments, the osmolality of the aqueous solution
4
is from about 50 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the
osmolality of the aqueous solution is from about 50 mOsmol/kg to about 5000 mOsmol/kg.
In some embodiments, the osmolality of the aqueous solution is from about 100 mOsmol/kg
to about 5000 mOsmol/kg, from about 300 mOsmol/kg to about 5000 mOsmol/kg, from
about 400 mOsmol/kg to about 5000 mOsmol/kg, from about 600 mOsmol/kg to about 5000
mOsmol/kg, from about 1000 mOsmol/kg to about 5000 mOsmol/kg, or from about 2000
mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the total concentration of cosolvents is from about 1% to about 40% v/v. In some embodiments, the total concentration
of co-solvents is from about 1% to about 30% v/v. In some embodiments, the total
concentration of co-solvents is from about 1% to about 25% v/v. In some embodiments, the
one or more co-solvents are selected from ethanol, propylene glycol, and glycerol. In some
embodiments, the one or more co-solvents are selected from ethanol, and propylene glycol.
In some embodiments, the aqueous solution includes both ethanol and propylene glycol. In
some embodiments, the solution further comprises one or more additional ingredients
selected from surfactants, taste masking agents/sweeteners and salts. In some embodiments,
the tastemaking agent/sweetener is saccharin, or salt thereof. In some embodiments, the
solution further comprises one or more additional ingredients selected from surfactants and
salts. In some embodiments, the surfactant is polysorbate 80 or cetylpyridinium bromide. In
some embodiments, the salt is sodium chloride or magnesium chloride. In some
embodiments, the surfactant is polysorbate 80 or cetylpyridinium bromide, and the salt is
sodium chloride or magnesium chloride. In some embodiments, the aqueous solution
includes one more buffers selected from a citrate buffer and a phosphate buffer. In some
embodiments, the aqueous solution includes a phosphate buffer. In some embodiments, the
aqueous solution includes a citrate buffer. In some embodiments, described herein is from
about 0.5 mL to about 6 mL of the aqueous solution described herein.
In some embodiments, the solution further comprises one or more additional
ingredients selected from surfactants, buffers and salts. In some embodiments, the surfactant
is polysorbate 80 or cetylpyridinium bromide; the buffer is a citrate buffer or phosphate
buffer; and the salt is sodium chloride or magnesium chloride.
In some embodiments, the aqueous solution comprises: water; pirfenidone or
pyridone analog compound at a concentration from about 10 mg/mL to about 60 mg/mL; one
or more co-solvents, wherein the total amount of the one or more co-solvents is about 1% to
about 40% v/v, where the one or more co-solvents are selected from about 1% to about 25%
v/v of ethanol, about 1% to about 25% v/v of propylene glycol, and about 1% to about 25%
v/v of glycerol; and optionally a phosphate buffer that maintains the pH of the solution from
about pH 6.0 to about pH 8.0.
In some embodiments, the aqueous solution comprises: water; pirfenidone or
pyridone analog compound at a concentration from about 15 mg/mL to about 50 mg/mL; one
or more co-solvents, wherein the total amount of the one or more co-solvents if about 1 to
about 30% v/v, where the one or more co-solvents are selected from about 1% to about 10%
v/v of ethanol, and about 1% to about 20% v/v of propylene glycol; and optionally a
phosphate buffer that maintains the pH of the solution from about pH 6.0 to about pH 8.0;
wherein the osmolality of the aqueous solution is from about 400 mOsmol/kg to about 6000
mOsmol/kg.
In some embodiments, the aqueous solution for nebulized inhalation administration
described herein comprises: water; pirfenidone or pyridone analog compound at a
concentration from about 10 mg/mL to about 50 mg/mL; optionally a phosphate buffer that
maintains the pH of the solution from about pH 6.0 to about pH 8.0; one or more co-solvents
selected from about 1% to about 25% v/v of ethanol and about 1% to about 25% v/v of
propylene glycol, where the total amount of co-solvents is from 1% to 25% v/v. In some
embodiments, the aqueous solution for nebulized inhalation administration described herein
comprises: water; pirfenidone or pyridone analog compound at a concentration from about 10
mg/mL to about 50 mg/mL; optionally a phosphate buffer that maintains the pH of the
solution from about pH 6.0 to about pH 8.0; about 8% v/v of ethanol; and about 16% v/v of
propylene glycol. In some embodiments, the aqueous solution for nebulized inhalation
administration described herein consists essentially of: water; pirfenidone or pyridone analog
compound at a concentration from about 10 mg/mL to about 50 mg/mL; optionally a
phosphate buffer that maintains the pH of the solution from about pH 6.0 to about pH 8.0;
one or more co-solvents selected from about 1% to about 25% v/v of ethanol and about 1% to
about 25% v/v of propylene glycol, where the total amount of co-solvents is from 1% to 25%
v/v. In some embodiments, the aqueous solution for nebulized inhalation administration
described herein consists essentially of: water; pirfenidone or pyridone analog compound at a
6
concentration from about 10 mg/mL to about 50 mg/mL; optionally a phosphate buffer that
maintains the pH of the solution from about pH 6.0 to about pH 8.0; about 8% v/v of ethanol;
and about 16% v/v of propylene glycol. In some embodiments, described herein is from
about 0.5 mL to about 6 mL of the aqueous solution described herein.
In some embodiments, described herein is a unit dosage adapted for use in a liquid
nebulizer comprising from about 0.5 mL to about 6 mL of an aqueous solution of pirfenidone
or a pyridone analog compound, wherein the concentration of pirfenidone or pyridone analog
compound in the aqueous solution is from about 0.1 mg/mL to about 60 mg/mL. In some
embodiments, the aqueous solution further comprises one or more additional ingredients
selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating
agents, anti-oxidants, salts, and buffers; and the osmolality of the aqueous solution is from
about 50 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the aqueous solution
further comprises: one or more co-solvents selected from ethanol, propylene glycol, and
glycerol; and one or both of a citrate buffer or a phosphate buffer. In some embodiments, the
aqueous solution comprises: pirfenidone or pyridone analog compound dissolved in water at
a concentration from about 15 mg/mL to about 50 mg/mL; optionally a phosphate buffer that
maintains the pH of the solution from about pH 6.0 to about pH 8.0; one or more co-solvents,
wherein the total amount of the one or more co-solvents if about 1 to about 30% v/v, where
the one or more co-solvents are selected from about 1% to about 10% v/v of ethanol, and
about 1% to about 20% v/v of propylene glycol; wherein the osmolality of the aqueous
solution is from about 400 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the
aqueous solution is as described herein.
In some embodiments, described herein is a kit comprising: a unit dosage of an
aqueous solution of pirfenidone or pyridone analog as described herein in a container that is
adapted for use in a liquid nebulizer.
In some embodiments, provided herein is an aqueous droplet of pirfenidone or
pyridone analog compound, wherein the aqueous droplet has a diameter less than about 5.0
μm. In some embodiments, the aqueous droplet was produced from a liquid nebulizer and an
aqueous solution of pirfenidone or pyridone analog compound. In some embodiments, the
aqueous solution of pirfenidone or pyridone analog compound is as described herein. In
some embodiments, the aqueous solution has concentration of pirfenidone or pyridone analog
7
compound from about 0.1 mg/mL and about 60 mg/mL and an osmolality from about 50
mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the aqueous droplet is
produced by a nebulizing an aqueous solution of pirfenidone or pyridone analog compound
as described herein with a nebulizer. In some embodiments, the nebulizer is a liquid
nebulizer. In some embodiments, the nebulizer is a high efficiency liquid nebulizer.
In some embodiments, provided herein is an aqueous aerosol comprising a plurality of
aqueous droplets of pirfenidone or pyridone analog compound. In some embodiments,
described herein is an aqueous aerosol comprising a plurality of aqueous droplets of
pirfenidone or pyridone analog compound, wherein the plurality of aqueous droplets have a
volumetric mean diameter (VMD), mass median aerodynamic diameter (MMAD), and/or
mass median diameter (MMD) of less than about 5.0 μm. In some embodiments, the
plurality of aqueous droplets was produced from a liquid nebulizer and an aqueous solution
of pirfenidone or pyridone analog compound. In some embodiments, the aqueous solution
has concentration of pirfenidone or pyridone analog compound from about 10 mg/mL and
about 60 mg/mL and an osmolality from about 50 mOsmol/kg to about 6000 mOsmol/kg. In
some embodiments, at least 30% of the aqueous droplets in the aerosol have a diameter less
than about 5 μm. In some embodiments, the aqueous aerosol is produced by a nebulizing an
aqueous solution of pirfenidone or pyridone analog compound as described herein with a
nebulizer. In some embodiments, the nebulizer is a liquid nebulizer. In some embodiments,
the nebulizer is a high efficiency liquid nebulizer.
In some embodiments, the nebulizer used in any of the methods described herein is a
liquid nebulizer. In some embodiments, the nebulizer used in any of the methods described
herein is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer
comprising a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a
vibration generator and an aqueous chamber. In some embodiments, the nebulizer used in
any of the methods described herein is a nebulizer comprising a vibrating mesh or plate with
multiple apertures. In some embodiments, the liquid nebulizer: (i) achieves lung deposition
of at least 7% of the pirfenidone or pyridone analog compound administered to the mammal;
(ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of
the aqueous solution of about 1.0 μm to about 2.5 μm; (iii) provides: a) a mass median
aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high
8
efficiency liquid nebulizer of about 1 μm to about 5 μm; b) a volumetric mean diameter
(VMD) of about 1 μm to about 5 μm; and/or c) a mass median diameter (MMD) of about 1
μm to about 5 μm; (iv) provides a fine particle fraction (FPF= % ≤ 5 microns) of droplets
emitted from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least
0.1 mL/min; and/or (vi) provides at least about 25% of the aqueous solution to the mammal.
In some embodiments, the liquid nebulizer is characterized as having at least two, at
least three, at least four, at least five, or all six of (i), (ii), (iii), (iv), (v), (vi). In some
embodiments, the liquid nebulizer: (i) achieves lung deposition of at least 5%, at least 6%, at
least 7%, at least 8%, at least 9%, at least 10%, at least 12%, at least 14%, at least 16%, at
least 18%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% at least 45%, at
least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80%
of the pirfenidone or pyridone analog compound administered to the mammal. In some
embodiments, the liquid nebulizer: (ii) provides a Geometric Standard Deviation (GSD) of
emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm,
about 1.2 μm to about 2.3 μm, about 1.4 μm to about 2.1 μm, or about 1.5 μm to about 2.0
μm. In some embodiments, the liquid nebulizer: (iii) provides a) a mass median aerodynamic
diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency
liquid nebulizer of about less than 5 μm or about 1 μm to about 5 μm; b) a volumetric mean
diameter (VMD) of about less than 5 μm or about 1 μm to about 5 μm; and/or c) a mass
median diameter (MMD) of about less than 5 μm or about 1 μm to about 5 μm. In some
embodiments, the liquid nebulizer: (iv) provides a fine particle fraction (FPF= % ≤ 5
microns) of droplets emitted from the liquid nebulizer of at least about 30%, at least about
%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least
about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at
least about 85%, or at least about 90%. In some embodiments, the liquid nebulizer: (v)
provides an output rate of at least 0.1 mL/min, of at least 0.2 mL/min, of at least 0.3 mL/min,
of at least 0.4 mL/min, of at least 0.5 mL/min, of at least 0.6 mL/min, of at least 0.7 mL/min,
of at least 0.8 mL/min, of at least 0.9 mL/min, of at least 1.0 mL/min, or less than about 1.0
mL/min. In some embodiments, the liquid nebulizer: (vi) provides at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least
9
about 75%, at least about 80%, at least about 85%, or at least about 95%,of the aqueous
solution to the mammal. In some embodiments, the liquid nebulizer provides an respirable
delivered dose (RDD) of at least 5%, at least 6%, at least 7%, at least 8%, at least 10%, at
least 12%, at least 16%, at least 20%, at least 24%, at least 28%, at least 32%, at least 36%, at
least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at
least 75%, at least 80%, at least 85%, or at least 90%.
In some embodiments, described herein is a method for the treatment of lung disease
in a mammal comprising: administering to mammal in need thereof an aqueous solution
comprising pirfenidone or a pyridone analog compound with a liquid nebulizer. In some
embodiments, described herein is a method for the treatment of lung disease in a mammal
comprising: administering to mammal in need thereof an aqueous solution comprising
pirfenidone or a pyridone analog compound with a liquid nebulizer; wherein the aqueous
solution comprises water; pirfenidone, or a pyridone analog compound, at a concentration
from about 0.1 mg/mL to about 60 mg/mL; and one or more co-solvents, wherein the
osmolality of the aqueous solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg.
In some embodiments, the aqueous solution comprises water; pirfenidone or pyridone analog
compound at a concentration from about 10 mg/mL to about 60 mg/mL; one or more cosolvents, wherein the total amount of the one or more co-solvents is about 1% to about 40%
v/v, where the one or more co-solvents are selected from about 1% to about 25% v/v of
ethanol, about 1% to about 25% v/v of propylene glycol, and about 1% to about 25% v/v of
glycerol; and optionally a phosphate buffer that maintains the pH of the solution from about
pH 6.0 to about pH 8.0. In some embodiments, the aqueous solution comprises water;
pirfenidone or pyridone analog compound at a concentration from about 15 mg/mL to about
50 mg/mL; one or more co-solvents, wherein the total amount of the one or more co-solvents
if about 1 to about 30% v/v, where the one or more co-solvents are selected from about 1% to
about 10% v/v of ethanol, and about 1% to about 20% v/v of propylene glycol; and
optionally a phosphate buffer that maintains the pH of the solution from about pH 6.0 to
about pH 8.0; wherein the osmolality of the aqueous solution is from about 400 mOsmol/kg
to about 6000 mOsmol/kg. In some embodiments, the nebulizer is a jet nebulizer, an
ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating
mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an
aqueous chamber. In some embodiments, the liquid nebulizer: (i) achieves lung deposition
of at least 7% of the pirfenidone or pyridone analog compound administered to the mammal;
(ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of
the aqueous solution of about 1.0 μm to about 2.5 μm; (iii) provides: a) a mass median
aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high
efficiency liquid nebulizer of about 1 μm to about 5 μm; b) a volumetric mean diameter
(VMD) of about 1 μm to about 5 μm; and/or c) a mass median diameter (MMD) of about 1
μm to about 5 μm; (iv) provides a fine particle fraction (FPF= % ≤ 5 microns) of droplets
emitted from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least
0.1 mL/min; and/or (vi) provides at least about 25% of the aqueous solution to the mammal.
In some embodiments, the mammal is a human. In some embodiments, the lung disease is
lung fibrosis and the mammal is a human. In some embodiments, the lung disease is
idiopathic pulmonary fibrosis and the mammal is a human. In some embodiments, the liquid
nebulizer delivers from about 0.1 mg to about 360 mg of pirfenidone or pyridone analog
compound to the lungs of the mammal in less than about 20 minutes with mass median
diameter (MMAD) particles sizes from about 1 to about 5 micron.
In some embodiments, the lung tissue Cmax and/or AUC of pirfenidone or pyridone
analog compound that is obtained after a single administration of the aqueous solution to the
mammal with a liquid nebulizer is about the same or greater than the lung tissue Cmax and/or
AUC of pirfenidone or pyridone analog compound that is obtained after a single dose of
orally administered pirfenidone or pyridone analog compound at a dose that is from about
80% to about 120% of the dose administered with the liquid nebulizer; and/or the plasma
Cmax and/or AUC of pirfenidone or pyridone analog compound that is obtained after a single
administration of the aqueous solution to the mammal with a liquid nebulizer is at least 10%
or greater than the plasma Cmax and/or AUC of pirfenidone or pyridone analog compound
that is obtained after a single dose of orally administered pirfenidone or pyridone analog
compound at a dose that is from about 80% to about 120% of the dose administered with the
liquid nebulizer. In some embodiments, the lung tissue Cmax of pirfenidone or pyridone
analog compound that is obtained after a single administration of the aqueous solution to the
mammal with a liquid nebulizer is greater than the lung tissue Cmax of pirfenidone or
pyridone analog compound that is obtained after a single dose of orally administered
11
pirfenidone or pyridone analog compound at a dose that is from about 80% to about 120% of
the dose administered with the liquid nebulizer. In some embodiments, the lung tissue AUC
of pirfenidone or pyridone analog compound that is obtained after a single administration of
the aqueous solution to the mammal with a liquid nebulizer is greater than the lung tissue
AUC of pirfenidone or pyridone analog compound that is obtained after a single dose of
orally administered pirfenidone or pyridone analog compound at a dose that is from about
80% to about 120% of the dose administered with the liquid nebulizer. In some
embodiments, the plasma Cmax of pirfenidone or pyridone analog compound that is obtained
after a single administration of the aqueous solution to the mammal with a liquid nebulizer is
at least 10% or greater than the plasma Cmax of pirfenidone or pyridone analog compound
that is obtained after a single dose of orally administered pirfenidone or pyridone analog
compound at a dose that is from about 80% to about 120% of the dose administered with the
liquid nebulizer. In some embodiments, the plasma AUC of pirfenidone or pyridone analog
compound that is obtained after a single administration of the aqueous solution to the
mammal with a liquid nebulizer is at least 10% or greater than the plasma AUC of
pirfenidone or pyridone analog compound that is obtained after a single dose of orally
administered pirfenidone or pyridone analog compound at a dose that is from about 80% to
about 120% of the dose administered with the liquid nebulizer.
In some embodiments, the liquid nebulizer delivers from about 0.1 mg to about 360
mg of pirfenidone or pyridone analog compound to the lungs of the mammal in less than
about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about
micron.
In some embodiments, administration with the liquid nebulizer does not include an
initial dose-escalation period.
In some embodiments, described herein is a method of reducing the risk of
gastrointestinal (GI) adverse events in the treatment of a human with pirfenidone or pyridone
analog compound, comprising: administering to the human in need thereof a nebulized
aqueous solution comprising pirfenidone or a pyridone analog compound with a liquid
nebulizer; wherein the aqueous solution comprises water; pirfenidone, or a pyridone analog
compound, at a concentration from about 0.1 mg/mL to about 60 mg/mL; and one or more
co-solvents, wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to
12
about 6000 mOsmol/kg. In some embodiments, the aqueous solution comprises water;
pirfenidone or pyridone analog compound at a concentration from about 10 mg/mL to about
60 mg/mL; one or more co-solvents, wherein the total amount of the one or more co-solvents
is about 1% to about 40% v/v, where the one or more co-solvents are selected from about 1%
to about 25% v/v of ethanol, about 1% to about 25% v/v of propylene glycol, and about 1%
to about 25% v/v of glycerol; and optionally a phosphate buffer that maintains the pH of the
solution from about pH 6.0 to about pH 8.0.
In some embodiments, the aqueous solution comprises water; pirfenidone or pyridone
analog compound at a concentration from about 15 mg/mL to about 50 mg/mL; one or more
co-solvents, wherein the total amount of the one or more co-solvents if about 1 to about 30%
v/v, where the one or more co-solvents are selected from about 1% to about 10% v/v of
ethanol, and about 1% to about 20% v/v of propylene glycol; and optionally a phosphate
buffer that maintains the pH of the solution from about pH 6.0 to about pH 8.0; wherein the
osmolality of the aqueous solution is from about 400 mOsmol/kg to about 6000 mOsmol/kg.
In some embodiments, the pirfenidone or pyridone analog is administered to treat lung
disease in the human. In some embodiments, lung disease is idiopathic pulmonary fibrosis.
In some embodiments, the liquid nebulizer delivers about 0.1 mg to about 360 mg of
prifenidone or pyridone analog compound to the lungs in less than about 20 minutes with
mass median diameter (MMAD) particles sizes from about 1 to about 5 micron.
In some embodiments, administration with the liquid nebulizer does not include an
initial dose-escalation period.
In some embodiments, about 0.5 mL to about 6 mL of the aqueous solution is
administered to the mammal with a liquid nebulizer, the solution having a concentration of
pirfenidone or pyridone analog compound from about 0.1 mg/mL to about 60 mg/mL and the
osmolality of the aqueous solution is from about 50 mOsmol/kg to about 5000 mOsmol/kg;
and the liquid nebulizer is a nebulizer comprising a vibrating mesh or plate with multiple
apertures.
In some embodiments, the liquid nebulizer delivers about 0.1 mg to about 360 mg of
prifenidone or pyridone analog compound to the lungs in less than about 20 minutes with
mass median diameter (MMAD) particles sizes from about 1 to about 5 micron. In some
13
embodiments, the aqueous solution has a pH from about 4.0 to about 8.0 and an osmolality
from about 400 mOsmol/kg to about 5000 mOsmol/kg.
In some embodiments, described herein is an inhalation system for administration of
pirfenidone or pyridone analog compound to the respiratory tract of a human, the system
comprising: (a) about 0.5 mL to about 6 mL of an aqueous solution of pirfenidone or
pyridone analog compound; and (b) a high efficiency liquid nebulizer. In some
embodiments, the aqueous solution is any of the aqueous solutions described herein. In some
embodiments, the concentration of pirfenidone or pyridone analog compound in the aqueous
solution is from about 0.1 mg/mL and about 60 mg/mL and the osmolality of the aqueous
solution is from about 400 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the
aqueous solution comprises: water; pirfenidone, or a pyridone analog compound, at a
concentration from about 10 mg/mL to about 50 mg/mL; optionally a phosphate buffer that
maintains the pH of the solution from about pH 6.0 to about pH 8.0; about 1% to about 8% of
ethanol; and/or about 2% to about 16% of propylene glycol. In some embodiments, the
aqueous solution is as described herein.
In one aspect, described herein is a method of achieving a lung tissue Cmax of
pirfenidone or pyridone analog compound that is at least 1.5 times, at least 2 times, at least 3
times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at
least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10
times, at least 1.5-20 times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or
at least 1.5-3 times times a Cmax of up to 801 mg of an orally administered dosage of
pirfenidone or pyridone analog compound, the method comprising nebulizing an aqueous
solution comprising pirfenidone or pyridone analog compound and administering the
nebulized aqueous solution to a human. In some embodiments, described herein is a method
of achieving a lung tissue Cmax of pirfenidone or pyridone analog compound that is at least
equivalent to or greater than a Cmax of up to 801 mg of an orally administered dosage of
pirfenidone or pyridone analog compound, the method comprising nebulizing an aqueous
solution comprising pirfenidone or pyridone analog compound and administering the
nebulized aqueous solution to a human.
In one aspect, described herein is a method of achieving a lung tissue AUC0-24 of
pirfenidone or pyridone analog compound that is at least 1.5 times, at least 2 times, at least 3
14
times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at
least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10
times, at least 1.5-20 times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or
at least 1.5-3 times times AUC0-24 of up to 801 mg of an orally administered dosage of
pirfenidone or pyridone analog compound, the method comprising nebulizing an aqueous
solution comprising pirfenidone or pyridone analog compound and administering the
nebulized aqueous solution to a human. In some embodiments, described herein is a method
of achieving a lung tissue AUC0-24 of pirfenidone or pyridone analog compound that is at
least equivalent to or greater than AUC0-24 of up to 801 mg of an orally administered dosage
of pirfenidone or pyridone analog compound, the method comprising nebulizing an aqueous
solution comprising pirfenidone or pyridone analog compound and administering the
nebulized aqueous solution to a human.
In one aspect, described herein is a method of administering pirfenidone or a pyridone
analog compound to a human, comprising administering a nebulized aqueous solution
containing the pirfenidone or pyridone analog, wherein the lung tissue Cmax achieved with
the nebulized solution is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at
least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least
1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5-20
times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times
times the lung tissue Cmax achieved with an orally administered pirfenidone or pyridone
analog compound dosage that is from 80% to 120% of the dose amount of pirfenidone that is
administered by nebulization.
In one aspect, described herein is a method of administering pirfenidone or a pyridone
analog compound to a human, comprising administering a nebulized aqueous solution
containing the pirfenidone or pyridone analog, wherein the lung tissue Cmax achieved with
the nebulized solution is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at
least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least
1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5-20
times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times
times the lung tissue Cmax achieved with an orally administered pirfenidone or pyridone
analog compound dosage that is from 80% to 120% of the dosage of pirfenidone or pyridone
analog compound in the nebulized aqueous solution of pirfenidone or pyridone analog
compound. In some embodiments, described herein is a method of administering pirfenidone
or a pyridone analog compound to a human, comprising administering a nebulized aqueous
solution containing the pirfenidone or pyridone analog, wherein the lung tissue Cmax
achieved with the nebulized solution is at least equivalent to or greater than the lung tissue
Cmax achieved with an orally administered pirfenidone or pyridone analog compound dosage
that is from 80% to 120% of the dosage of pirfenidone or pyridone analog compound in the
nebulized aqueous solution of pirfenidone or pyridone analog compound that is administered.
In some embodiments, described herein is a method of administering pirfenidone or a
pyridone analog compound to a human, comprising administering a nebulized aqueous
solution containing the pirfenidone or pyridone analog, wherein the plasma AUC0-24 achieved
with the nebulized solution is at least 10% or greater than the plasma AUC0-24 achieved with
an orally administered pirfenidone or pyridone analog compound dosage that is from 80% to
120% of the dosage of pirfenidone or pyridone analog compound in the nebulized aqueous
solution of pirfenidone or pyridone analog compound that is administered.
In one aspect, described herein is a method of administering pirfenidone or a pyridone
analog compound to a human, comprising administering a nebulized aqueous solution
containing the pirfenidone or pyridone analog, wherein the lung tissue AUC0-24 achieved with
the nebulized solution is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at
least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least
1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5-20
times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times
times the lung tissue AUC0-24 achieved with an orally administered pirfenidone or pyridone
analog compound dosage that is from 80% to 120% of the dosage of pirfenidone or pyridone
analog compound in the nebulized aqueous solution of pirfenidone or pyridone analog
compound. In some embodiments, described herein is a method of administering pirfenidone
or a pyridone analog compound to a human, comprising administering a nebulized aqueous
solution containing the pirfenidone or pyridone analog, wherein the lung tissue AUC0-24
achieved with the nebulized solution is at least 1.5 times the lung tissue AUC0-24 achieved
with an orally administered pirfenidone or pyridone analog compound dosage that is from
16
80% to 120% of the dosage of pirfenidone or pyridone analog compound in the nebulized
aqueous solution of pirfenidone or pyridone analog compound.
In one aspect, provided herein is a method of improving the pharmacokinetic profile
obtained in a human following a single oral dose administration of pirfenidone or pyridone
analog. In some embodiments, the human the pirfenidone or pyridone analog is administered
to the human to treat lung disease. In some embodiments, the lung disease is lung fibrosis.
In some embodiments, the lung disease is idiopathic pulmonary fibrosis. In some
embodiments, the single oral dose comprises up to about 801mg of pirfenidone or pyridone
analog compound. In some embodiments, the method of improving the pharmacokinetic
profile comprises the step of administering pirfenidone or pryridone analog by inhalation. In
some embodiments, the pharmacokinetic profile comprises the lung tissue pharmacokinetic
profile. In some embodiments, the pharmacokinetic profile comprises the lung tissue
pharmacokinetic profile and/or plasma pharmacokinetic profile. In some embodiments, the
pirfenidone or pryridone analog is administered as an aqueous solution with a liquid
nebulizer. In some embodiments, the aqueous solution of pirfenidone or pyridone analog is
as described herein. In some embodimenents, the method of improving the pharmacokinetic
profile further comprises a comparison of the pharmacokinetic parameters following
inhalation administration to the same parameters obtained following oral administration. In
some embodiments, the improvement in pharmacokinetic profile is subtantially the same as
depicted in Figure 1. In some embodiments, the initial improvement in pharmacokinetic
profile is subtantially the same as depicted in Figure 1, but the pulmonary half-life is
extended providing longer pulmonary residence time.
In some embodiments, described herein is a pharmaceutical composition for
pulmonary delivery, comprising a solution of pirfenidone or pyridone analog having a
concentration greater than about 34 mcg/mL, having an osmolality greater than about 100
mOsmol/kg, and having a pH greater than about 4.0. In some embodiments, the pirfenidone
or pyridone analog concentration is greater than about 1.72 mg/mL. In some embodiments,
the pirfenidone or pyridone analog concentration is greater than about 86 mg/mL. In some
embodiments, the pirfenidone or pyridone analog solution has a permeant ion concentration
from about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or
17
bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from
about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution
has an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some
embodiments, the pirfenidone or pyridone analog solution has an osmolality from about 50
mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the composition comprises a
taste masking agent. In some embodiments, the taste masking agent is selected from the
group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and
citrate. In some embodiments, the composition comprises a mucolytic agent suitable for
pulmonary delivery. In some embodiments, the composition comprises a second anti-fibrotic
agent suitable for pulmonary delivery. In some embodiments, the composition comprises a
second anti-inflammatory agent suitable for pulmonary delivery.
In some embodiments, described herein is a pharmaceutical composition for
pulmonary delivery, comprising a solution of pirfenidone or pyridone analog and a taste
masking agent, wherein the solution has an osmolality greater than about 100 mOsmol/kg,
and a pH greater than about 4.0. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 34 mcg/mL. In some embodiments, the pirfenidone or
pyridone analog concentration is greater than about 1.72 mg/mL. In some embodiments, the
pirfenidone or pyridone analog concentration is greater than about 86 mg/mL. In some
embodiments, the pirfenidone or pyridone analog solution has a permeant ion concentration
from about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from
about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution
has an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some
embodiments, the pirfenidone or pyridone analog solution has an osmolality from about 50
mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the composition comprises a
taste masking agent. In some embodiments, the taste masking agent is selected from the
group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and
citrate. In some embodiments, the composition comprises a mucolytic agent suitable for
pulmonary delivery. In some embodiments, the composition comprises a second anti-fibrotic
agent suitable for pulmonary delivery. In some embodiments, the composition comprises a
second anti-inflammatory agent suitable for pulmonary delivery.
18
In some embodiments, described herein is a sterile, single-use container comprising
from about 0.1 mL to about 20 mL of a solution of pirfenidone or pyridone analog having a
concentration greater than about 34 mcg/mL, having an osmolality greater than about 100
mOsmol/kg, and having a pH greater than about 4.0. In some embodiments, the pirfenidone
or pyridone analog concentration is greater than about 1.72 mg/mL. In some embodiments,
the pirfenidone or pyridone analog concentration is greater than about 86 mg/mL. In some
embodiments, the pirfenidone or pyridone analog solution has a permeant ion concentration
from about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from
about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution
has an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some
embodiments, the pirfenidone or pyridone analog solution has an osmolality from about 50
mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the container further
comprises a taste masking agent. In some embodiments, the taste masking agent is selected
from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucrulose,
ascorbate and citrate. In some embodiments, the container further comprises a mucolytic
agent suitable for pulmonary delivery. In some embodiments, the container further comprises
a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the
container further comprises a second anti-inflammatory agent suitable for pulmonary
delivery.
In one aspect, described herein is a method to treat a pulmonary disease comprising
inhaling an aerosol of pirfenidone or pyridone analog solution having a concentration greater
than about 34 mcg/mL, having an osmolality greater than about 100 mOsmol/kg, and having
a pH greater than about 4.0. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 1.72 mg/mL. In some embodiments, the pirfenidone or
pyridone analog concentration is greater than about 86 mg/mL. In some embodiments, the
pirfenidone or pyridone analog solution has a permeant ion concentration from about 30 mM
to about 300 mM. In some embodiments, the permeant ion is chloride or bromide. In some
embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about
8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality
from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
19
pirfenidone or pyridone analog solution has an osmolality from about 50 mOsmol/kg to about
5000 mOsmol/kg. In some embodiments, the pirfenidone or pyridone analog solution has a
taste masking agent. In some embodiments, the taste masking agent is selected from the
group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and
citrate. In some embodiments, the method further comprises administering a mucolytic agent
suitable for pulmonary delivery. In some embodiments, the method further comprises
administering a second anti-fibrotic agent suitable for pulmonary delivery. In some
embodiments, the method further comprises administering a second anti-inflammatory agent
suitable for pulmonary delivery. In some embodiments, the pulmonary disease is interstitial
lung disease. In some embodiments, the interstitial lung disease is idiopathic pulmonary
fibrosis. In some embodiments, the interstitial lung disease is radiation-therapy-induced
pulmonary fibrosis. In some embodiments, the pulmonary disease is chronic obstructive
pulmonary disease. In some embodiments, the pulmonary disease is chronic bronchitis. In
some embodiments, the pulmonary disease is asthma. In some embodiments, the aerosol
comprises particles having a mean aerodynamic diameter from about 1 micron to about 5
microns. In some embodiments, the aerosol has a mean particle size from about 1 microns to
about 5 microns volumetric mean diameter and a particle size geometric standard deviation of
less than or equal to 3 microns. In some embodiments, the inhaling step delivers a dose of a
least 6.8 mcg pirfenidone or pyridone analog. In some embodiments, the inhaling step
delivers a dose of a least 340 mcg pirfenidone or pyridone analog. In some embodiments, the
inhaling step delivers a dose of a least 740 mcg pirfenidone or pyridone analog. In some
embodiments, the inhaling step delivers a dose of a least 1.7 mg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a least 93 mg pirfenidone
or pyridone analog. In some embodiments, the inhaling step delivers a dose of a least 463 mg
pirfenidone or pyridone analog. In some embodiments, the inhaling step is performed in less
than about 20 minutes. In some embodiments, the inhaling step is performed in less than
about 10 minutes. In some embodiments, the inhaling step is performed in less than about
7.5 minutes. In some embodiments, the inhaling step is performed in less than about 5
minutes. In some embodiments, the inhaling step is performed in less than about 2.5 minutes.
In some embodiments, the inhaling step is performed in less than about 1.5 minutes. In some
embodiments, the inhaling step is performed in less than about 30 seconds. In some
embodiments, the inhaling step is performed in less than about 5 breaths. In some
embodiments, the inhaling step is performed in less than about 3 breaths.
In one aspect, described herein is a method to administer an anti-fibrotic agent to
lungs of a patient, comprising: introducing in a nebulizer a pirfenidone or pyridone analog
solution having a concentration greater than about 34 mcg/mL, having an osmolality greater
than about 100 mOsmol/kg, and having a pH greater than about 4.0. In another aspect,
described herein is a method to administer an anti-inflammatory agent to lungs of a patient,
comprising: introducing in a nebulizer a pirfenidone or pyridone analog solution having a
concentration greater than about 34 mcg/mL, having an osmolality greater than about 100
mOsmol/kg, and having a pH greater than about 4.0. In some embodiments, the pirfenidone
or pyridone analog concentration is greater than about 1.72 mg/mL. In some embodiments,
the pirfenidone or pyridone analog concentration is greater than about 86 mg/mL. In some
embodiments, the pirfenidone or pyridone analog solution has a permeant ion concentration
from about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from
about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution
has an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some
embodiments, the pirfenidone or pyridone analog solution has an osmolality from about 50
mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the pirfenidone or pyridone
analog solution has a taste masking agent. In some embodiments, the taste masking agent is
selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame,
sucrulose, ascorbate and citrate. In some embodiments, the method further comprises
administering a mucolytic agent suitable for pulmonary delivery. In some embodiments, the
mucolytic agent is inhaled separately from the pirfenidone or pyridone analog solution. In
some embodiments, the method further comprises administering a second anti-fibrotic agent
suitable for pulmonary delivery. In some embodiments, the method further comprises
administering a second anti-inflammatory agent suitable for pulmonary delivery.
In one aspect, described herein is a method to treat an extrapulmonary disease target
comprising inhaling an aerosol of pirfenidone or pyridone analog solution having a
concentration greater than about 34 mcg/mL, having an osmolality greater than about 100
mOsmol/kg, and having a pH greater than about 4.0 for the purpose of absorbing into the
21
pulmonary vasculature and exposing downstream disease targets to delivered pirfenidone or
pyridone analog. In some embodiments, the pirfenidone or pyridone analog concentration is
greater than about 1.72 mg/mL. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 86 mg/mL. In some embodiments, the pirfenidone or
pyridone analog solution has a permeant ion concentration from about 30 mM to about 300
mM. In some embodiments, the permeant ion is chloride or bromide. In some embodiments,
the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some
embodiments, the pirfenidone or pyridone analog solution has an osmolality from about 100
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the pirfenidone or pyridone
analog solution has an osmolality from about 50 mOsmol/kg to about 5000 mOsmol/kg. In
some embodiments, the pirfenidone or pyridone analog solution has a taste masking agent. In
some embodiments, the taste masking agent is selected from the group consisting of lactose,
sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and citrate. In some
embodiments, the method further comprises administering a mucolytic agent suitable for
pulmonary delivery. In some embodiments, the mucolytic agent is inhaled separately from
the pirfenidone or pyridone analog solution. In some embodiments, the method further
comprises administering a second anti-fibrotic agent suitable for pulmonary delivery. In
some embodiments, the method further comprises administering a second anti-inflammatory
agent suitable for pulmonary delivery. In some embodiments, the extrapulmonary disease
target is the heart. In some embodiments, the extrapulmonary disease target is the kidney. In
some embodiments, the extrapulmonary disease target is the liver.
In any of the methods described herein using an aerosol or nebeulizer to deliver a
pirfenidone or pyridone analog compound to the lungs, the aerosol comprises particles having
a mean aerodynamic diameter from about 1 micron to about 5 microns. In some
embodiments, the aerosol has a mean particle size from about 1 microns to about 5 microns
volumetric mean diameter and a particle size geometric standard deviation of less than or
equal to 3 microns. In some embodiments, the inhaling step delivers a dose of a least 6.8
mcg pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a dose
of a least 340 mcg pirfenidone or pyridone analog. In some embodiments, the inhaling step
delivers a dose of a least 740 mcg pirfenidone or pyridone analog. In some embodiments, the
inhaling step delivers a dose of a least 17 mg pirfenidone or pyridone analog. In some
22
embodiments, the inhaling step delivers a dose of a least 93 mg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a least 463 mg pirfenidone
or pyridone analog. In some embodiments, the inhaling step is performed in less than about
minutes. In some embodiments, the inhaling step is performed in less than about 10
minutes. In some embodiments, the inhaling step is performed in less than about 7.5 minutes.
In some embodiments, the inhaling step is performed in less than about 5 minutes. In some
embodiments, the inhaling step is performed in less than about 2.5 minutes. In some
embodiments, the inhaling step is performed in less than about 1.5 minutes. In some
embodiments, the inhaling step is performed in less than about 30 seconds. In some
embodiments, the inhaling step is performed in less than about 5 breaths. In some
embodiments, the inhaling step is performed in less than about 3 breaths.
In one aspect, described herein is a method to treat a neurologic disease comprising
intranasal inhalation of an aerosol of pirfenidone or pyridone analog solution having a
concentration greater than about 34 mcg/mL, having an osmolality greater than about 100
mOsmol/kg, and having a pH greater than about 4.0. In some embodiments, the pirfenidone
or pyridone analog concentration is greater than about 1.72 mg/mL. In some embodiments,
the pirfenidone or pyridone analog concentration is greater than about 86 mg/mL. In some
embodiments, the pirfenidone or pyridone analog solution has a permeant ion concentration
from about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or
bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from
about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution
has an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some
embodiments, the pirfenidone or pyridone analog solution has an osmolality from about 50
mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the aerosol further comprises
a taste masking agent. In some embodiments, the taste masking agent is selected from the
group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and
citrate. In some embodiments, the method further comprises administering a mucolytic agent
suitable for intranasal delivery. In some embodiments, the method further comprises
administering a second anti-fibrotic agent suitable for intranasal delivery. In some
embodiments, the method further comprises administering a second anti-inflammatory agent
suitable for intranasal delivery. In some embodiments, the neurologic disease is multiple
23
sclerosis. In some embodiments, the aerosol comprises particles having a mean aerodynamic
diameter from about 1 micron to about 20 microns. In some embodiments, the aerosol has a
mean particle size from about 1 microns to about 20 microns volumetric mean diameter and a
particle size geometric standard deviation of less than or equal to 3 microns. In some
embodiments, the inhaling step delivers a dose of a least 6.8 mcg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a least 340 mcg
pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a dose of a
least 740 mcg pirfenidone or pyridone analog. In some embodiments, the inhaling step
delivers a dose of a least 1.7 mg pirfenidone or pyridone analog. In some embodiments, the
inhaling step delivers a dose of a least 93 mg pirfenidone or pyridone analog. In some
embodiments, the inhaling step delivers a dose of a least 463 mg pirfenidone or pyridone
analog. In some embodiments, the inhaling step is performed in less than about 20 minutes.
In some embodiments, the inhaling step is performed in less than about 10 minutes. In some
embodiments, the inhaling step is performed in less than about 7.5 minutes. In some
embodiments, the inhaling step is performed in less than about 5 minutes. In some
embodiments, the inhaling step is performed in less than about 2.5 minutes. In some
embodiments, the inhaling step is performed in less than about 1.5 minutes. In some
embodiments, the inhaling step is performed in less than about 30 seconds. In some
embodiments, the inhaling step is performed in less than about 5 breaths. In some
embodiments, the inhaling step is performed in less than about 3 breaths.
In some embodiments, described herein is a method to administer an antidemylination agent to nasal cavity of a patient, comprising: introducing in a nebulizer a
pirfenidone or pyridone analog solution having a concentration greater than about 34
mcg/mL, having an osmolality greater than about 100 mOsmol/kg, and having a pH greater
than about 4.0. In some embodiments, the pirfenidone or pyridone analog concentration is
greater than about 1.72 mg/mL. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 86 mg/mL. In some embodiments, the pirfenidone or
pyridone analog solution has a permeant ion concentration from about 30 mM to about 300
mM. In some embodiments, the permeant ion is chloride or bromide. In some embodiments,
the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some
embodiments, the pirfenidone or pyridone analog solution has an osmolality from about 100
24
mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the pirfenidone or pyridone
analog solution has an osmolality from about 50 mOsmol/kg to about 5000 mOsmol/kg. In
some embodiments, the solution further comprises a taste masking agent. In some
embodiments, the taste masking agent is selected from the group consisting of lactose,
sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and citrate. In some
embodiments, the method further comprises administering a mucolytic agent suitable for
intranasal delivery. In some embodiments, the mucolytic agent is inhaled separately from the
pirfenidone or pyridone analog solution. In some embodiments, the method further
comprises administering a second agent suitable for intranasal delivery.
In any of the methods described herein involving introducing in a nebulizer a
pirfenidone or pyridone analog solution , the method involves a step of opening a sterile
single-use container containing between about 0.5 mL to about 10 mL of a solution of
pirfenidone or pyridone analog solution for introduction into a nebulizer.
In any of the methods described herein involving a nebulizer, the aerosol comprises
particles having a mean aerodynamic diameter from about 1 micron to about 5 microns. In
some embodiments, the aerosol has a mean particle size from about 1 microns to about 5
microns volumetric mean diameter and a particle size geometric standard deviation of less
than or equal to 3 microns. In some embodiments, the aerosol comprises particles having a
mean aerodynamic diameter from about 1 micron to about 20 microns. In some
embodiments, the aerosol has a mean particle size from about 1 microns to about 20 microns
volumetric mean diameter and a particle size geometric standard deviation of less than or
equal to 3 microns. In some embodiments, the inhaling step delivers a dose of a least 6.8
mcg pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a dose
of a least 340 mcg pirfenidone or pyridone analog. In some embodiments, the inhaling step
delivers a dose of a least 740 mcg pirfenidone or pyridone analog. In some embodiments, the
inhaling step delivers a dose of a least 1.7 mg pirfenidone or pyridone analog. In some
embodiments, the inhaling step delivers a dose of a least 93 mg pirfenidone or pyridone
analog. In some embodiments, the inhaling step delivers a dose of a least 463 mg pirfenidone
or pyridone analog. In some embodiments, the inhaling step is performed in less than about
20 minutes. In some embodiments, the inhaling step is performed in less than about 10
minutes. In some embodiments, the inhaling step is performed in less than about 7.5 minutes.
In some embodiments, the inhaling step is performed in less than about 5 minutes. In some
embodiments, the inhaling step is performed in less than about 2.5 minutes. In some
embodiments, the inhaling step is performed in less than about 1.5 minutes. In some
embodiments, the inhaling step is performed in less than about 30 seconds. In some
embodiments, the inhaling step is performed in less than about 5 breaths. In some
embodiments, the inhaling step is performed in less than about 3 breaths. In some
embodiments, the inhaling step is performed in one breath.
In one aspect, provided herein is a kit comprising: a pharmaceutical composition
comprising a pirfenidone or pyridone analog solution in a sterile container, wherein the
pirfenidone or pyridone analog solution has a concentration greater than about 34 mcg/mL,
an osmolality greater than about 100 mOsmol/kg, and a pH greater than about 4.0, and a
nebulizer adapted to aerosolize the pirfenidone or pyridone analog solution for delivery to the
middle to lower respiratory tract through oral inhalation. In some embodiments, the
pirfenidone or pyridone analog concentration is greater than about 1.72 mg/mL. In some
embodiments, the pirfenidone or pyridone analog concentration is greater than about 86
mg/mL. In some embodiments, the pirfenidone or pyridone analog solution has a permeant
ion concentration from about 30 mM to about 300 mM. In some embodiments, the permeant
ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog
solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or
pyridone analog solution has an osmolality from about 100 mOsmol/kg to about 1000
mOsmol/kg. In some embodiments, the pirfenidone or pyridone analog solution has an
osmolality from about 50 mOsmol/kg to about 5000 mOsmol/kg. In some embodiments, the
solution further comprises a taste masking agent. In some embodiments, the taste masking
agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin,
aspartame, sucrulose, ascorbate and citrate. In some embodiments, the kit further comprises
a mucolytic agent suitable for pulmonary delivery. In some embodiments, the kit further
comprises a second anti-fibrotic agent suitable for pulmonary delivery. In some
embodiments, the kit further comprises a second anti-inflammatory agent suitable for
pulmonary delivery.
In another aspect, provided herein is a kit comprising: a pharmaceutical composition
comprising a pirfenidone or pyridone analog solution in a sterile container, wherein the
26
pirfenidone or pyridone analog solution has a concentration greater than about 34 mcg/mL,
an osmolality greater than about 100 mOsmol/kg, and a pH greater than about 4.0, and a
nebulizer adapted to aerosolize the pirfenidone or pyridone analog solution for delivery to the
nasal cavity through intranasal inhalation.
In some embodiments, the pirfenidone or pyridone analog concentration is greater
than about 1.72 mg/mL. In some embodiments, the pirfenidone or pyridone analog
concentration is greater than about 86 mg/mL. In some embodiments, the pirfenidone or
pyridone analog solution has a permeant ion concentration from about 30 mM to about 300
mM. In some embodiments, the permeant ion is chloride or bromide. In some
embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about
8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality
from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the
pirfenidone or pyridone analog solution has an osmolality from about 50 mOsmol/kg to about
5000 mOsmol/kg. In some embodiments, the solution further comprises a taste masking
agent. In some embodiments, the taste masking agent is selected from the group consisting
of lactose, sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate and citrate. In some
embodiments, the kit further comprises a mucolytic agent suitable for intranasal delivery. In
some embodiments, the kit further comprises a second anti-fibrotic agent suitable for
intranasal delivery. In some embodiments, the kit further comprises a second anti20 inflammatory agent suitable for intranasal delivery.
In one aspect, described herein is a method for treating lung disease, comprising
administering pirfenidone or pyridone analog to a middle to lower respiratory tract of a
subject having or suspected of having interstitial lung disease through oral inhalation of an
aerosol comprising pirfenidone or pyridone analog, wherein the disease is selected from
interstitial lung disease, including idiopathic pulmonary fibrosis and radiation therapyinduced fibrosis; chronic obstructive pulmonary disease; and asthma. In some embodiments,
the subject is identified as having interstitial lung disease. In some embodiments, the subject
is identified as having idiopathic pulmonary fibrosis. In some embodiments, the subject is
identified as having radiation therapy-induced pulmonary fibrosis. In some embodiments, the
subject is identified as having chronic obstructive pulmonary disease. In some embodiments,
the subject is identified as having chronic bronchitis. In some embodiments, the subject is
27
identified as having asthma. In some embodiments, the subject is a subject being
mechanically ventilated.
A method for treating extrapulmonary disease, comprising administering pirfenidone
or pyridone analog to a middle to lower respiratory tract of a subject having or suspected of
having extrapulmonary fibrosis, inflammatory and/or toxicity-related diseases through oral
inhalation of an aerosol comprising pirfenidone or pyridone analog for purposes of
pulmonary vascular absorption and delivery to extrapulmonary diseased tissues, wherein the
disease is selected from cardiac fibrosis, kidney fibrosis, hepatic fibrosis, kidney toxicity and
heart toxicity. In some embodiments, the subject is identified as having cardiac fibrosis. In
some embodiments, the subject is identified as having kidney fibrosis. In some
embodiments, the subject is identified as having hepatic fibrosis. In some embodiments, the
subject is identified as having kidney toxicity. In some embodiments, the subject is identified
as having heart toxicity. In some embodiments, the subject is a subject being mechanically
ventilated.
In one aspect, described herein is a method for treating neurologic disease, comprising
administering pirfenidone or pyridone analog to the nasal cavity of a subject having or
suspected of having neurologic disease through intranasal inhalation of an aerosol comprising
pirfenidone or pyridone analog for purposes of nasal vascular absorption and delivery to
central nervous system, wherein the disease is multiple sclerosis. In some embodiments, the
subject is identified as having multiple sclerosis. In some embodiments, the subject is a
subject being mechanically ventilated.
In one aspect, described herein is a pharmaceutical composition for pulmonary
delivery, comprising a dry powder containing pirfenidone or pyridone analog having a
dosage content greater than about 1%. In some embodiments, the pirfenidone or pyridone
analog dose content is greater than about 6.8 mcg. In some embodiments, the pirfenidone or
pyridone analog content is greater than about 340 mcg. In some embodiments, the
pirfenidone or pyridone analog content is greater than about 17 mg. In some embodiments,
the pirfenidone or pyridone analog content is greater than about 463 mg. In some
embodiments, the powder further comprises a blending agent. In some embodiments, the
blending agent is selected from the group consisting of lactose.
28
In one aspect, described herein is a pharmaceutical composition for pulmonary
delivery, comprising a dry powder containing pirfenidone or pyridone analog having a
dosage content greater than about 1%. In yet another aspect, described herein is a sterile,
single-use container comprising from about 0.5 mg to about 100 mg dry powder containing
pirfenidone or pyridone analog having a dosage content greater than about 1%. In a further
aspect, described is a method to treat a pulmonary disease comprising inhalation of a dry
powder aerosol containing pirfenidone or pyridone dosage content greater than about 1%. In
some embodiments, the pirfenidone or pyridone analog dose content is greater than about 6.8
mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than about
340 mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than
about 17 mg. In some embodiments, the pirfenidone or pyridone analog content is greater
than about 463 mg. In some embodiments, the dry powder further comprises a blending
agent. In some embodiments, the blending agent is lactose. In some embodiments, the
pulmonary disease is interstitial lung disease. In some embodiments, the interstitial lung
disease is idiopathic pulmonary fibrosis. In some embodiments, the interstitial lung disease is
radiation-therapy-induced pulmonary fibrosis. In some embodiments, the pulmonary disease
is chronic obstructive pulmonary disease. In some embodiments, the pulmonary disease is
chronic bronchitis. In some embodiments, the pulmonary disease is asthma. In some
embodiments, the aerosol comprises particles having a mean aerodynamic diameter from
about 1 micron to about 5 microns. In some embodiments, the aerosol has a mean particle
size from about 1 microns to about 5 microns volumetric mean diameter and a particle size
geometric standard deviation of less than or equal to 3 microns. In some embodiments, the
inhaling step delivers a dose of a least 6.8 mcg pirfenidone or pyidone analog. In some
embodiments, the inhaling step delivers a dose of a least 340 mcg pirfenidone or pyidone
analog. In some embodiments, the inhaling step delivers a dose of a least 740 mcg
pirfenidone or pyidone analog. In some embodiments, the inhaling step delivers a dose of a
least 1.7 mg pirfenidone or pyidone analog. In some embodiments, the inhaling step delivers
a dose of a least 93 mg pirfenidone or pyidone analog. In some embodiments, the inhaling
step delivers a dose of a least 463 mg pirfenidone or pyidone analog. In some embodiments,
the inhaling step is performed in less than about 5 breaths. In some embodiments, the
inhaling step is performed in less than about 3 breaths. In some embodiments, the inhaling
29
step is performed in less than about 2 breaths. In some embodiments, the inhaling step is
performed in one breath.
In one aspect, provided herein is a method to administer an anti-fibrotic agent to lungs
of a subject, comprising: introducing in a dry powder inhaler a pirfenidone or pyridone
analog dry powder formulation having a dosage content greater than about 1%. In another
aspect, provided herein is a method to administer an anti-inflammatory agent to lungs of a
subject, comprising: introducing in a dry powder inhaler a pirfenidone or pyridone analog dry
powder formulation having a dosage content greater than about 1%. In yet another aspect,
provided herein is a method to treat an extrapulmonary disease target comprising inhalation
of a dry powder aerosol containing pirfenidone or pyridone dosage content greater than about
1%. In some embodiments, the extrapulmonary disease target is the heart. In some
embodiments, the extrapulmonary disease target is the kidney. In some embodiments, the
extrapulmonary disease target is the liver. In yet another aspect, provided herein is a method
to treat a neurologic disease comprising intranasal inhalation of a dry powder aerosol
containing pirfenidone or pyridone dosage content greater than about 1%. In some
embodiments, the neurologic disease is multiple sclerosis. In yet another aspect, provided
herein is a method to administer an anti-demylination agent to nasal cavity of a subject,
comprising: introducing in a dry powder inhaler a pirfenidone or pyridone analog dry powder
formulation having a dosage content greater than about 1%. In some embodiments, the
pirfenidone or pyridone analog dose content is greater than about 6.8 mcg. In some
embodiments, the pirfenidone or pyridone analog content is greater than about 340 mcg. In
some embodiments, the pirfenidone or pyridone analog content is greater than about 17 mg.
In some embodiments, the pirfenidone or pyridone analog content is greater than about 463
mg. In some embodiments, the dry powder comprises a blending agent. In some
embodiments, the blending agent is lactose. In some embodiments, the aerosol comprises
particles having a mean aerodynamic diameter from about 1 micron to about 5 microns. In
some embodiments, the aerosol has a mean particle size from about 1 microns to about 5
microns volumetric mean diameter and a particle size geometric standard deviation of less
than or equal to 3 microns. In some embodiments, the aerosol comprises particles having a
mean aerodynamic diameter from about 1 micron to about 20 microns. In some
embodiments, the aerosol has a mean particle size from about 1 microns to about 20 microns
volumetric mean diameter and a particle size geometric standard deviation of less than or
equal to 3 microns. In some embodiments, the inhaling step delivers a dose of a least 6.8
mcg pirfenidone or pyidone analog. In some embodiments, the inhaling step delivers a dose
of a least 340 mcg pirfenidone or pyidone analog. In some embodiments, the inhaling step
delivers a dose of a least 740 mcg pirfenidone or pyidone analog. In some embodiments, the
inhaling step delivers a dose of a least 1.7 mg pirfenidone or pyidone analog. In some
embodiments, the inhaling step delivers a dose of a least 17 mg pirfenidone or pyidone
analog. In some embodiments, the inhaling step delivers a dose of a least 93 mg pirfenidone
or pyidone analog. In some embodiments, the inhaling step delivers a dose of a least 463 mg
pirfenidone or pyidone analog. In some embodiments, the inhaling step is performed in less
than about 5 breaths. In some embodiments, the inhaling step is performed in less than about
3 breaths. In some embodiments, the inhaling step is performed in less than about 2 breaths.
In some embodiments, the inhaling step is performed in one breath. In some embodiments,
the method further comprises the step of opening a single-use dry powder container holding
between about 0.5 mg to about 10 mg dry powder formulation containing pirfenidone or
pyridone analog for introduction into a dry powder inhaler.
In one aspect, described herein is a kit comprising: a pharmaceutical composition
comprising a dry powder pirfenidone or pyridone analog formulation in a container, wherein
the pirfenidone or pyridone analog dosage content is greater than about 1%; and a dry powder
inhaler adapted to aerosolize the pirfenidone or pyridone analog dry powder formulation for
delivery to the middle to lower respiratory tract through oral inhalation. In another aspect,
described herein is a kit comprising: a pharmaceutical composition comprising a dry powder
pirfenidone or pyridone analog formulation in a container, wherein the pirfenidone or
pyridone analog dosage content is greater than about 1%, and a dry powder inhaler adapted to
aerosolize the pirfenidone or pyridone analog dry powder formulation for delivery to the
nasal cavity through intranasal inhalation. In some embodiments, the pirfenidone or pyridone
analog dose content is greater than about 6.8 mcg. In some embodiments, the pirfenidone or
pyridone analog content is greater than about 340 mcg. In some embodiments, the
pirfenidone or pyridone analog content is greater than about 17 mg. In some embodiments,
the pirfenidone or pyridone analog content is greater than about 463 mg. In some
31
embodiments, the powder further comprises a blending agent. In some embodiments, the
blending agent is lactose.
In one aspect, described herein is a method for treating lung disease, comprising
administering pirfenidone or pyridone analog to a middle to lower respiratory tract of a
subject having or suspected of having interstitial lung disease through oral inhalation of an
aerosol comprising pirfenidone or pyridone analog, wherein the disease is selected from
interstitial lung disease, including idiopathic pulmonary fibrosis and radiation therapyinduced fibrosis; chronic obstructive pulmonary disease; and asthma. In some embodiments,
the subject is identified as having interstitial lung disease. In some embodiments, the subject
is identified as having idiopathic pulmonary fibrosis. In some embodiments, the subject is
identified as having radiation therapy-induced pulmonary fibrosis. In some embodiments, the
subject is identified as having chronic obstructive pulmonary disease. In some embodiments,
the subject is identified as having chronic bronchitis. In some embodiments, the subject is
identified as having asthma. In some embodiments, the subject is a subject being
mechanically ventilated.
In one aspect, described herein is a method for treating extrapulmonary disease,
comprising administering pirfenidone or pyridone analog to a middle to lower respiratory
tract of a subject having or suspected of having extrapulmonary fibrosis, inflammatory and/or
toxicity-related diseases through oral inhalation of an aerosol comprising pirfenidone or
pyridone analog for purposes of pulmonary vascular absorption and delivery to
extrapulmonary diseased tissues, wherein the disease is selected from cardiac fibrosis, kidney
fibrosis, hepatic fibrosis, kidney toxicity and heart toxicity.
In some embodiments, the subject is identified as having cardiac fibrosis. In some
embodiments, the subject is identified as having kidney fibrosis. In some embodiments, the
subject is identified as having hepatic fibrosis. In some embodiments, the subject is
identified as having kidney toxicity. In some embodiments, the subject is identified as having
heart toxicity. In some embodiments, the subject is a subject being mechanically ventilated.
In one aspect, described herein is a method for treating neurologic disease, comprising
administering pirfenidone or pyridone analog to the nasal cavity of a subject having or
suspected of having neurologic disease through intranasal inhalation of an aerosol comprising
pirfenidone or pyridone analog for purposes of nasal vascular absorption and delivery to
32
central nervous system, wherein the disease is multiple sclerosis. In some embodiments, the
subject is identified as having multiple sclerosis. In some embodiments, the subject is a
subject being mechanically ventilated.
In one aspect, described herein is a method of administering pirfenidone or pyridone
analog to treat a patient with idiopathic pulmonary fibrosis (IPF), wherein the patient avoids
abnormal liver function exhibited by a grade 2 or higher abnormality following oral
administration in one or more biomarkers of liver function after pirfenidone or pyridone
analog administration, comprising administering to said patient pirfenidone or pyridone
analog at doses less than 300 mg per day. In some embodiments, "Grade 2 liver function
abnormalities" include elevations in alanine transaminase (ALT), aspartate transaminase
(AST), alkaline phosphatase (ALP), or gamma-glutamyl transferase (GGT) greater than 2.5-
times and less than or equal to 5-times the upper limit of normal (ULN). Grade 2 liver
function abnormalities also include elevations of bilirubin levels greater than 1.5-times and
less than or equal to 3-times the ULN. In some embodiments, the pirfenidone or pyridone
analog is delivered to the patient by oral inhalation or intranasal inhalation. In some
embodiments, said one or more biomarkers of liver function is selected from the group
consisting of alanine transaminase, aspartate transaminase, bilirubin, and alkaline
phosphatase. In some embodiments, the method further comprises the step of measuring one
or more biomarkers of liver function. In some embodiments, the blood Cmax following
administration of pirfenidone or pyridone analog is less than 10 mcg/mL. In some
embodiments, the blood Cmax following administration of pirfenidone or pyridone analog is
greater than 10 mcg/mL.
In one aspect, described herein is a method of administering pirfenidone or pyridone
analog to treat a patient with idiopathic pulmonary fibrosis (IPF), wherein the patient avoids
the incidence of photosensitivity reaction observed following oral administration, comprising
administering to said patient pirfenidone or pyridone analog at doses less than 360 mg per
day. In some embodiments, the pirfenidone or pyridone analog is delivered to the patient by
oral inhalation or intranasal inhalation. In some embodiments, the incidence of
photosensitivity reaction adverse events is less than about 12%. In some embodiments, the
blood Cmax following administration of pirfenidone or pyridone analog is less than 10
33
mcg/mL. In some embodiments, the blood Cmax following administration of pirfenidone or
pyridone analog is greater than 10 mcg/mL.
In one aspect, described herein is a method of administering pirfenidone or pyridone
analog to treat a patient with idiopathic pulmonary fibrosis (IPF), wherein the patient avoids
the incidence of phototoxicity observed following oral administration, comprising
administering to said patient pirfenidone or pyridone analog at doses less than 360 mg per
day. In some embodiments, the pirfenidone or pyridone analog is delivered to the patient by
oral inhalation or intranasal inhalation. In some embodiments, the incidence of
photosensitivity reaction adverse events is less than about 12%. In some embodiments, the
blood Cmax following administration of pirfenidone or pyridone analog is less than 10
mcg/mL. In some embodiments, the blood Cmax following administration of pirfenidone or
pyridone analog is greater than 10 mcg/mL.
In one aspect, described herein is a method of administering pirfenidone or pyridone
analog to treat a patient with idiopathic pulmonary fibrosis (IPF), wherein the patient avoids
the incidence of gastrointestinal adverse events observed following oral administration, by
delivering pirfenidone or pyridone analog directly to the lung by oral inhalation or intranasal
inhalation. In some embodiments, gastrointestinal adverse events observed following oral
administration of pirfenidone or pyridone analog include, but are not limited to any one or
more of the following: dyspepsia, nausea, diarrhea, gastroesophageal reflux disease (GERD)
and vomiting. In some embodiments, less than 360 mg per day of pirfenidone or pyridone
analog is delivered to the patient by inhalation. In some embodiments, less than 1000mg, less
than 900mg, less 600 mg, or less than 300 mg per day of pirfenidone or pyridone analog is
delivered to the patient by inhalation. In some embodiments, less than 300 mg per day of
pirfenidone or pyridone analog is delivered per dose to the patient by inhlaltion. In some
embodiments, pirfenidone or pyridone analog is delivered by inhalaltion once per day, twice
per day, three time a day, or four time a day.
In some embodiments, up to about 360 mg of pirfenidone or pyridone analog is
delivered to the patient by inhalation per dose. In some embodiments, about 1mg to about
360mg, about 10mg to about 360mg, about 20mg to about 360mg, about 30mg to about
360mg, about 40mg to about 360mg, about 50mg to about 360mg, about 60mg to about
70mg, about 80mg to about 360mg, about 90mg to about 360mg, about 100mg to about
34
360mg, about 120mg to about 360mg, about 140mg to about 360mg, about 160mg to about
360mg, about 180mg to about 360mg, or about 200mg to about 360mg, of pirfenidone or
pyridone analog is delivered to the patient by inhalation per dose. In some embodiments,
pirfenidone or pyridone analog is delivered by inhalaltion once per day, twice per day, three
time a day, or four time a day.
In one aspect, described herein is a pharmaceutical composition comprising a
therapeutically effective amount of an inhaled agent, wherein the agent is pirfenidone or
pyridone analog, wherein the agent is in a particle less than 5 microns in mass mean
aerodynamic diameter or less than 10 microns volumetric mean diameter wherein the
composition, upon inhalation, delivers a dose to the lung greater than 1 mcg pirfenidone or
pyridone analog compound per gram of adult human lung tissue.
In one aspect, described herein is a pharmaceutical composition for aerosol delivery
to the lung, comprising a solution of pirfenidone or pyridone analog containing a divalent
cation. In some embodiments, the divalent cation is selected from the group consisting of
calcium, iron, magnesium, and beryllium. In some embodiments, the ratio of pirfenidone or
pyridone analog to divalent cation is within the molar range of 1 to about 0.1 to 10, in unit
increments of about 0.01. By example, 1 to about 10, 1 to about 9, 1 to about 8, 1 to about 7,
1 to about 6, 1 to about 5, 1 to about 4, 1 to about 3, 1 to about 2, 1 to about 1.5, 1 to about 1,
1 to about 0.75, 1 to about 0.5, 1 to about 0.25, and 1 to about 0.1. In some embodiments, the
active pharmaceutical ingredient is pirfenidone or pyridone analog concentration is between
0.1 mg/mL and 50 mg/mL in unit increments of about 0.01 mg/mL composition. By
example, about about 0.1 mg/mL, about 0.5 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3
mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL,
about 9 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about
30 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50
mg/mL, about 55 mg/mL, and about 60 mg/mL. In some embodiments, the active
pharmaceutical ingredient is not a salt of pirfenidone or pyridone analog. In some
embodiments, the composition is a stable, water-soluble formulation. In some embodiments,
the osmolality is greater than about 50 mOsmol/kg composition in unit increments of about 1
mOsmol/kg. By example, greater than about 50 mOsmol/kg, about 100 mOsmol/kg, about
150 mOsmol/kg, about 200 mOsmol/kg, about 250 mOsmol/kg, about 300 mOsmol/kg, about
350 mOsmol/kg, about 400 mOsmol/kg, about 450 mOsmol/kg, about 500 mOsmol/kg, about
550 mOsmol/kg, about 600 mOsmol/kg, about 650 mOsmol/kg, about 700 mOsmol/kg, about
750 mOsmol/kg, about 800 mOsmol/kg, about 850 mOsmol/kg, about 900 mOsmol/kg, about
950 mOsmol/kg, about 1000 mOsmol/kg, greater than about 1500 mOsmol/kg, about 2000
mOsmol/kg, about 2500 mOsmol/kg, greater than about 3000 mOsmol/kg, about 3500
mOsmol/kg, about 4000 mOsmol/kg, greater than about 4500 mOsmol/kg, about 5000
mOsmol/kg, about 5500 mOsmol/kg, about 6000 mOsmol/kg, or greater than about 6000
mOsmol/kg. In some embodiments, the pH is greater than about 3.0 in pH unit increments of
about 0.1. By example, a pH of about 3, a pH of about 3.5, a pH of about 4, a pH of about
4.5, a pH of about 5, a pH of about 5.5, a pH of about 6, a pH of about 6.5, a pH of about 7, a
pH of about 7.5, a pH of about 8, a pH of about 8.5, a pH of about 9, a pH of about 9.5, a pH
of about 10 a pH of about 10.5, and a pH of about 11. In some embodiments, the pH is
balanced by the inclusion of an organic buffer selected from the group consisting of citric
acid, citrate, malic acid, malate, pyridine, formic acid, formate, piperazine, succinic acid,
succinate, histidine, maleate, bis-tris, pyrophosphate, phosphoric acid, phosphate, PIPES,
ACES, MES, cacodylic acid, carbonic acid, carbonate, ADA (N-(2-Acetamido)
iminodiacetic acid). In some embodiments, the pirfenidone or pyridone analog solution
contains a permeant ion concentration. In some embodiments, the permeant ion is selected
from the group consisting of bromine, chloride, and lithium. In some embodiments, the
permeant ion concentration is from about 30 mM to about 300 mM in about 0.1 mM
increments. By example, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70
mM, about 80 mM, about 90 mM, about 100 mm, about 150 mM, about 200 mM, about 250
mM, and about 300 mM. In some embodiments, the composition further comprises a taste
masking agent. In some embodiments, the taste masking agent is selected from the group
consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucrulose, ascorbate,
multivalent cation and citrate. In some embodiments, the taste masking agent concentration
is from 0.01 mM to about 50 mM in about 0.01 mM increments. By examples, about 0.01
mM, about 0.05 mM, about 0.1 mM, about 0.2 mM, about 0.3 mM, about 0.4 mM, about 0.5
mM, about 0.6 mM, about 0.7 mM, about 0.8 mM, about 0.9 mM, about 1 mM, about 2 mM,
about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM,
36
about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about
40 mM, about 45 mM, and about 50 mM.
In some embodiments, the formulations described herein are filled into a primary
package. In some embodiments, primary packaging material is taken from the group
consisting of glass or plastic, wherein plastic materials may be selected from the group
consisting of low-density polyethylene (LDPE), high-density polypropylene (HDPP), or
high-density polyethylene (HDPE). In some embodiments, the primary packaging consists of
a vial, syringe or ampoule. In some embodiments, the composition is protected from light.
In some embodiments, the compositions described herein are formulated under or to
result in conditions of reduced oxygen. In some embodiments, oxygen is reduced by
sparging the formulation diluent prior to addition of the active pharmaceutical ingredient.
Sparging gases may be selected from the group consisting of carbon dioxide, argon or
nitrogen. In some embodiments, oxygen is reduced by sparging the formulation diluent after
addition of the active pharmaceutical ingredient. Sparging gases may be selected from the
group consisting of carbon dioxide, argon or nitrogen. In some embodiments, oxygen
exposure is reduced by replacing the ambient gas headspace of the formulation container with
an inert gas. Inert gases may be selected from the group consisting of argon or nitrogen.
In some embodiments, oxygen exposure is reduced by replacing the ambient gas
headspace of the primary packaging container with an inert gas. Inert gases may be selected
from the group consisting of argon or nitrogen.
In some embodiments, oxygen exposure is reduced by inserting the primary
packaging into a gas-impermeable secondary packaging container.
In some embodiments, oxygen exposure is reduced by replacing the ambient gas
headspace of the secondary packaging with an inert gas. Inert gases may be selected from the
group consisting of argon or nitrogen.
In some embodiments, the aerosol for delivery to the lungs of a mammal described
herein contains a fine particle fraction between 10 and 100% with increment units of 1%. By
example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,
about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about
80%, about 85%, about 90%, about 95%, and about 100%. In some embodiments, the fine
particle dose is between about 0.1 mg to about 360 mgs prifenidone or pyridone analog, in
37
0.1 mg increments. By example, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about
3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10
mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about
17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,
about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90
mg, about 100 mg, about 150 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg,
about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg.
In some embodiments, the compositions further comprise a mucolytic agent suitable
for pulmonary delivery. In some embodiments, the compositions further comprise a second
anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the compositions
further comprise a second anti-inflammatory agent suitable for pulmonary delivery.
These and other aspects of the invention will be evident upon reference to the
following detailed description. All of the U.S. patents, U.S. patent application publications,
U.S. patent applications, foreign patents, foreign patent applications and non-patent
publications referred to in this specification, are incorporated herein by reference in their
entirety, as if each was incorporated individually. Aspects of the invention can be modified,
if necessary, to employ concepts of the various patents, applications and publications to
provide yet further embodiments of the invention.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form part
of the common general knowledge in the art.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows a modeled nebulized aerosol administration of pirfenidone and oral
administration of pirfenidone to a human subject.
DETAILED DESCRIPTION
A number of undesirable pulmonary diseases such as interstitial lung disease (ILD;
and sub-class diseases therein), chronic obstructive pulmonary disease (COPD; and sub-class
38
diseases therein), asthma, and fibrotic indications of the lungs, kidney, heart and eye, are
initiated from an external challenge. By non-limiting example, these effectors can include
infection, cigarette smoking, environmental exposure, radiation exposure, surgical procedures
and transplant rejection. However, other causes related to genetic disposition and the effects
of aging may also be attributed.
In epithelium, scarring serves a valuable healing role following injury. However,
epithelium tissue may become progressively scarred following more chronic and or repeated
injuries resulting in abnormal function. In the case of idiopathic pulmonary fibrosis (IPF; and
other subclasses of ILD), if a sufficient proportion of the lung becomes scarred respiratory
failure can occur. In any case, progressive scarring may result from a recurrent series of
insults to different regions of the organ or a failure to halt the repair process after the injury
has healed. In such cases the scarring process becomes uncontrolled and deregulated. In some
forms of fibrosing disease scarring remains localized to a limited region, but in others it can
affect a more diffuse and extensive area resulting in direct or associated organ failure.
In neurologic disease, inflammatory destruction of myelin (demylination) is
considered the initial event in diseases such as multiple sclerosis. Demyelination causes
scarring and hardening (sclerosis) of nerve tissue in the spinal cord, brain, and optic nerves.
Demyelination slows conduction of nerve impulses, which results in weakness, numbness,
pain, and vision loss.
In epithelial injury, epithelial cells are triggered to release several pro-fibrotic
mediators, including the potent fibroblast growth factors transforming growth factor-beta
(TGF-beta), tumor necrosis factor (TNF), endothelin, cytokines, metalloproteinases and the
coagulation mediator tissue factor. Importantly, the triggered epithelial cell becomes
vulnerable to apoptosis, and together with an apparent inability to restore the epithelial cell
layer are the most fundamental abnormalities in fibrotic disease. In the case of demylination,
abnormal TNF expression or activity is considered a primary cause of multiple sclerosis and
other neurologic disorders, such as rheumatoid disease.
In conditions such as pulmonary, kidney, cardiac and ocular fibrosis, multiple
sclerosis and rheumatoid disease, physiological responses characterized by control of pro30 inflammatory and pro-fibrotic factors with pyridone analogs, such as pirfenidone may be
beneficial to attenuate and/or reverse fibrosis and demyelination. Therapeutic strategies
39
exploiting such pyridone analog and/or pirfenidone effects in these and other indications are
contemplated herein.
TNF-alpha is expressed in asthmatic airways and may play a key role in amplifying
asthmatic inflammation through the activation of NF-kappaB, AP-1 and other transcription
factors. IgE receptor activation induces TNF-alpha release from human lung tissue and
upregulates eosinophil TNF mRNA levels. TNF-alpha causes transient bronchial hyperresponsiveness likely through a muscarinic receptor expression-mediated response.
TNF-alpha is also believed to play a central role in the pathophysiology of COPD. It
is produced by alveolar macrophages, neutrophils, T cells, mast cells and epithelial cells
following contact with different pollutants including cigarette smoke. TNF-alpha has been
shown in animal models to induce pathological features associated with COPD, such as an
inflammatory cell infiltrate into the lungs, pulmonary fibrosis and emphysema. Intriguingly,
TNF-alpha levels in sputum increase significantly during acute exacerbations of COPD.
The mechanism of action for pyridone analogs, such as pirfenidone is believed to be
both anti-inflammatory and anti-fibrotic. Pirfenidone inhibits synthesis and release of proinflammatory cytokines and reduces the accumulation of inflammatory cells in response to
various stimuli. Pirfenidone also attenuates fibroblast proliferation, production of fibrosis
associated proteins and cytokines, and the increased biosynthesis and accumulation of
extracellular matrix in response to cytokine growth factors such as TGF-beta and platelet20 derived growth factor (PDGF).
In in vitro cell-based assays, pirfenidone suppressed the proliferation of fibroblasts;
inhibited lipopolysaccharide (LPS)-stimulated release of PDGF, tumor necrosis factor alpha
(TNF-alpha), and TGF- beta1; and inhibited collagen synthesis. Depending on the assay
conditions, these in vitro activities were evident at pirfenidone concentrations of about 30
microM to about 10 mM (about 5.5 mcg/mL to about 1.85 mg/mL). Given that the oral
Cmax of pirfenidone in IPF patients is about 42 microM in the recommended fed-state to
about 84 microM in the fasting-state (or about 7.9 mcg/mL to about 15.7 mcg/mL,
respectively), these same activities may be promoted in vivo, albeit in the lower range of
observed efficacy.
Oral administration of pirfenidone to LPS-challenged mice resulted in dose-dependent
decreased mortality, reduced serum levels of the pro-inflammatory cytokines TNF-alpha,
40
interleukin (IL-12) and interferon gamma, and increased serum levels of the antiinflammatory cytokine, IL-10. Pirfenidone treatment also prevented LPS-related
hemorrhagic necrosis and apoptosis in the liver, and suppressed increases in TGF-beta.
In vitro studies suggest that pirfenidone may also suppress fibrogenesis through
selective inhibition of p38 mitogen-activated protein kinase (MAPK). These observations
have been associated with an attenuation of TGF-beta-induced collagen synthesis. The
parallel observation that silencing p38 may also restore sensitivity to coriticosteroids in
COPD is also promising for this and other disease populations. Unfortunately, compounds
that inhibit p38 MAPK have also proven toxic and have been withdrawn from the clinical
setting. These compounds have each employed oral administration.
In rat, hamster, and mouse models of bleomycin-induced lung fibrosis, prophylactic
administration of pirfenidone reduced pulmonary fibrosis assessed by both histopathological
analysis and quantitative determination of collagen content. Pirfenidone treatment also
reduced pulmonary edema and pulmonary levels of TGF-beta, basic fibroblast growth factor
(bFGF), and various pro-inflammatory cytokines.
In rat, pirfenidone decreased collagen production and deposition in hepatic fibrosis,
reversed cardiac and renal fibrosis, and attenuated the increase in diastolic stiffness of
diabetic hearts from streptozotocin-treated animals without normalizing cardiac contractility
or renal function. In DOCA-salt hypertensive rats, pirfenidone also reversed and prevented
cardiac remodeling, and reversed and prevented increased cardiac stiffness without reversing
the increased vascular responses to noradrenaline.
Human studies have shown some clinical anti-inflammatory and anti-fibrotic benefit
of oral pirfenidone. Phototoxicity, gastrointestinal disorders and abnormal liver function test
values may result in human populations following oral administration of pirfenidone. As a
consequence patient dosing must be closely monitored. In Phase 3 clinical studies with orally
administered pirfenidone, initial dose escalation was required to establish gastrointestinal
tolerance. However, dose levels are also limited during or following escalation due to
occurrence of nausea, rash, dyspepsia, dizziness, vomiting, photosensitivity reaction,
anorexia, and elevated AST and ALT serum transaminases. In some cases, oral
administration of pirfendione may result in dose de-escalation or discontinuation of
pirfenidone administration.
41
In addition to required pirfenidone dose escalation to establish gastrointestinal
tolerance, dose de-escalation and the use of food has been employed to enable oral
administration to individuals unable to achieve tolerance and would otherwise be removed
from therapy, for example, dose de-escalation of up to and greater than 50%. Further,
clinical studies utilizing the use of food to enable dose tolerability may also be attempted. In
both cases, the plasma Cmax is reduced dose-proportionately. More specifically, the fedstate results in about a 50% reduction in Cmax, about a seven-fold increase in Tmax and a
reduction in overall exposure of 10-15%. Both fed and fasted state resulted in a plasma halflife of about 2.5 hours. While this approach may reduce gastrointestinal-related adverse
events, the lack of clinically-significant efficacy in recent orally-administered clinical studies
may have been influenced by these approaches.
Based upon clinical observations and adverse events as well as observed toxicities,
oral pirfenidone therapy is limited to doses up to about 1800 mg/day to about 2400 mg/day
(from 600 mg TID or 801 mg TID, respectively). Thus, while pirfenidone exhibits a wide
range of non-human efficacy, human adverse events and toxicities have limited oral dosing to
the lower end of this range.
Regulatory risk-benefit analysis between observed efficacy and associated adverse
events of orally administered pirfendione has led to concerns that these doses do not provide
sufficient efficacy to warrant the safety risk; even in a terminal population of unmet clinical
need. Provided herein in certain embodiments, is a method of administering an equivalent or
increased pirfenidone or pyridone analog dose directly to the disease site (e.g., inhalation
delivery to the lung) would provide equivalent or improved efficacy over oral routes. In
certain embodiments, these doses require less administered drug. In certain embodiments,
this approach of administering pirfenidone by inhalation may also benefit from reduced
systemic exposure and an increased safety margin when compared to oral administration of
pirfenidone. Described herein are compositions of pirfenidone or a pyridone analog
compound that are suitable for delivery to a mammal by inhalation and methods of using
such compositions.
It is unclear from the existing data whether pirfenidone anti-inflammatory or anti30 fibrotic mechanism or mechanisms of action are driven by Cmax or exposure (area under the
curve, AUC). In some embodiments, low to moderately-observed clinical efficacy may be
42
associated with pirfenidone plasma levels about or greater than 5 mcg/mL, exposures (AUC0-
infinitiy) about or greater than 50 mg⋅hr/L, and/or a plasma elimination rate of about 2.5 hours.
In some embodiments, intravenous or oral administration of pirfenidone may result in
lung epithelial lining fluid (ELF) levels comparable to that observed in plasma, and thus, in
some embodiments, clinically-measured plasma Cmax of about or greater than 5 mcg/mL are
directly associated with low to moderately-observed clinical pulmonary efficacy. In some
embodiments, plasma levels of pirfendione resulting from oral administration are associated
with lower efficacy, and thus is some embodiments the resultant ELF and lung tissue levels
are also associated with lower efficacy. In other embodiments, intravenous or oral
administration of pirfenidone may result in lung epithelial lining fluid (ELF) levels less than
that observed as efficacious from the plasma. In some embodiments, ELF levels
corresponding with oral or intravenous-delivered, plasma-observed efficacious levels may be
0.1 mcg/mL to about 5 mcg/mL. In some embodiments, ELF levels corresponding with
plasma-observed efficacious levels may be 0.1 mcg/mL to about 1 mcg/mL. In some
embodiments, ELF levels corresponding with oral or intravenous-delivered, plasma-observed
efficacious levels may be 0.5 mcg/mL to about 5 mcg/mL. In some embodiments, ELF levels
corresponding with oral or intravenous-delivered, plasma-observed efficacious levels may be
0.3 mcg/mL to about 3 mcg/mL. In some embodiments, direct administration of pirfenidone
to the lung, results in delivery of about or greater than 5 mcg pirfenidone to one mL ELF, and
may result in equivalent pulmonary efficacy without elevated systemic levels associated with
adverse events and toxicities observed with administration. By non-limiting example, this
may be accomplished by oral or intranasal inhaled delivery of aerosolized pirfenidone or
pyridone analog to the lung providing about or greater than 0.1 mcg/mL, for example greater
than about 0.2 mcg/mL, 0.4 mcg/mL, 0.6 mcg/mL, 0.8 mcg/mL, 1.0 mcg/mL, 2 mcg/mL, 3
mcg/mL, 4 mcg/mL, 5 mcg/mL, 6 mcg/mL, 7 mcg/mL, 8 mcg/mL, 9 mcg/mL, or greater than
mcg/mL of pirfenidone or pyridone analog to the ELF. Once in the ELF, pirfenidone or
pyridone analog will in some embodiments penetrate lung tissue resulting in between about
0.004 mcg and 0.7 mcg pirfenidone or pyridone analog to one gram lung tissue (about 0.1
mcg/mL in about 25 mL ELF to about 5 mcg/mL in about 75 mL ELF, about 600 grams adult
human lung tissue weight).
43
In some embodiments, pirfenidone may readily equilibrate between the plasma and
lung, and/or other organs. In some embodiments, organ pirfenidone levels may also mimic
that of plasma, such as for example, the lung, heart, kidney or nervous system. In some
embodiments, delivery of about or greater than 0.004 mcg to 0.7 mcg pirfenidone to one
gram tissue may provide a similar therapeutic benefit to other organs. In some embodiments,
providing additional pirfenidone or pyridone analog may provide additional efficacy. In
some embodiments, this may be accomplished by inhalation (i.e. oral inhalation or intranasal
inhalation) delivery of aerosolized pirfenidone or pyridone analog to the lung. In some
embodiments, pirfenidone or pyridone analog delivered to the lung may, in some
embodiments, become readily available to the heart. In some embodiments, providing about
0.1 mcg/mL to about 5 mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung tissue
pirfenidone or pyridone analog pyridone analog to the ELF or 0.2 to 0.7 mcg/gram lung
tissue pirfenidone or pyridine analog may result in a similar efficacious dose to the heart in
the absence of elevated systemic adverse events or toxicities observed with oral dosing. In
some embodiments, intranasal inhalation or oral inhalation delivery of aerosolized
pirfenidone or pyridone analog to the lung may result in efficacious delivery of pirfenidone or
pyridone analog to the liver. In some embodiments, pirfenidone or pyridone analog delivered
to the lung will become available to the liver. In some embodiments, providing about 0.1
mcg/mL to about 5 mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung tissue
pirfenidone or pyridone analog pyridone analog may result in a similar efficacious dose to the
liver in the absence of elevated systemic adverse events or toxicities observed with oral
dosing. In some embodiments, intranasal or oral inhalation delivery of aerosolized
pirfenidone or pyridone analog to the lung may result in efficacious delivery of pirfenidone or
pyridone analog to the kidney. In some embodiments, pirfenidone or pyridone analog
delivered to the lung will become available to the kidney. In some embodiments, providing
about 0.1 mcg/mL to about 5 mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung
tissue pirfenidone or pyridone analog pyridone analog may result in a similar efficacious dose
to the kidney in the absence of elevated systemic adverse events or toxicities observed with
oral dosing. In some embodiments, intranasal inhalation delivery of aerosolized pirfenidone
or pyridone analog to the nasal cavity may result in efficacious delivery of pirfenidone or
pyridone analog to the central nervous system (CNS). In some embodiments, inhalation
44
delivery of pirfenidone or pyridone analog to the nasal cavity will become readily available to
the CNS. In some embodiments, providing a nasal cavity-delivered dose equivalent to about
0.1 mcg/mL to about 5 mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung tissue
pirfenidone or pyridone analog may result in similar efficacy in the CNS in the absence
elevated systemic adverse events or toxicities observed with oral dosing.
In some embodiments, topical delivery of aerosolized, liquid or cream pirfenidone or
pyridone analog to a site of desired effect providing about 0.004 mcg/gram to about 0.7
mcg/gram tissue weight may result in a similar efficacious dose in the absence of systemic
adverse events or toxicities. In some embodiments, topical delivery of aerosolized, liquid or
cream pirfenidone or pyridone analog to damaged skin epithelium may prevent or reverse
scarring, fibrosis and/or inflammation. This damage could be the result of infection, burn,
surgery, acute of chronic injury (such as bed soars), or other event. In some embodiments,
topical delivery of liquid or dry powder pirfenidone or pyridone analog to the bladder may
prevent scarring, fibrosis and/or inflammation associated with bladder infection, bladder
cancer, in-dwelling catheter or other event. In some embodiments, topical delivery of liquid
pirfenidone or pyridone analog to the eye may prevent development of post-operative fibrosis
in the conjunctiva and/or episclera following glaucoma surgery.
In some embodiments, injection delivery of liquid pirfenidone or pyridone analog to a
site of desired effect providing about 0.004 mcg/gram to about 0.7 mcg/gram tissue weight
pirfenidone or pyridone analog may result in a similar efficacious dose in the absence of
systemic adverse events or toxicities. In some embodiments, injection delivery of liquid
pirfenidone or pyridone analog to skeletal joints may prevent scarring, fibrosis and/or
inflammation associated with autoimmune diseases, arthritis, rheumatoid arthritis, infection
or other event.
In some embodiments, in addition to Cmax, and in additional embodiments,
pirfenidone exposure (AUC) to the disease site may also be critical for efficacy. In some
embodiments, plasma AUC0-infinity about or greater than 50 mg⋅hr/L is also associated with
pulmonary efficacy. In some embodiments, partial or ready equilibrium of pirfenidone
between the plasma and lung ELF and between the plasma and lung tissue, in some
embodiments, may provide that AUC may also be mimicked in the lung. In other
embodiments, lung ELF and tissue AUC may be less.
45
In some embodiments, individually or in combination Cmax, AUC and/or half-life are
required for efficacy, and thus in some embodiments are provided a conservative model with
all three parameters (Cmax, AUC and half-life) required for efficacy. In some embodiments,
and by non-limiting example, direct inhalation delivery of about 0.1 mcg to about 5 mcg
pirfenidone or pyridone analog to one mL lung ELF, providing an ELF AUC0-infinity about 1.0
mg⋅hr/L or about 50 mg⋅hr/L, and maintaining these levels for the same period of time as that
delivered via the oral route are equivalently efficacious. Similarly, in other embodiments,
direct inhalation delivery of about or greater than 0.2004 to 0.7 mcg pirfenidone or pyridone
analog to one gram lung tissue, provides a tissue AUC0-infinity less than to equivalent or
substantially equivalent to that of the plasma following oral delivery, and in further
embodiments, maintaining these levels for the same period of time as that delivered via the
oral route is equivalently efficacious. In some embodiments, the following assumptions and
theoretical calculations are described for inhalation therapy:
ELF Delivery Assumptions:
1. The total volume of human ELF is 25 mL;
2. The inhaled route of administration is dependent upon a respirable delivered
dose (RDD); RDD is the fraction of drug inhaled in aerosol particles less than 5 microns in
diameter;
3. RDD of typical dry powder, liquid nebulization or meter-dose inhalation
devices ranges from 10% to 70%. In some embodiments, higher and lower efficiency devices
with RDDs greater than 70% and less than 10% are contemplated.
4. Plasma pirfenidone or pyridone analog half-life following oral
administration is around 2.5 hours. In some embodiments, intestinal absorption affects this
vule but for exemplary purposes of this model the lung ELF pirfenidone half-life following
inhalation delivery is assumed to be one-half that following oral administration (e.g. 2.5
hours/2 = 1.25 hours). Half-life values may be supported by measurements indicating
intravenous administration of pirfenidone results in a lung ELF half-life of around one-half
that following oral administration;
. In some embodiments, a lung ELF level of 5 mcg/mL may be the lower
limit of efficacy; and
46
6. 801 mg oral pirfenidone results in a plasma level at or greater than 5
mcg/mL for 4 hours (human-measured value). For purposes of comparing routes, this model
will assume lung ELF pirfenidone levels following oral administration remain at or above 5
mcg/mL lung ELF for the same duration as plasma.
Exemplary ELF Calculations:
1. Mcg pirfenidone delivered to 25 mL ELF to make 5 mcg/mL = 125
mcg;
2. Based upon an RDD efficiency of 30%, the unit dose required is 416
mcg (125 mcg / 0.3 = 416 mcg);
3. Based upon an RDD efficiency of 50%, the unit dose required is 250
mcg (125 mcg / 0.5 = 250 mcg);
4. Based upon an RDD efficiency of 70%, the unit dose required is 179
mcg (125 mcg / 0.7 = 179 mcg); and
Compensating to maintain at or above these levels for 3.2 half lives of 1.25
hours each (4 hours at or above 5 mcg/mL with a lung half-life of 1.25 hours = 3.2 half lives):
. For an RDD efficiency of 30%, the unit dose required to maintain the
lower limit of clinically-observed efficacy (in this case 416 mcg) for 3.2
half lives is 3994 mcg;
6. For an RDD efficiency of 50%, the unit dose required to maintain the
lower limit of clinically-observed efficacy (in this case 250 mcg) for 3.2
half lives 2400 mcg; and
7. For an RDD efficiency of 70%, the unit dose required to maintain the
lower limit of clinically-observed efficacy (in this case 179 mcg) for 3.2
half lives 1718 mcg.
By non-limiting example, based upon the above assumptions and in certain
embodiments, a dose of approximately 4 mg in a device delivering pirfenidone or pyridone
analog with 30% efficiency may result in lung ELF levels at or above 5 mcg/mL for the same
duration as that obtained following 801 mg administered orally. Moreover, while the
minimally efficacious pirfenidone dose may be maintained for this duration, local pirfenidone
levels may also exhibit significantly higher ELF Cmax levels providing improved efficacy.
In some embodiments, delivery of 4 mg pirfenidone or pyridone analog with a 30%
47
efficiency device may result in a lung ELF Cmax up to about 48 mcg/mL (4 mg X 30% = 1.2
mg. 1.2 mg/25 mL ELF = 48 mcg/mL). In some embodiments, based upon the above
assumptions a dose of approximately 66 mg in a device delivering pirfenidone or pyridone
analog with 70% efficiency may result in a lung ELF Cmax up to 1.85 mg/mL (66 mg X 70%
= 46.2 mg. 46.2 mg/25 mL ELF = 1.85 mg/mL). In some embodiments, based upon the
above assumptions a dose of approximately 154 mg in a device delivering pirfenidone or
pyridone analog with 30% efficiency may also result in a lung ELF Cmax up to 1.85 mg/mL
(154 mg X 30% = 46.2 mg. 46.2 mg/25 mL ELF = 1.85 mg/mL). In some embodiments,
based upon the above assumptions a dose of approximately 12 mg in a device delivering
pirfenidone or pyridone analog with 70% efficiency may result in a lung ELF Cmax up to
336 mcg/mL (12 mg X 70% = 8.4 mg. 8.4 mg/25 mL ELF = 336 mcg/mL). In some
embodiments, based upon the above assumptions a dose of approximately 28 mg in a device
delivering pirfenidone or pyridone analog with 30% efficiency may also result in a lung ELF
Cmax up to 336 mcg/mL (28 mg X 30% = 8.4 mg. 8.4 mg/25 mL ELF = 336 mcg/mL). In
some embodiments, this dose may result in maintaining at or above the 5 mcg/mL minimally
efficacious dose for about 6 half-lifes, or about 15 hours. In some embodiments, the
embodiments described for inhalation therapy provide beneficial efficacy through an
increased Cmax and maintaining drug exposure at or above the 5 mcg/mL minimal efficacy
range for a longer duration than that currently limited by oral dosing. In some embodiments,
prolonged exposure may enable a reduced dosing interval (by example once-a-day or twice-aday versus the current three times a day oral dosing regimen). In some embodiments, while
delivery is directly to the lung, these doses may result in very low systemic plasma levels
(e.g. around 2 mcg/mL pirfenidone). In some embodiments, although about 28 mg
pirfenidone or pyridone analog delivered with a 30% efficiency aerosol device may initially
result in elevated levels in vasculature and tissues immediately downstream of the lung (or
nasal cavity), the dilute systemic plasma concentration may be around 1.7 mcg/mL (28 mg X
% = 8.4 mg. 8.4 mg / 5 L total body blood = 1.7 mcg/mL). In some embodiments,
delivery of about 46 mg pirfenidone or pyridone analog may result in a dilute systemic
plasma concentration of about 9.3 mcg/mL.
One of skill in the art whill recognize from the discussions herein that doses
calculated in the above model will change if the actual measured lung ELF half-life of
48
pirfenidone or pyridone analog elimination changes. If the half-life is shorter, more
administered pirfenidone or pyridone analog will be required to maintain the lung ELF
concentration above that considered the minimal efficacious level. Additional increases in
administered pirfenidone or pyridone analog may be desired to further improve efficacy.
Further, in addition to delivering desired lung tissue Cmax and AUC, oral inhaled or
intranasal inhaled delivery of aerosol pirfenidone or pyridone analog may also serve an
efficient route for systemic delivery. In some embodiments, dosing schemes are
contemplated that enable inhaled delivery of pirfenidone or pyridone analog to initially
achieve desired lung tissue Cmax and AUC, with plasma half-life slower than that of the lung
ELF, and targeting the delivery of specific plasma concentrations may in turn prolong lung
ELF-pirfenidone or pyridone analog exposure.
Exemplary Lung Tissue Delivery Assumptions:
1. The total wet weight of the adult human lung is about 685 to 1,050 grams
(for calculations, conservatively about 1,000 grams);
2. The adult human lung blood volume is about 450 mL;
3. The tissue weight of the adult human lung is conservatively 1,050 grams
wet weight minus 450 mL blood weight (assuming density of 1.0), equals 600 grams;
4. In some embodiments, following intravenous push of pirfenidone to a
mouse:
- plasma pirfenidone Tmax is equivalent to lung Tmax
- 40 mg/kg intravenous dose results in plasma Cmax of about 55
mcg/mL and a lung Cmax of 30 mcg/gram wet tissue
- Conservatively, blood makes up about 40% of the wet lung weight.
Given that the plasma and lung Tmax are, in some embodiments, equivalent, it follows that
much of the 30 mcg/g pirfenidone measured in the wet lung is due to the presence of blood.
Conservatively, if blood makes up about 40% of the wet lung weight, then 40% of the plasma
Cmax (or 55 mcg/mL X 40%) is about 22 mcg/gram pirfenidone in the measured lung weight
is due to blood. Taking the difference between the wet lung Cmax and this number (or 30
mcg/g minus 22 mcg/g), about 8 mcg/g is in the lung tissue.
- a measured wet lung half-life that is about 45% longer than the
plasma half-life may be considered. Taking the argument above that about 40% of the wet
49
lung pirfenidone is in the blood, the actual lung tissue half-life is much greater then 45%
longer than plasma;
. From the above observations and calculations that 55 mcg/mL plasma
Cmax results in a lung tissue Cmax of about 8 mcg/gram, the following comparison to
humans can be made:
- Taking an early assumption, the lower end of human efficacy is 5
mcg/mL plasma pirfenidone.
- Assuming the above ratio (55 mcg/mL plasma results in 8 mcg/gram
lung tissue) is true for humans, 5 mcg/mL divided by 55 mcg/mL is about 9.1%. 9.1% of 8
mcg/gram is about 0.7 mcg/gram.
- Taken together, 5 mcg/mL plasma pirfenidone may result in 0.7
mcg/gram lung tissue pirfenidone. Thus, about 0.7 mcg/gram lung tissue pirfenidone is the
lower end of efficacy.
6. The inhaled route of administration is dependent upon a respirable delivered
dose (RDD). The RDD is the fraction of drug inhaled in aerosol particles less than 5 microns
in diameter;
7. RDD of typical dry powder, liquid nebulization or meter-dose inhalation
devices ranges from 10% to 70%. Higher and lower efficiency devices with RDDs greater
than 70% and less than 10% also exist;
8. As discussed above, lung tissue pirfenidone half-life is much longer than the
intravenously delivered plasma pirfenidone half-life (by as much or greater than 2-4X).
Plasma pirfenidone half-life following oral administration is around 2.5 hours. However,
continued intestinal absorption affects this number and hence is much longer than that
following intravenous delivery. Therefore, for purposes of this model the lung tissue
pirfenidone half-life following inhalation delivery will be considered equivalent to that
following oral administration (e.g. 2.5 hours);
9. From the above observations and calculations, the lower limit of efficacy in
lung tissue is 8 mcg/gram; and
. Incorporating that 801 mg oral pirfenidone results in a human plasma level
at or greater than 5 mcg/mL for 4 hours and that 5 mcg/mL plasma results in 0.7 mcg/gram
lung tissue pirfenidone, what is delivered by oral or intranasal inhalation must be at or above
50
0.7 mcg/gram lung tissue pirfenidone for at least 4 hours for equivalent lung fibrosis efficacy
to the oral dose.
Exemplary Lung Tissue Calculations:
1. Mcg pirfenidone delivered to 1000 grams wet lung tissue (blood plus lung
tissue) to make 0.7 mcg/gram = 700 mcg;
2. Based upon an RDD efficiency of 30%, the unit dose required is 2,333
mcg (700 mcg / 0.3 = 2,333 mcg);
3. Based upon an RDD efficiency of 50%, the unit dose required is 1,400
mcg (700 mcg / 0.5 = 1,400 mcg);
4. Based upon an RDD efficiency of 70%, the unit dose required is 1,000
mcg (700 mcg / 0.7 = 1,000 mcg); and
Compensating to maintain at or above these levels for 2 half lives of 2.5 hours
each (4 hours at or above 0.7 mcg/gram wet lung tissue with a lung half-life of 2.5 hours =
1.6 half lives):
5. For an RDD efficiency of 30%, the unit dose required to match the lower
limit of clinically-observed oral route efficacy (in this case 2,333 mcg) for
1.6 half lives is 3,733 mcg;
6. For an RDD efficiency of 50%, the unit dose required to match the lower
limit of clinically-observed oral route efficacy (in this case 1,400 mcg) for
1.6 half lives 2,240 mcg; and
7. For an RDD efficiency of 70%, the unit dose required to match the lower
limit of clinically-observed oral route efficacy (in this case 1,000 mcg) for
1.6 half lives 1,600 mcg.
By non-limiting example, based upon the above assumptions a dose of approximately
3.7 mg in a device delivering pirfenidone or pyridone analog with 30% efficiency may result
in wet lung tissue levels at or above 0.7 mcg/gram for the same duration as that obtained
following 801 mg administered orally. Moreover, while the minimally efficacious
pirfenidone dose is maintained for this duration, local pirfenidone levels may exhibit
significantly higher wet lung tissue Cmax levels providing improved efficacy. By non30 limiting example, delivery of 3.7 mg pirfenidone or pyridone analog with a 30% efficiency
device may result in a wet lung tissue Cmax up to about 1.1 mcg/gram (3.7 mg X 30% = 1.1
51
mg. 1.1 mg/1,050 grams wet lung weight = 1.1 mcg/gram). This number is near about 1.5-
fold higher than that delivered following oral delivery. By another non-limiting example,
based upon the above assumptions a dose of approximately 50 mg in a device delivering
pirfenidone or pyridone analog with 30% efficiency may result in a wet lung tissue Cmax up
to 14.3 mcg/mL (50 mg X 30% = 15 mg. 15 mg/1,050 grams wet lung weight = 14.3
mcg/gram), or about 20-fold higher than that delivered following oral delivery. Under this
scenario, this dose may result in maintaining at or above the 0.7 mcg/gram wet lung tissue
minimally efficacious dose for at least about 5 half-lifes, or about 12.5 hours; compared to 4
hours following 801 mg oral dose administration. Similarly, by another non-limiting
example, based upon the above assumptions a dose of approximately 15 mg in a device
delivering pirfenidone or pyridone analog with 70% efficiency may result in a wet lung tissue
Cmax up to 10 mcg/mL (15 mg X 70% = 10.5 mg. 10.5 mg/1,050 grams wet lung weight =
mcg/gram), or about 14-fold higher than that delivered following oral delivery. Under this
scenario, this dose may result in maintaining at or above the 0.7 mcg/gram wet lung tissue
minimally efficacious dose for about 4.5 half-lifes, or at least about 11 hours; compared to 4
hours following 801 mg oral dose administration. Such duration over 0.7 mcg/gram lung
tissue may permit twice a day dosing (BID). Similarly, by another non-limiting example,
based upon the above assumptions a dose of approximately 75 mg in a device delivering
pirfenidone or pyridone analog with 70% efficiency may result in a wet lung tissue Cmax up
to 50 mcg/mL (75 mg X 70% = 52.5 mg. 52.5 mg/1,050 grams wet lung weight = 50
mcg/gram), or about 71-fold higher than that delivered following oral delivery. Under this
scenario, this dose may result in maintaining at or above the 0.7 mcg/gram wet lung tissue
minimally efficacious dose for at least about 6 half-lifes, or about 15 hours; compared to 4
hours following 801 mg oral dose administration. Such duration over 0.7 mcg/gram lung
tissue may permit BID dosing. Similary, by another non-limiting example, based upon the
above assumptions a dose of approximately 15 mg in a device delivering pirfenidone or
pyridone analog with 30% efficiency may result in a wet lung tissue Cmax up to 4.3 mcg/mL
(15 mg X 30% = 4.5 mg. 4.5 mg/1,050 grams wet lung weight = 4.3 mcg/gram), or about 6-
fold higher than that delivered following oral delivery. Under this scenario, this dose may
result in maintaining at or above the 0.7 mcg/gram wet lung tissue minimally efficacious dose
for at least about 3 half-lifes, or about 7.5 hours; compared to 4 hours following 801 mg oral
52
dose administration. Similarly, by another non-limiting example, based upon the above
assumptions a dose of approximately 75 mg in a device delivering pirfenidone or pyridone
analog with 30% efficiency may result in a wet lung tissue Cmax up to 21 mcg/mL (75 mg X
% = 22.5 mg. 52.5 mg/1,050 grams wet lung weight = 21 mcg/gram), or about 31-fold
higher than that delivered following oral delivery. Under this scenario, this dose may result
in maintaining at or above the 0.7 mcg/gram wet lung tissue minimally efficacious dose for at
least about 5 half-lifes, or about 12.5 hours; compared to 4 hours following 801 mg oral dose
administration. Such duration over 0.7 mcg/gram lung tissue may permit BID dosing.
Similary, by another non-limiting example, based upon the above assumptions a dose of
approximately 15 mg in a device delivering pirfenidone or pyridone analog with 10%
efficiency may result in a wet lung tissue Cmax up to 1.4 mcg/mL (15 mg X 10% = 1.5 mg.
1.5 mg/1,050 grams wet lung weight = 1.4 mcg/gram), or about 2-fold higher than that
delivered following oral delivery. Under this scenario, this dose may result in maintaining at
or above the 0.7 mcg/gram wet lung tissue minimally efficacious dose for about 1 half-lifes,
or at least about 2.5 hours; compared to 4 hours following 801 mg oral dose administration.
Similarly, by another non-limiting example, based upon the above assumptions a dose of
approximately 75 mg in a device delivering pirfenidone or pyridone analog with 10%
efficiency may result in a wet lung tissue Cmax up to 21 mcg/mL (75 mg X 10% = 7.5 mg.
7.5 mg/1,050 grams wet lung weight = 7.1 mcg/gram), or about 10-fold higher than that
delivered following oral delivery. Under this scenario, this dose may result in maintaining at
or above the 0.7 mcg/gram wet lung tissue minimally efficacious dose for about 3.5 half-lifes,
or at least about 8.8 hours; compared to 4 hours following 801 mg oral dose administration.
Such duration over 0.7 mcg/gram lung tissue may permit TID dosing. Such an approach
could benefit efficacy through an increased Cmax and maintaining drug exposure at or above
the 0.7 mcg/gram wet lung tissue minimal efficacy range for a longer duration than that
currently limited by oral dosing. Such prolonged exposure may enable a reduced dosing
interval (by example once-a-day or twice-a-day versus the current three times a day oral
dosing regimen). Moreover, while this approach delivers directly to the lung, using the above
non-limiting examples these doses may result in reduced systemic plasma levels (e.g. Cmax
from less than 0.6 mcg/mL pirfenidone from a 4.5 mg delivered dose to 5,000 mL blood to
53
less than 2 mcg/mL pirfenidone from a 15 mg delivered dose to less than 10 mcg/mL from a
75 mg dose).
Doses calculated in the above model will change considerably if the actual measured
lung tissue half-life of pirfenidone or pyridone analog elimination changes. If the half-life is
faster, more inhaled pirfenidone or pyridone analog will be required to maintain the lung
tissue concentration above that considered the minimal efficacious level. Additional
increases in inhaled pirfenidone or pyridone analog may be desired to further improve
efficacy. Further, in addition to delivering desired lung tissue Cmax and AUC, inhaled
delivery of aerosol pirfenidone or pyridone analog may also serve an efficient route for
systemic delivery. In some embodiments, dosing schemes are contemplated that enable
inhaled delivery of pirfenidone or pyridone analog to initially achieve desired lung tissue
Cmax and AUC, and as plasma half-life is predicted to be slower than that of the lung tissue,
targeting the delivery of specific plasma concentrations may in turn prolong lung tissuepirfenidone or pyridone analog exposure.
As scarring is irreversible, IPF efficacy is the act of protecting native lung tissue
against invading fibrosis. Therefore, maintaining regular efficacious drug levels in unaffected
tissue is critical for improved patient survival. Clinical and nonclinical studies have suggested
pirfenidone efficacy is dose-responsive ranging from slowed-disease progression to
improvement. Unfortunately, substantial gastrointestinal (GI) side effects and systemic
toxicity have forced an approved oral dose that is limited to the lower end of this range.
Complicating matters, recommendations for dose-absorbing food and frequent triggering of
dose-reduction/discontinuation protocols addressing these issues further reduce lung dose and
interrupt required maintenance therapy of this otherwise promising drug. Inhalation delivery
of aerosol pirfenidone or pyridone analog directly to the lung will reduce or eliminate these
safety or tolerability limitations associated with the oral route of delivery.
Oral pirfenidone efficacy has been moderately demonstrated in human clinical studies
and the data suggests that this effect increases with higher doses. Unfortunately, significant
side effects and toxicity have limited the oral dose to the lower end of this efficacy range
(Esbriet approved up to 2403 mg/d). Jeopardizing this already low efficacy dose, the Esbriet
prescription requires an initial dose-escalation scheme and recommended administration with
food to acquire minimal GI tolerance and an acceptable side-effect/toxicity profile (range up
54
to three 267 mg capsules, or 801 mg three times a day (TID)). Unfortunately, not all patients
reach this recommended dose and food further reduces bioavailability (food reduces Cmax
and AUC ~50% and ~20%, respectively). Further, elevated liver enzyme levels and skin
photoreactivity initiate a physician-guided dose-reduction and stoppage protocol that in Phase
3 studies permitted up to a 50% dose reduction before discontinuation (in these studies
between 48% and 67% of patient doses were reduced). As chronic lung tissue dosing of
effective drug levels is critical for maintenance protection against invading fibrosis, it is
likely that oral pirfenidone prescription and practice result in sub-efficacious dosing of this
otherwise promising drug; a hypothesis that may in part explain the moderate efficacy
observed in Phase 3 studies.
For oral administration in the context of treatment of pulmonary fibrosis high oral
doses are required to achieve plasma levels required for efficacious lung tissue exposure.
However, gastrointestinal side-effects and systemic toxicities have limited the approved oral
dose to a level restricted to the low end of the efficacy and dose-response curve. In one
embodiment, inhaled pirfenidone or pyridone analog improves pirfenidone treatment
effectiveness through increased lung dose and improved compliance. In one embodiment,
inhalation of pirfenidone or pyridone analog (e.g. with a nebulizer) delivers pirfenidone or
pyridone analog directly to the lung and whole-body dilution of the delivered dose is
minimized. In some embodiments, inhalation of pirfenidone reduces or eliminates GI
exposure and/or systemic toxicities that are common with oral administration of pirfenidone
or pyridone analog. In some embodiments, inhalation delivery of pirfenidone or pyridone
analog provided herein provides higher lung tissue levels of pirfenidone than is possible
through oral administration. In some embodiments, inhalation delivery of pirfenidone or
pyridone analog serves as an efficient means of delivering pirfenidone or pyridone analog to
the systemic compartment. In some embodiments, inhalation delivery of pirfenidone or
pyridone analog provides Cmax and AUC benefits over the oral route. In some
embodiments, inhalation delivery of pirfenidone or pyridone analog provides Cmax and AUC
benefits over the oral route, wherein plasma re-circulated, aerosol-delivered pirfenidone or
pyridone analog maintains these beneficial properties. In some embodiments, the methods
described herein may be used to treat patients diagnosed with mild-to-moderate IPF. In some
embodiments, the methods described herein may be used to treat patients diagnosed with
55
mild-to-severe IPF. In some embodiments, the methods described herein may be used to treat
patients diagnosed with mild-to-moderate IPF without the need to initially dose-escalate the
patient. In some embodiments, the methods described herein may be used to treat patients
diagnosed with mild-to-severe IPF without the need to initially dose-escalate the patient. In
some embodiments, the methods described herein may be used to treat patients diagnosed
with mild-to-moderate IPF without the need to monitor and dose-reduce or stop therapy due
to gastrointestinal, phototoxic or liver enzyme-associated adverse events. In some
embodiments, the methods described herein may be used to treat patients diagnosed with
mild-to-severe IPF without the need to monitor and dose-reduce or stop therapy due to
gastrointestinal, phototoxic or liver enzyme-associated adverse events. In some
embodiments, the methods described herein may be used to provide a prophylactic therapy to
patients diagnosed with mild-to-moderate IPF. In some embodiments, the methods described
herein may be used to provide a prophylactic therapy to patients diagnosed with mild-tosevere IPF. In some embodiments, the methods described herein may be used to provide a
prophylactic therapy to patients with mild-to-moderate IPF without the need to initially doseescalate the patient. In some embodiments, the methods described herein may be used
provide a prophylactic therapy to patients diagnosed with mild-to-severe IPF without the
need to initially dose-escalate the patient. In some embodiments, the methods described
herein may be used to provide a prophylactic therapy to patients diagnosed with mild-to20 moderate IPF without the need to monitor and dose-reduce or stop therapy due to
gastrointestinal, phototoxic or liver enzyme-associated adverse events. In some
embodiments, the methods described herein may be used to provide a prophylactic therapy to
patients diagnosed with mild-to-severe IPF without the need to monitor and dose-reduce or
stop therapy due to gastrointestinal, phototoxic or liver enzyme-associated adverse events. In
some embodiments, the methods described herein may be used to slow disease progression of
patients diagnosed with mild-to-moderate IPF without the need to initially dose-escalate the
patient. In some embodiments, the methods described herein may be used to slow disease
progression of patients diagnosed with mild-to-severe IPF without the need to initially doseescalate the patient. In some embodiments, the methods described herein may be used to
slow disease progression of patients diagnosed with mild-to-moderate IPF without the need to
monitor and dose-reduce or stop therapy due to gastrointestinal, phototoxic or liver enzyme-
56
associated adverse events. In some embodiments, the methods described herein may be used
to slow disease progression of patients diagnosed with mild-to-severe IPF without the need to
monitor and dose-reduce or stop therapy due to gastrointestinal, phototoxic or liver enzymeassociated adverse events. By non-limiting example, clincal end points of IPF efficacy
include reduced decline in forced vital capacity (FVC), reduced decline in distance walked
over a six-minute interval (six-minute walk test; 6MWT), slowed decline in carbon monoxide
diffusion capacity (DLCO), improved progression-free survival (PFS), reduced mortality and
monitoring changes in biomarkers such as MMP7, and CCL18. In some embodiments, a
comparison of oral and inhaled aerosol properties that may be observed is shown in Table A.
Table A. Advantages of inhaling pirfenidone
Oral Pirfenidone Inhaled Pirfenidone
High oral dose = minimally-effective
lung levels Lower inhaled dose = superior lung levels
Oral route = significant GI side effects Inhaled route = no/reduced GI side effects
High dose = toxicity Lower dose = reduced toxicity
Low efficacy:
1. Pirfenidone is a low potency drug.
The oral route requires a very high
dose to deliver sufficient lung levels.
Significant GI side effects and to a
lesser extent systemic toxicities limit
the oral dose to the lower end of the
efficacy and dose-response curve.
2. Initial dose escalation required to
obtain maximum-tolerated
maintenance dose. Due to poor
tolerability, this maintenance dose is
often set below the approved dose
level
3. Continued intolerability and safety
concerns reduce adherence to
maintenance therapy
• Dose reduced and interrupted
- Recommended food absorbs
drug
- Side effects and toxicity trigger
dose reduction/stoppage
protocols
High efficacy:
1. Inhaled route permits use of smaller
pirfenidone doses to deliver superior
initial pirfenidone lung tissue Cmax
and AUC in the absence of GI sideeffects. In some embodiments, inhaled
administration also serves as non-oral
route for systemic delivery; enabling
sufficient circulating plasma
pirfenidone levels to extend the
duration of superior efficacy.
2. Good tolerability permits establishing
the maintenance dose a the approved
level
3. Strong adherence to maintenance
therapy
• Dose and chronic therapy maintained
- Inhaled drug unaffected by food
- Safe & well-tolerated; no need for
special protocols
57
In some embodiments the methods described herein provide for delivery of high
concentration, readily bioavailable pirfenidone or pyridone analog compound which in turn
provides improved efficacy over pirfenidone or pyridone analog compound admininstered by
the oral route or by inhalation of a slow-dissolving or otherwise slowly bioavailable
compound formulation. In some embodiments, such slow-dissolving or otherwise slowly
bioavailable compound formulations for inhalation include, but are not limited to a dry
powder formulation, a liposomal formulation, a nano-suspension formulation, or a microsuspension formulation. In some embodiments, the aqueous solutions of pirfenidone or
pyridone analog described and contemplated herein for administration by inhalation are
completely homogeneous and soluble.
In some embodiments, an obstacle to patient compliance with oral pirfenidone therapy
is GI intolerability. Pirfenidone blood levels may also be important has they have been
implicated in other observed toxicities. Thus, factors contributing to increased blood levels
must be considered. For the oral route of administration, toxicity and GI intolerability have
limited the dose to 801 mg three times a day. While elevated liver enzymes, photosensitivity
reaction and phototoxicity occur at this dose, they occur with higher frequency and greater
severity with higher doses. Secondly, pirfenidone is primarily metabolised by CYP1A2. In
vitro metabolism studies with hepatic microsomes indicate that approximately 48% of
pirfenidone is metabolised via CYP1A2 with other CYP isoenzymes including CYP2C9,
2C19, 2D6, and 2E1 each contributing less than 13%. Thus, inhibiting these enzyme systems
results in elevated pirfenidone blood levels, resulting in increased incidence and severity of
toxicity. To this end, items such as grapefruit juice, fluvoxamine and other inhibitors of
CYP1A2 should be avoided during oral treatment with pirfenidone.
Oral administration of pirfenidoen is contraindicated in patients with concomitant use
of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Esbriet therapy
and avoided during Esbriet therapy due to the reduced clearance of pirfenidone. Other
therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes
involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should also be
avoided during pirfenidone treatment.
Also for the oral administration, special care should also be exercised if CYP1A2
inhibitors are being used concomitantly with potent inhibitors of one or more other CYP
58
isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g amiodarone,
fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
The oral product should be used with caution in patients treated with other moderate
or strong inhibitors of CYP1A2 (e.g. ciprofloxacin, amiodarone, propafenone).
As many products effecting CYP enzymes are useful to fibrosis patients, permitting
their use would be beneficial. While the oral route is already at the maximum permissible
dose (which provides only moderate efficacy), any inhibition of the enzymes described above
elevates pirfenidone blood levels and increases the rate and severity of the toxic events
described herein. In some embodiments oral inhalation and intranasal inhalation delivery of
pirfenidone or pyridone analogs can achieve effective tissue levels with much less drug than
that required by the oral product, and in some embodiments result in blood levels are
significantly lower and consequences associated with CYP enzyme inhibitory properties
described herein are removed. In some embodiments, use of these CYP inhibitory enzyme
products currently contraindicated with the oral medicine may be administered with
pirfenidone or pyridone analog.
The primary metabolite of pirfenidone is 5-carboxy-pirfenidone. Following oral or
intravenous administration, this metabolite appears quickly at at high concetrations in blood.
-carboxy-pirfenidone does not appear to have anti-fibrotic or anti-inflammatory activity, its
high blood levels occur at the loss of pirfenidone blood concentrations. Thus, while the oral
product is dosed at the highest possible level, once pirfenidone enters the blood it is rapidly
metabolized to a non-active species further reducing the drugs potential to achieve sufficient
lung levels required for substantital efficacy. In some embodiments, because oral inhalation
and intranasal inhalation delivery of pirfenidone or pyridone analogs can achieve effective
lung tissue levels directly, extra-lung metabolism is minimized.
In some embodiments, administration of pirfenidone or pyridone analog compound by
inhalation has reduced gastroinstestinal side-effects when compared to oral administration. In
some embodiments, the reduced gastroinstestinal side-effects with administration by
inhalation avoids the need for initial dose-escalation. In some embodiments, administration
of pirfenidone or pyridone analog by inhalation avoids or substantially avoids the
gastronintestinal tract and therefore effects observed with oral administration of pirfenidone
59
or pyridone analog compound will be minimized or not present. In some embodiments, the
lack of food effects with administration by inhalation will allow for full dose delivery.
In some embodiments, pharmaceutical compositions described herein are used in the
treatment of lung disease in mammal. In some embodiments, the pharmaceutical
compositions described herein are administered to a mammal by oral inhalation or intranasal
inhalation methods for the purpose of treating lung disease in the mammal. In some
embodiments, lung disease includes, but is not limited to, asthma, chronic obstructive
pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation
induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury,
acute respiratory distress syndrome (ARDS), sarcoidosis, usual interstitial pneumonia (UIP),
cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich
syndrome, Caplan syndrome, coal worker’s pneumoconiosis, cryptogenic fibrosing alveolitis,
obliterative bronchiolitis, chronic bronchitis, emphysema, pneumonitis, Wegner’s
granulamatosis, lung scleroderma, silicosis, interstitial lung disease, asbestos induced
pulmonary and/or pleural fibrosis. In some embodiments, lung disease is lung fibrosis (i.e.
pulmonary fibrosis). In some embodiments, lung disease is idiopathic pulmonary fibrosis.
Pulmonary Fibrosis
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent pulmonary fibrosis. In some embodiments,
pulmonary fibrosis includes interstitial pulmonary fibrosis. This group of disorders is
characterized by scarring of deep lung tissue, leading to shortness of breath and loss of
functional alveoli, thus limiting oxygen exchange. Etiologies include inhalation of inorganic
and organic dusts, gases, fumes and vapors, use of medications, exposure to radiation, and
development of disorders such as hypersensitivity pneumonitis, coal worker's
pneumoconiosis, radiation, chemotherapy, transplant rejection, silicosis, byssinosis and
genetic factors
IPF as described herein refers to “idiopathic pulmonary fibrosis” and is in some
embodiments a chronic disease that manifests over several years and is characterized by scar
tissue within the lungs, in the absence of known provocation. Exercise-induced
breathlessness and chronic dry cough may be the prominent symptoms. IPF belongs to a
family of lung disorders known as the interstitial lung diseases (ILD) or, more accurately, the
60
diffuse parenchymal lung diseases. Within this broad category of diffuse lung diseases, IPF
belongs to the subgroup known as idiopathic interstitial pneumonia (IIP). There are seven
distinct IIPs, differentiated by specific clinical features and pathological patterns. IPF is the
most common form of IIP. It is associated with the pathologic pattern known as usual
interstitial pneumonia (UIP); for that reason, IPF is often referred to as IPF/UIP. IPF is
usually fatal, with an average survival of approximately three years from the time of
diagnosis. There is no single test for diagnosing pulmonary fibrosis; several different tests
including chest x-ray, pulmonary function test, exercise testing, bronchoscopy and lung
biopsy are used in conjunction with the methods described herein.
Idiopathic pulmonary fibrosis (also known as cryptogenic fibrosing alveolitis) is the
most common form of interstitial lung disease, and may be characterized by chronic
progressive pulmonary parenchymal fibrosis. It is a progressive clinical syndrome with
unknown etiology; the outcome is frequently fatal as no effective therapy exists. In some
embodiments, pirfenidone inhibits fibroblast proliferation and differentiation related to
collagen synthesis, inhibits the production and activity of TGF-beta, reduces production of
fibronectiv and connective tissue growth factor, inhibits TNF-alpha and I-CAM, increase
production of IL-10, and/or reduces levels of platelet-derived growth factor (PDGF) A and B
in belomycin-induced lung fibrosis. The pirfenidone methods and compositions described
herein may provide tolerability and usefulness in patients with advanced idiopathic
pulmonary fibrosis and other lung diseases. In some embodiments, pirfenidone methods and
compositions described herein may provide tolerability and usefulness in patients with mild
to moderate idiopathic pulmonary fibrosis. In some embodiments, increased patient survival,
enhanced vital capacity, reduced episodes of acute exacerbation (compared to placebo),
and/or slowed disease progression are observed following pirfenidone treatment. In some
embodiments inhaled delivery of pirfenidone or pyridone analog may be an effective means
to prevent, manage or treat idiopathic pulmonary fibrosis or other pulmonary fibrotic
diseases.
The term “pulmonary fibrosis”, includes all interstitial lung disease associated with
fibrosis. In some embodiments, pulmonary fibrosis includes the term “idiopathic pulmonary
fibrosis” or “IPF”. In some embodiments, pulmonary fibrosis, by non-limiting example, may
result from inhalation of inorganic and organic dusts, gases, fumes and vapors, use of
61
medications, exposure to radiation or radiation therapy, and development of disorders such as
hypersensitivity pneumonitis, coal worker's pneumoconiosis, chemotherapy, transplant
rejection, silicosis, byssinosis and genetic factors.
Exemplary lung diseases for the treatment or prevention using the methods described
herein include, but are not limited, idiopathic pulmonary fibrosis, pulmonary fibrosis
secondary to systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus,
cryptogenic fibrosing alveolitis, radiation induced fibrosis, chronic obstructive pulmonary
disease (COPD), sarcoidosis, scleroderma, chronic asthma, silicosis, asbestos induced
pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress (including
bacterial pneumonia induced, trauma induced, viral pneumonia induced, ventilator induced,
non-pulmonary sepsis induced, and aspiration induced).
Kidney Fibrosis
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent kidney fibrosis. Kidney fibrosis may develop as a
result of chronic infection, obstruction of the ureter by calculi, malignant hypertension,
radiation therapy, transplant rejection, severe diabetic conditions, or chronic exposure to
heavy metals. In addition, idiopathic glomerulosclerosis and renal interstitial fibrosis have
been reported in children and adults. Kidney fibrosis correlates well with the overall loss of
renal function. Studies have shown that oral pirfenidone provides protective effect against
heavy metal challenge and fibrosis reversal following diabetic challenge in rats.
Additionally, the antifibrotic action of pirfenidone in renal fibrosis following partial
nephrectomy in rats has also been shown. Moreover, clinical studies administering oral
pirfenidone have shown slowed renal function decline in focal segmental glomeruloschlerosis
patients. In some embodiments, because the kidneys vasculature is immediately downstream
of the lung, inhaled delivery of pirfenidone or pyridone analog may be an effective means to
prevent, manage or treat kidney fibrosis resulting from various medical conditions or
procedures without exposing the systemic compartment to otherwise toxic drug levels
associated with oral administration.
The term “kidney fibrosis” by non-limiting example relates to remodeling associated
with or resulting chronic infection, obstruction of the ureter by calculi, malignant
hypertension, radiation therapy, transplant rejection, severe diabetic conditions or chronic
62
exposure to heavy metals. In some embodiments, kidney fibrosis correlates well with the
overall loss of renal function.
Heart and Kidney Toxicity
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent heart and/or kidney toxicity. Chemotherapeutic
agents have toxic effects upon multiple organ during therapy. By non-limiting example
doxorubicin has a broad spectrum of therapeutic activity against various tumors. However, its
clinical use is limited by its undesirable systemic toxicity, especially in the heart and kidney.
Treatment with pirfenidone reduced the severity of doxorubicin-induced toxicity as assessed
by reduced mortality, diminished volume of recovered fluid in the abdominal cavity, and
severity of cardiac and renal lesions at both the biochemical and morphological levels. In
some embodiments, because the heart and kidney vasculature are immediately downstream of
the lung, inhaled delivery of pirfenidone or pyridone analog may be an effective means to
prevent, manage or treat chemotherapy-induced cardiac and/or renal inflammation without
exposing the systemic compartment to otherwise toxic drug levels associated with oral
administration. In some embodiments, inhaled delivery of pirfenidone or pyridone analog
compound is used in the treatment of heart toxicity and/or kidney toxicity associated with
chemotherapy or other therapeutic agents in a human.
The term “heart toxicity” by non-limiting example may be associated with or caused
by exposure to chemotherapeutic agents having toxic effects. By non-limiting example
doxorubicin has a broad spectrum of therapeutic activity against various tumors. However, its
clinical use is limited by its undesirable systemic toxicity, especially in the heart and kidney.
The term “kidney toxicity” by non-limiting example may be associated with or
caused by exposure to chemotherapeutic agents having toxic effects. By non-limiting
example doxorubicin has a broad spectrum of therapeutic activity against various tumors.
However, its clinical use is limited by its undesirable systemic toxicity, especially in the heart
and kidney.
Cardiac Fibrosis
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent cardiac fibrosis. Cardiac remodeling as in chronic
hypertension involves myocyte hypertrophy as well as fibrosis, an increased and non-uniform
63
deposition of extracellular matrix proteins. The extracellular matrix connects myocytes,
aligns contractile elements, prevents overextending and disruption of myocytes, transmits
force and provides tensile strength to prevent rupture. Fibrosis occurs in many models of
hypertension leading to an increased diastolic stiffness, a reduction in cardiac function and an
increased risk of arrhythmias. If fibrosis rather than myocyte hypertrophy is the critical factor
in impaired cardiovascular function, then reversal of cardiac fibrosis by itself may return
cardiac function towards normal. Since collagen deposition is a dynamic process, appropriate
pharmacological intervention could selectively reverse existing fibrosis and prevent further
fibrosis and thereby improve function, even if the increased systolic blood pressure was
unchanged.
Treatment of DOCA-salt hypertensive rats with pirfenidone reversed and prevented
fibrosis. Suggesting that pirfenidone or pyridone analog therapy may be an effective means
to attenuate cardiac fibrosis associated with chronic hypertension and also the functional
impairment of the heart in hypertensive humans. Moreover, the reversal of fibrosis following
pirfenidone treatment of streptozotocin-diabetic rats was also shown (Miric et al., 2001).
Together, and because the heart vasculature are immediately downstream of the lung, inhaled
delivery of pirfenidone or pyridone analog may be an effective means to prevent, manage or
treat cardiac fibrosis resulting from various medical conditions or procedures, including by
non-limiting example viral or bacterial infection, surgery, Duchenne muscular dystrophy,
radiation, chemotherapy, and transplant rejection.
The term “cardiac fibrosis” by non-limiting example relates to remodeling associated
with or resulting from viral or bacterial infection, surgery, Duchenne muscular dystrophy,
radiation therapy, chemotherapy, transplant rejection and chronic hypertension where
myocyte hypertrophy as well as fibrosis is involved and an increased and non-uniform
deposition of extracellular matrix proteins occurs. Fibrosis occurs in many models of
hypertension leading to an increased diastolic stiffness, a reduction in cardiac function, an
increased risk of arrhythmias and impaired cardiovascular function.
Hepatic Fibrosis
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent hepatic fibrosis. Hepatic fibrosis occurs
consequence of severe liver damage in patients with chronic liver disease, caused by non-
64
limiting example persistent viral hepatitis, alcohol overload and autoimmune. Hepatic fibrosis
involves an abnormal accumulation of extracellular matrix components, particularly
collagens. Hepatic stellate cells are non-parenchymal liver cells residing in the perisinusoidal
space. These cells have been shown to be the major cellular source of extracellular matrix in
hepatic fibrosis. Studies have shown that oral pirfenidone provides protective effect against
dimethylnitrosamine-induced hepatic fibrosis in preventing weight loss, suppressed loss in
liver weight, suppressed induction of hepatic fibrosis determined by histological evaluation
and reduced hepatic hydroxyproline levels. Expression of mRNA for type I collagen and
transforming growth factor-beta in the liver were also suppressed by pirfenidone treatment.
Additionally, clinical studies administering oral pirfenidone have shown decreased fibrosis
and improved quality of life in Hepatitis C viral-related liver disease patients. Together, and
because the liver vasculature is downstream of the lung, these results suggest that inhaled
delivery of pirfenidone or pyridone analog may be an effective means to prevent, manage or
treat hepatic fibrosis resulting from various medical conditions or procedures without
exposing the systemic compartment to otherwise toxic drug levels associated with oral
administration.
The term “hepatic fibrosis” by non-limiting example may be associated with or
caused by severe liver damage in patients with chronic liver disease, caused by non-limiting
example persistent viral hepatitis, alcohol overload and autoimmune diseases. Hepatic
fibrosis involves an abnormal accumulation of extracellular matrix components, particularly
collagens. Hepatic stellate cells are non-parenchymal liver cells residing in the perisinusoidal
space.
Multiple Sclerosis
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent multiple sclerosis. Multiple sclerosis is a
demyelinating disorder that is characterized by neurological deficits attributable to
demyelinating lesions and progressive axonal loss in the white matter. The evidence that
TNF-alpha plays a pivotal role in the pathogenesis of multiple sclerosis led to evaluation of
pirfenidone in this indication. In a clinical study, oral pirfenidone improved the Scripps
Neurological Rating Scale scores over placebo. Further, pirfenidone reduced the incidence of
relapses and was associated with a marked improvement in bladder dysfunction. Together,
65
and because the central nervous system vasculature is immediately downstream of the lung,
these results suggest that inhaled delivery of pirfenidone or pyridone analog may be an
effective means to prevent, manage or treat multiple sclerosis without exposing the systemic
compartment to otherwise toxic drug levels associated with oral administration.
The term “multiple sclerosis” is a demyelinating disorder that is characterized by
neurological deficits attributable to demyelinating lesions and progressive axonal loss in the
white matter.
Chronic Obstructive Pulmonary Disease (COPD)
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent COPD. Oxidants and oxidative stress due to, by
non-limiting example, cigarette smoking promote lung inflammation, which is mediated, at
least in part, by activation of the transcription factors nuclear factor (NF)-κB and activator
protein (AP)-1. These coordinate the expression of several genes thought to be important in
COPD, such as interleukin (IL)-8 and TNFα. These pro-inflammatory cytokines and
chemokines, together with IL-1β, strongly activate the p38 subgroup of mitogen-activated
protein kinases (MAPKs), a family of signal transduction enzymes that also include
extracellular signal-regulated kinases (ERK) and c-jun NH2-terminal kinases (JNK). JNK
and p38 members are activated mainly by cytokines implicated in inflammation and
apoptosis. Within the MAPK family, both the JNK and the p38 subgroups are involved in
mediating pro-inflammatory responses, though p38 seems to play a prominent role in COPD.
Pirfenidone has been shown to inhibit both TNF-alpha and p38-gamma MAPK. Moreover,
silencing p38-gamma MAPK has been demonstrated to have potential to restore COPD
sensitivity to corticosteroids (Mercado et al., 2007). In some embodiments, inhaled delivery
of pirfenidone or pyridone analog compound is used in the treatment of COPD in a human.
In some embodiments, inhaled delivery of pirfenidone or pyridone analog may be an
effective means to prevent, manage or treat COPD or associated illness without exposing the
systemic compartment to otherwise toxic drug levels associated with oral administration.
Moreover, inhaled delivery of pirfenidone or pyridone analog may serve as conjunctive
therapy with corticosteroids to restore their usefulness in this indication.
66
The term “chronic obstructive pulmonary disesase” or “COPD” by non-limiting
example may be associated with or caused by exposure to tobacco smoke and preexisting
asthma. COPD describes a wide range of airway disorders that range from simple chronic
bronchitis (smokers cough) to the more severe chronic obstructive bronchitis. The addition of
episodes of airway hyper-reactivity to the above syndrome establishes the diagnosis of
chronic asthmatic bronchitis. Chronic obstructive pulmonary disease includes, but is not
limited to, chronic bronchitis, emphysema, and/or pulmonary hypertension.
Asthma
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent asthma. TNF-alpha has been shown to be a highly
pro-inflammatory cytokine in asthma, as it upregulates adhesion molecules, increases mucin
secretion, and promotes airway remodeling. TNF-alpha is produced by a large number of
cells in the airways, including mast cells, smooth muscle cells, epithelial cells, monocytes,
and macrophages. This cytokine has been shown to be relevant and increased in patients with
asthma. Clinical studies using anti-TNF-alpha therapy have produced encouraging results. In
one set of studies using a soluble form of recombinant human TNF-alpha receptor
(etanercept) the medication improved FEV1 and improved quality of life. Another clinical
study administering an anti-TNF-alpha antibody reduced asthma exacerbation (infliximab).
However, because of concerns associated with adverse events future investigation of these
therapies in asthma is unlikely. Because pirfenidone has been shown to inhibit TNF-alpha,
inhaled delivery of pirfenidone or pyridone analog may be an effective means to manage or
treat asthma or associated illness without exposing the systemic compartment to otherwise
toxic drug levels associated with oral administration. In some embodiments, inhaled delivery
of pirfenidone or pyridone analog compound is used in the treatment of asthma in a human.
Moreover, inhaled delivery of pirfenidone or pyridone analog may serve as conjunctive
therapy with corticosteroids to restore their usefulness in asthma patients exhibiting steroid
resistance.
The term “asthma” is associated with or caused by environmental and genetic factors.
Asthma is a common chronic inflammatory disease of the airways characterized by variable
67
and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms
include wheezing, coughing, chest tightness, and shortness of breath. The term asthma may
be used with one or more adjectives to indicate cause. Non-limiting examples of asthma
include, but are not limited to, allergic asthma, non-allergic asthma, acute severe asthma,
chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive
asthma, exercise-induced asthma, child-onset asthma, adult-onset asthma, cough-variant
asthma, occupational asthma, steroid-resistant asthma, or seasonal asthma.
Lung Inflammation
In some embodiments, the compositions and methods described herein can treat or
slow down the progression of or prevent lung inflammation. Pirfenidone therapy has shown
to have anti-inflammatory effects in addition to anti-fibrotic effects. In some embodiments,
pirfenidone or pyridone analog compound is administered to a human to treat lung
inflammation. Lung inflammation is associated with or contributes to the symptoms of
bronchitis, asthma, lung fibrosis, chronic obstructive pulmonary disorder (COPD), and
pneumonitis.
Glaucoma Surgery Post-Operative Fibrosis
The success of glaucoma filtration surgery is dependent on the degree of post20 operative wound healing and the amount of scar tissue formation. Bleb failure occurs as
fibroblasts proliferate and migrate toward the wound, eventually causing scarring and closure
of the fistula tract. This frequently leads to poor postoperative intraocular pressure control
with subsequent progressive optic nerve damage. The use of adjunctive antifibrotic agents
such as 5-fluorouracil and mitomycin C has significantly improved the success rate of
filtration surgery. However, because of their nonspecific mechanisms of action, these agents
can cause widespread cell death and apoptosis, resulting in potentially sight-threatening
complications such as severe postoperative hypotony, bleb leaks, and endophthalmitis. Thus,
alternative antifibrotic agents are needed. For this purpose, the anti-fibrotic agent pirfenidone
or pyridone analog may prove beneficial.
The present specification provides, in several embodiments as herein disclosed,
compositions and methods for pirfenidone and pyridone analog compound formulations that
68
offer unprecedented advantages with respect to localized delivery of pirfenidone or pyridone
analog in a manner that permits both rapid and sustained availability of therapeutically useful
pirfenidone or pyridone analog levels to one or more desired tissues.
In certain preferred embodiments, and as described in greater detail below, delivery of
the pirfenidone or pyridone analog compound formulation is to the respiratory tract tissues in
mammalian subjects, for example, via the respiratory airways to middle airways and/or
pulmonary beds (e.g., alveolar capillary beds) in human patients. According to certain
particularly preferred embodiments, delivery to these regions of the lungmay be achieved by
inhalation therapy of a pirfenidone or pyridone analog compound formulation as described
herein.
These and related embodiments will usefully provide therapeutic and/or prophylactic
benefit, by making therapeutically effective pirfenidone or pyridone analog available to a
desired tissue promptly upon administration, while with the same administration event also
offering time periods of surprisingly sustained duration during which locally delivered
pirfenidone or pyridone analog is available for a prolonged therapeutic effect.
The compositions and methods disclosed herein provide for such rapid and sustained
localized delivery of a pirfenidone or pirfenidone or pyridone analog pyridone analog
compound to a wide variety of tissues. Contemplated are embodiments for the treatment of
numerous clinically significant conditions including pulmonary fibrosis, chronic obstructive
pulmonary disease (COPD), asthma, cystic fibrosis, cardiac fibrosis, transplantation (e.g.,
lung, liver, kidney, heart, etc.), vascular grafts, and/or other conditions such as multiple
sclerosis for which rapid and sustained bioavailable pirfenidone or pyridone analog therapy
may be indicated.
Various embodiments thus provide compositions and methods for optimal
prophylactic and therapeutic activity in prevention and treatment of pulmonary fibrosis in
human and/or veterinary subjects using aerosol administration, and through the delivery of
high-concentration (or dry formulation), sustained-release active drug exposure directly to the
affected tissue. Specifically, and in certain preferred embodiments, concentrated doses are
delivered of a pirfenidone or pyridone analog.
Without wishing to be bound by theory, according to certain of these and related
embodiments as described in greater detail herein, a pirfenidone or pyridone analog is
69
provided in a formulation having components that are selected to deliver an efficacious dose
of pirfenidone or pyridone analog following aerosolization of a liquid, dry powder or
metered-dose formulation providing rapid and sustained localized delivery of pirfenidone or
pyridone analog to the site of desired effect.
According to certain related embodiments, regulation of the total amount of dissolved
solutes in a pirfenidone or pyridone analog compound formulation is believed, according to
non-limiting theory, to result in aqueous pirfenidone or pyridone analog compound
formulations having therapeutically beneficial properties, including the properties of
nebulized liquid particles formed from aqueous solutions of such formulations. Additionally,
and as disclosed herein, it has been discovered that within the parameters provided herein as
pertain to pirfenidone or pyridone analog compound concentration, pH, and total solute
concentration, tolerability of formulations at or near the upper portion of the total solute
concentration range can be increased by inclusion of a taste-masking agent as provided
herein.
An unexpected observation is that exposure of inhaled pirfenidone to the lung surface
results in depletion of essential lung-surface cations and increased propensity for acute
toxicity. The apparent mechanism for this depletion is pirfenidone’s ability to chelate ions
such as iron(III) in a ratio of three pirfenidone molecules per on iron(III) ion. Chelation of
iron(III) occurs at about one-half the chelation strength of EDTA. One method to prevent
lung-surface ion depletion is to formulation prifenidone with a multivalent ion. By nonlimiting example, such multi-valent cations may include iron(II), iron(III), calcium,
magnesium, etc. By non-limiting example, formulation of pirfenidone was found to chlate
magnesium at a ratio of two pirfenidone molecules to one magnesium ion. Thus, formulation
of between about two and ten pirfenidone molecules with one magnesium molecule results in
filling or saturating the chelation capacity of prifenidone and reduces pirfenidone’s to deplete
lung-surface cations. Coupling this solution with the need to adjust formulation osmolality
and permeant ion content, the salt form of multivalent ion may also be beneficial. By nonlimiting example, using magnesium chloride to formulate pirfenidone reduces pirfenidone’s
ability to deplete essential lung-surface cations, contributes to adjusting the formulations
osmolality and serves to provide the formulation a chloride permeant ion.In certain such
embodiments, for example, a pirfenidone or pyridone analog compound formulation that
70
comprises pirfenidone or a pyridone analog alone or formulated with excipients dissolved in
a simple aqueous solution that may be aerosolized and injected or inhaled to the nasal or
pulmonary compartment. Such a formulation may contain a multivalent cation and/or be
buffered to a pH from about 4.0 to about 11.0, more preferably from about pH 4.0 to about
pH 8.0, at a concentration of at least 34 mcg/mL to about 463 mg/mL, and having a total
osmolality at least 100 mOsmol/kg to about 6000 mOsmol/kg, or 300 to about 5000
mOsmol/kg. Such a simple aqueous formulation may further comprise a taste-masking agent
thereby to become tolerable for inhalation administration (i.e., to overcome undesirable taste
or irritative properties that would otherwise preclude effective therapeutic administration).
Hence and as described in greater detail herein, regulation of formulation conditions with
respect to pH, buffer type, pirfenidone or pyridone analog concentration, total osmolality and
potential taste-masking agent, provides certain therapeutic and other advantages.
In certain such embodiments, for example, a pirfenidone or pyridone analog
compound formulation that comprises pirfenidone or a pyridone analog in a dry powder
formulation alone or formulated with an excipient, such as a multivalent cation providing
improved stability and/or dispersion properties, such that at least 0.1 mg to about 100 mg
may be dispersed and injected or inhaled to the nasal or pulmonary compartment. Hence and
as described in greater detail herein, regulation of formulation conditions with respect to
dispersion excipient, pirfenidone or pyridone analog stability (including, by non-limiting
example polymorph, amorphic content and water content), pirfenidone or pyridone analog
amount and potential taste-masking agent, provides certain therapeutic and other advantages.
In certain such embodiments, for example, a pirfenidone or pyridone analog
compound formulation that comprises pirfenidone or a pyridone analog in a pressurized
meter-dose inhaler configuration providing improved stability and/or aerosol properties, such
that at least 0.1 mg to about 100 mg may be aerosolized and injected or inhaled to the nasal or
pulmonary compartment. Hence and as described in greater detail herein, regulation of
formulation conditions with respect to propellant, suitable pressurized metered-dose inhaler
canister, pirfenidone or pyridone analog stability provides certain therapeutic and other
advantages.
In certain preferred embodiments, a pirfenidone or pyridone analog compound
formulation or salts thereof may serve as prodrugs, sustained-release or active substances in
71
the presently disclosed formulations and compositions and may be delivered, under
conditions and for a time sufficient to produce maximum concentrations of sustained-release
or active drug to the respiratory tract (including pulmonary beds, nasal and sinus cavities),
and other non-oral topical compartments including, but not limited to the skin, rectum,
vagina, urethra, urinary bladder, eye, and ear. As disclosed herein, certain particularly
preferred embodiments relate to administration, via oral and/or nasal inhalation, of a
pirfenidone or pyridone analog compound to the lower respiratory tract, in other words, to the
lungs or pulmonary compartment (e.g., respiratory bronchioles, alveolar ducts, and/or
alveoli), as may be effected by such “pulmonary delivery” to provide effective amounts of
the pirfenidone or pyridone analog compound to the pulmonary compartment and/or to other
tissues and organs as may be reached via the circulatory system subsequent to such
pulmonary delivery of the pirfenidone or pyridone analog compound to the pulmonary
vasculature.
Because different drug products are known to have varying efficacies depending on
the dose, form, concentration and delivery profile, certain presently disclosed embodiments
provide specific formulation and delivery parameters that produce anti-inflammatory, antifibrotic, anti-demylination and/or tissue-remodeling results that are prophylactic or
therapeutically significant. These and related embodiments thus preferably include a
pirfenidone or pyridone analog compound such as pirfenidone or pyridone analog alone or a
salt thereof. As noted above, however, the invention is not intended to be so limited and may
relate, according to particularly preferred embodiments, to pirfenidone or a salt thereof.
Other contemplated embodiments may relate to another pyridone analog compound such as
those disclosed herein.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or treat patients with pulmonary
fibrosis.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
72
specific formulation and delivery parameters that produce protection against and treatment
for pulmonary fibrosis associated, by non-limiting example with infection, radiation therapy,
chemotherapy, inhalation of environmental pollutants (e.g. dust, vapors, fumes, and inorganic
and organic fibers), hypersensitivities, silicosis, byssinosis, genetic factors and transplant
rejection.
These and related applications are also contemplated for use in the diseased lung,
sinus, nasal cavity, heart, kidney, liver, nervous system and associated vasculature. The
pirfenidone or pyridone analog compound formulations and methods described herein may be
used with commercially available inhalation devices, or with other devices for aerosol
therapeutic product administration.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or treat cardiac fibrosis in human
and/or veterinary subjects. Such embodiments provide for direct and high concentration
delivery of the pirfenidone or pyridone analog compound to the pulmonary vasculature
immediately upstream of the left atrium and hence, to the coronary arterial system with
interlumenal atrial and ventricular exposure.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
for cardiac fibrosis associated, by non-limiting example with infection, surgery, radiation
therapy, chemotherapy and transplant rejection.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or treat kidney fibrosis. Such
embodiments provide for direct and high concentration delivery of the pirfenidone or
73
pyridone analog compound to the pulmonary vasculature immediately upstream of the left
atrium, left ventical and hence, to the kidney vasculature.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
for kidney fibrosis associated, by non-limiting example with infection, ureter calculi,
malignant hypertension, radiation therapy, diabetes, exposure to heavy metals, chemotherapy
and transplant rejection.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-inflammatory benefits, for
instance, to prevent, manage or treat heart or kidney toxicity. Such embodiments provide for
direct and high concentration delivery of the pirfenidone or pyridone analog compound to the
pulmonary vasculature immediately upstream of the left atrium, left ventical, and hence, to
the heart and kidney vasculature.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
for heart or kidney toxicity associated, by non-limiting example with chemotherapy.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or treat hepatic fibrosis. Such
embodiments provide for direct and high concentration delivery of the pirfenidone or
pyridone analog compound to the pulmonary vasculature immediately upstream of the left
atrium, left ventical and hence, to the hepatic vasculature.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
74
for hepatic fibrosis associated, by non-limiting example with hepatic infection, hepatitis,
alcohol overload, autoimmune disease, radiation therapy, chemotherapy and transplant
rejection.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose nasal-injected or inhaled, or orally-inhaled
aerosol administration to supply effective concentrations or amounts conferring desired antiinflammatory and/or anti-demylination benefits, for instance, to prevent, manage or treat
multiple sclerosis. If by oral inhalation, such embodiments provide for direct and high
concentration delivery of the pirfenidone or pyridone analog compound to the pulmonary
vasculature immediately upstream of the left atrium, left ventical and hence, to the central
nervous system. If by nasal injection or nasal inhalation, such embodiments provide for
direct and high concentration delivery of the pirfenidone or pyridone analog compound to the
nasal and sinus vasculature immediately upstream of the central nervous system.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
for multiple sclerosis associated.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-inflammatory, anti-fibrotic or
tissue-remodeling benefits, for instance, to prevent, manage or treat patients with diseases
associated with chronic obstructive pulmonary disease (COPD), including emphysema and
chronic bronchitis.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
for COPD associated, by non-limiting example with exposure to pipe, cigar and cigarette
smoke, secondhand smoke, air pollution, and chemical fumes or dust, and/or alpha-1
antitrypsin deficiency.
75
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-inflammatory benefits, for
instance, to prevent, manage or treat patients with asthma.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
for asthma associated, by non-limiting example with exercise, genetics, airborne allergens,
inhaled irritants such as pipe, cigar and cigarette smoke, and childhood respiratory infection.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts conferring desired anti-fibrotic, anti-inflammatory or
tissue-remodeling benefits, for instance, to prevent, manage or treat patients with cystic
fibrosis. Such embodiments may include co-formulation or co-administration of a pyridone
analog compound with an antibiotic, steroid, hyperosmolar solution, DNAse or other mucus
thinning agent, or other agent.
Because different drug products are known to vary in efficacy depending on the dose,
form, concentration and delivery profile, the presently disclosed embodiments provide
specific formulation and delivery parameters that produce protection against and treatment
for cystic fibrosis.
For the applications described herein, liquid nebulized, dry powder or metered-dose
aerosol pirfenidone or pyridone analog compound (or salt thereof) may be co-administered,
administered sequentially or prepared in a fixed combination with an antimicrobial (e.g.
tobramycin and/or other aminoglycoside such as amikacin, aztreonam and/or other beta or
mono-bactam, ciprofloxacin, levofloxacin and/or other, fluoroquinolones, azithromycin
and/or other macrolides or ketolides, tetracycline and/or other tetracyclines, quinupristin
and/or other streptogramins, linezolid and/or other oxazolidinones, vancomycin and/or other
glycopeptides, and chloramphenicol and/or other phenicols, and colisitin and/or other
polymyxins), bronchodilator (e.g. beta-2 agonists and muscarinic antagonists), corticosteroids
76
(e.g. salmeterol, fluticasone and budesonide), glucocorticoids (e.g. prednisone), Cromolyn,
Nedocromil, Leukotriene modifiers (e.g. montelukast, zafirlukast and zileuton) hyperosmolar
solution, DNAse or other mucus thinning agent, interferon gamma, cyclophosphamide,
colchicine, N-acetylcysteine, azathioprine, bromhexine, endothelin receptor antagonist (e.g.
bosentan and ambrisentan), PDE5 inhibitor (e.g. sildenafil, vardenafil and tadalafil), PDE4
inhibitor (e.g. roflumilast, cilomilast, oglemilast, tetomilast and SB256066), prostinoid (e.g.
epoprostenol, iloprost and treprostinin), nitric oxide or nitric oxide-donating compound, IL13 blocker, IL-10 blocker, CTGF-specific antibody, CCN2 inhibitors, angiotensin-converting
enzyme inhibitors, angiotensin receptor antagonists, PDGF inhibitors, PPAR antagonist,
imatinib, CCL2-specific antibody, CXCR2 antogonist, triple growth factor kinase inhibitor,
anticoagulant, TNF blocker, tetracycline or tetracycline derivative, 5-lipoxygenase inhibitor,
pituitary hormone inhibitor, TGF-beta-neutralizing antibody, copper chelator, angiotensin II
receptor antagonist, chemokine inhibitor, NF-kappaB inhibitor, NF-kappaB antisense
oligonucleotide, IKK-1 and -2 inhibitor (e.g. imidazoquinoxaline or derivative, and
quinazoline or derivative), JNK2 and/or p38 MAPK inhibitor (e.g. pyridylimidazolbutyn-I-ol,
SB856553, SB681323, diaryl urea or derivative, and indolecarboxamide), PI3K inhibitor,
LTB4 inhibitor, antioxidant (e.g. Mn-pentaazatetracyclohexacosatriene, M40419, N-acetyl-Lcysteine, Mucomyst, Fluimucil, Nacystelyn, Erdosteine, Ebeselen, thioredoxin, glutathione
peroxidase memetrics, Curcumin C3 complex, Resveratrol and analogs, Tempol, catalytic
antioxidants, and OxSODrol), TNF scavenger (e.g. infliximab, ethercept, adalumimab, PEGsTNFR 1, afelimomab, and antisense TNF-alpha oligonucleotide), Interferon beta-1a
(Avonex, Betaseron, or Rebif), glatiramer acetate (Copaxone), mitoxantrone (Novantrone),
natalizumab (Tysabri), Methotrexate, azathioprine (Imuran), intravenous immunoglobulin
(IVIg), cyclophosphamide (Cytoxan), lioresal (Baclofen), tizanidine (Zanaflex),
benzodiazepine, cholinergic medications, antidepressants and amantadine.
As shown as a promising approach to treat cancer and pulmonary arterial
hypertension, to enable “cocktail therapy” or “cocktail prophylaxis” in fibrotic disease, more
specifically idiopathic pulmonary fibrosis and other pulmonary fibrotic disease, methods to
administer pirfenidone or pyridone analog as either co-administered, administered
sequentially, or co-prescribed (such that medicines are requested by a prescribing physician
to be taken in some sequence as combination therapy to treat the same disease) with agents
77
targeting fibrotic or inflammatory disease. By non-limiting example, pirfenidone or pyridone
analog is administered either in fixed combination, co-administered, adminstered
sequentially, or co-prescribed with the monoclonal GS-6624 (formerly known as AB0024),
analog or another antibody targeting LOXL2 protein associated with connective tissue
biogenesis to reduce inflammation and/or fibrosis. By another non-limiting example,
pirfenidone or pyridone analog is administered either in fixed combination, co-administered,
adminstered sequentially, or co-prescribed with IW001 (Type V collagen), analog or other
collagen targeting immunogenic tolerance to reduce inflammation and/or fibrosis. By
another non-limiting example, pirfenidone or pyridone analog is administered either in fixed
combination, co-administered, adminstered sequentially, or co-prescribed with PRM-151
(recombinant pentraxin-2), analog or other molecule targeting regulation of the injury
response to reduce inflammation and/or fibrosis. By another non-limiting example,
pirfenidone or pyridone analog is administered either in fixed combination, co-administered,
adminstered sequentially, or co-prescribed with CC-903 (Jun kinase inhibitor), analog or
other Jun kinase inhibitor to reduce the inflammatory response. By another non-limiting
example, pirfenidone or pyridone analog is administered either in fixed combination, coadministered, adminstered sequentially, or co-prescribed with STX-100 (monoclonal
antibody targeting integrin alpha-v beta-6), analog or other antibody targeting integrin alphav beta-6 or other integrin to reduce fibrosis. By another non-limiting example, pirfenidone or
pyridone analog is administered either in fixed combination, co-administered, adminstered
sequentially, or co-prescribed with QAX576 (monoclonal antibody targeting interleukin 13
[IL-13]), analog or other antibody targeting IL-13 to reduce inflammation. By another nonlimiting example, pirfenidone or pyridone analog is administered either in fixed combination,
co-administered, adminstered sequentially, or co-prescribed with FG-3019 (monoclonal
antibody targeting connective tissue growth factor [CTGF]), analog or other antibody
targeting CTGF to reduce fibrosis. By another non-limiting example, pirfenidone or pyridone
analog is administered either in fixed combination, co-administered, adminstered
sequentially, or co-prescribed with CNTO-888 (a monoclonal antibody targeting chemokine
[C-C motif] ligand 2 [CCL2]), analog or other antibody targeting CCL2 to reduce fibrosis.
By another non-limiting example, pirfenidone or pyridone analog is administered either in
fixed combination, co-administered, adminstered sequentially, or co-prescribed with Esbriet,
78
Pirespa or Pirfenex (trade names for pirfenidone), or analog targeting inflammation and
fibrosis. By another non-limiting example, pirfenidone or pyridone analog is administered
either in fixed combination, co-administered, adminstered sequentially, or co-prescribed with
BIBF-1120 (also known as Vargatef; a triple kinase inhibitor targeting vascular endothelial
growth factor [VEGF], platelet-derived growth factor [PDGF] and fibroblast growth factor
[FGF]), analog or other triple kinase inhibitor to reduce fibrosis and/or inflammation.
As with administration of pirfenidone, oral and parenteral routes of administration (by
non-limiting example, intravenous and subcutaneous) of other compounds, molecules and
antibodies targeting the reduction of inflammation and/or fibrosis is often associated with, by
non-limiting example, adverse reactions such as gastrointestinal side effects, liver, kidney,
skin, cardiovascular or other toxicities. As described herein for pirfenidone or pyridone
analogs, the benefits of oral or intranasal inhalation directly to the lung or tissues
immediately downstream of the nasal and/or pulmonary compartments will also benefit these
compounds. Therefore, by non-limiting example, the monoclonal GS-6624 (formerly known
as AB0024), analog or another antibody targeting LOXL2 protein associated with connective
tissue biogenesis to reduce inflammation and/or fibrosis may be administered by oral or
intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the
nasal or pulmonary compartments. By another non-limiting example, PRM-151
(recombinant pentraxin-2), analog or other molecule targeting regulation of the injury
response to reduce inflammation and/or fibrosis may be administered by oral or intranasal
inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or
pulmonary compartments. By another non-limiting example, CC-903 (Jun kinase inhibitor),
analog or other Jun kinase inhibitor to reduce the inflammatory response may be
administered by oral or intranasal inhalation for direct delivery to the lung or tissues
immediately downstream of the nasal or pulmonary compartments. By another non-limiting
example, STX-100 (monoclonal antibody targeting integrin alpha-v beta-6), analog or other
antibody targeting integrin alpha-v beta-6 or other integrin to reduce fibrosis may be
administered by oral or intranasal inhalation for direct delivery to the lung or tissues
immediately downstream of the nasal or pulmonary compartments. By another non-limiting
example, QAX576 (monoclonal antibody targeting interleukin 13 [IL-13]), analog or other
antibody targeting IL-13 to reduce inflammation may be administered by oral or intranasal
79
inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or
pulmonary compartments. By another non-limiting example, FG-3019 (monoclonal antibody
targeting connective tissue growth factor [CTGF]), analog or other antibody targeting CTGF
to reduce fibrosis may be administered by oral or intranasal inhalation for direct delivery to
the lung or tissues immediately downstream of the nasal or pulmonary compartments. By
another non-limiting example, CNTO-888 (a monoclonal antibody targeting chemokine [C-C
motif] ligand 2 [CCL2]), analog or other antibody targeting CCL2 to reduce fibrosis may be
administered by oral or intranasal inhalation for direct delivery to the lung or tissues
immediately downstream of the nasal or pulmonary compartments. By another non-limiting
example, BIBF-1120 (also known as Vargatef; a triple kinase inhibitor targeting vascular
endothelial growth factor [VEGF], platelet-derived growth factor [PDGF] and fibroblast
growth factor [FGF]), analog or other triple kinase inhibitor to reduce fibrosis and/or
inflammation may be administered by oral or intranasal inhalation for direct delivery to the
lung or tissues immediately downstream of the nasal or pulmonary compartments.
Aerosol administration directly to one or more desired regions of the respiratory tract,
which includes the upper respiratory tract (e.g., nasal, sinus, and pharyngeal compartments),
the respiratory airways (e.g., laryngeal, tracheal, and bronchial compartments) and the lungs
or pulmonary compartments (e.g., respiratory bronchioles, alveolar ducts, alveoli), may be
effected (e.g., “pulmonary delivery”) in certain preferred embodiments through intra-nasal or
oral inhalation to obtain high and titrated concentration of drug, pro-drug active or sustainedrelease delivery to a site of respiratory pathology. Aerosol administration such as by intranasal or oral inhalation may also be used to provide drug, pro-drug active or sustained-release
delivery through the pulmonary vasculature (e.g., further to pulmonary delivery) to reach
other tissues or organs, by non-limiting example, the heart, brain, liver central nervous
system and/or kidney, with decreased risk of extra-respiratory toxicity associated with nonrespiratory routes of drug delivery. Accordingly, because the efficacy of a particular
pyridone compound (e.g., pirfenidone) therapeutic composition may vary depending on the
formulation and delivery parameters, certain embodiments described herein reflect reformulations of compositions and novel delivery methods for recognized active drug
compounds. Other embodiments contemplate topical pathologies and/or infections that may
also benefit from the discoveries described herein, for example, through direct exposure of a
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pirfenidone or pyridone analog compound formulation as provided herein to diseased skin,
rectum, vagina, urethra, urinary bladder, eye, and/or ear, including aerosol delivery to a burn
wound to prevent scarring.
In addition to the clinical and pharmacological criteria according to which any
composition intended for therapeutic administration (such as the herein described pirfenidone
or pyridone analog compound formulations) may be characterized, those familiar with the art
will be aware of a number of physicochemical factors unique to a given drug composition.
These include, but are not limited to aqueous solubility, viscosity, partitioning coefficient
(LogP), predicted stability in various formulations, osmolality, surface tension, pH, pKa, pKb,
dissolution rate, sputum permeability, sputum binding/inactivation, taste, throat irritability
and acute tolerability.
Other factors to consider when selecting the particular product form include physical
chemistry of the formulation (e.g., a pirfenidone or pyridone analog compound formulation),
the intended disease indication(s) for which the formulation is to be used, clinical acceptance,
and patient compliance. As non-limiting examples, a desired pirfenidone or pyridone analog
compound formulation for aerosol delivery (e.g., by oral and/or intra-nasal inhalation of a
mist such as a nebulized suspension of liquid particles, a dispersion of a dry powder
formulation or aerosol generated by meter-dose propellant), may be provided in the form of a
simple liquid such as an aqueous liquid (e.g., soluble pirfenidone or pyridone analog
compound with non-encapsulating soluble excipients/salts), a complex liquid such as an
aqueous liquid (e.g., pirfenidone or pyridone analog compound encapsulated or complexed
with soluble excipients such as lipids, liposomes, cyclodextrins, microencapsulations, and
emulsions), a complex suspension (e.g., pirfenidone or pyridone analog compound as a lowsolubility, stable nanosuspension alone, as co-crystal/co-precipitate complexes, and/or as
mixtures with low solubility lipids such as solid-lipid nanoparticles), a dry powder (e.g., dry
powder pirfenidone or pyridone analog compound alone or in co-crystal/co-precipitate/spraydried complex or mixture with low solubility excipients/salts or readily soluble blends such
as lactose), or an organic soluble or organic suspension solution, for packaging and
administration using an inhalation device such as a metered-dose inhalation device.
Selection of a particular pirfenidone or pyridone analog compound formulation or
pirfenidone or pyridone analog compound formulation composition as provided herein
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according to certain preferred embodiments may be influenced by the desired product
packaging. Factors to be considered in selecting packaging may include, for example,
intrinsic product stability, whether the formulation may be subject to lyophilization, device
selection (e.g., liquid nebulizer, dry-powder inhaler, meter-dose inhaler), and/or packaging
form (e.g., simple liquid or complex liquid formulation, whether provided in a vial as a liquid
or as a lyophilisate to be dissolved prior to or upon insertion into the device; complex
suspension formulation whether provided in a vial as a liquid or as a lyophilisate, and with or
without a soluble salt/excipient component to be dissolved prior to or upon insertion into the
device, or separate packaging of liquid and solid components; dry powder formulations in a
vial, capsule or blister pack; and other formulations packaged as readily soluble or lowsolubility solid agents in separate containers alone or together with readily soluble or lowsolubility solid agents.
Packaged agents may be manufactured in such a way as to be provide a pirfenidone or
pyridone analog compound formulation composition for pulmonary delivery that comprises a
solution which is provided as a pirfenidone or pyridone analog compound aqueous solution
having a pH from about 3.0 to about 11.0, more preferably from about pH 4 to about pH 8, at
a concentration of at least 0.1 mg/mL to about 50 mg/mL, and having a total osmolality at
least 50 mOsmol/kg to about 1000 mOsmol/kg, more preferably 200 to about 500
mOsmol/kg.
In some embodiments, described herein is the aerosol and/or topical delivery of a
pyridone analog compound (e.g., pirfenidone). Pirfenidone has favorable solubility
characteristics enabling dosing of clinically-desirable levels by aerosol (e.g., through liquid
nebulization, dry powder dispersion or meter-dose administration) or topically (e.g., aqueous
suspension, oily preparation or the like or as a drip, spray, suppository, salve, or an ointment
or the like), and can be used in methods for acute or prophylactic treatment of a subject
having pulmonary fibrosis, or of a subject at risk for having pulmonary fibrosis. Clinical
criteria for determining when pulmonary fibrosis is present, or when a subject is at risk for
having pulmonary fibrosis, are known to the art. Pulmonary delivery via inhalation permits
direct and titrated dosing directly to the clinically-desired site with reduced systemic
exposure.
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In a preferred embodiment, the method treats or serves as prophylaxis against
interstitial lung disease (ILD) by administering a pirfenidone or pyridone analog compound
formulation as an aerosol (e.g., a suspension of liquid particles in air or another gas) to a
subject having or suspected to have interstitial lung disease. Interstitial lung disease includes
those conditions of idiopathic interstitial pneumonias as defined by American Thoracic
Society/European Respiratory Society international multidisciplinary concensus classification
of the idiopathic interstitial pneumonias, AM. J. Respir. Crit. Care Med. 165, 277-304 (2002).
These include ILD of known cause or association with connective tissue diseases,
occupational causes or drug side effect, idiopathic interstitial pneumonias (e.g. idiopathic
pulmonary fibrosis, non-specific interstitial pneumonia, desquamative interstitial pneumonia,
respiratory bronchiolitis-ILD, cryptogenic organizing pneumonia, acute interstitial
pneumonia and lyphocytic interstitial pneumonia), granulomatous lung disease (e.g.,
sarcodosis, hypersensitity pneumonitis and infection), and other forms of ILD (e.g.,
lymphangioleiomyomatosis, pulmonary Langerhans’ cell histocytosis, eosinophilic
pneumonia and pulmonary alveolar proteinosis).
The therapeutic method may also include a diagnostic step, such as identifying a
subject with or suspected of having ILD. In some embodiments, the method further subclassifies into idiopathic pulmonary fibrosis. In some embodiments, the delivered amount of
aerosol pirfenidone or pyridone analog compound (or salt thereof) formulation is sufficient to
provide acute, sub-acute, or chronic symptomatic relief, slowing of fibrosis progression,
halting fibrosis progression, reversing fibrotic damage, and/or subsequent increase in survival
and/or improved quality of life.
The therapeutic method may also include a diagnostic step, such as identifying a
subject with or suspected of having fibrosis in other tissues, by non-limiting example in the
heart, liver, kidney or skin. In some embodiments, the delivered amount of liquid nebulized,
dry powder or metered-dose aerosol pirfenidone or pyridone analog compound (or salt
thereof) formulation is sufficient to provide acute, sub-acute, or chronic symptomatic relief,
slowing of fibrosis progression, halting fibrosis progression, reversing fibrotic damage,
and/or subsequent increase in survival and/or improved quality of life.
The therapeutic method may also include a diagnostic step, such as identifying a
subject with or suspected of having multiple sclerosis. In some embodiments, the delivered
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amount of liquid nebulized, dry powder or metered-dose aerosol pirfenidone or pyridone
analog compound (or salt thereof) formulation is sufficient to provide acute, sub-acute, or
chronic symptomatic relief, slowing of demylination progression, halting demylination
progression, reversing demylinated damage, and/or subsequent increase in survival and/or
improved quality of life.
In another embodiment, liquid nebulized, dry powder or metered-dose aerosol
pirfenidone or pyridone analog compound (or salt thereof) may be co-administered,
administered sequentially or prepared in a fixed-combination with antimicrobial agents to
also provide therapy for a co-existing bacterial infection. By non-limiting example the
bacteria may be a gram-negative bacteria such as Pseudomonas aeruginosa, Pseudomonas
fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida,
Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia
coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi,
Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter
cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia
marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus
vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter
calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia
pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis,
Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,
Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi,
Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter
pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia
burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria
monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,
Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A
homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron,
Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus. In some
embodiments of the methods described above, the bacteria are gram-negative anaerobic
bacteria, by non-limiting example these include Bacteroides fragilis, Bacteroides distasonis,
Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides
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thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides
splanchnicus. In some embodiments of the methods described above, the bacteria are grampositive bacteria, by non-limiting example these include: Corynebacterium diphtheriae,
Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae,
Streptococcus pyogenes, Streptococcus milleri ; Streptococcus (Group G); Streptococcus
(Group C/F); Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus,
Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius,
Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis,
and Staphylococcus saccharolyticus. In some embodiments of the methods described above,
the bacteria are gram-positive anaerobic bacteria, by non-limiting example these include
Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum.
In some embodiments of the methods described above, the bacteria are acid-fast bacteria, by
non-limiting example these include Mycobacterium tuberculosis, Mycobacterium avium,
Mycobacterium intracellulare, and Mycobacterium leprae. In some embodiments of the
methods described above, the bacteria are atypical bacteria, by non-limiting example these
include Chlamydia pneumoniae and Mycoplasma pneumoniae.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts to produce and maintain threshold drug concentrations in
the lung and/or targeted downstream tissue, which may be measured as drug levels in
epithelial lining fluid (ELF), sputum, lung tissue, bronchial lavage fluid (BAL), or by
deconvolution of blood concentrations through pharmacokinetic analysis. One embodiment
includes the use of aerosol administration, delivering high or titrated concentration drug
exposure directly to the affected tissue for treatment of pulmonary fibrosis and inflammation
associated with ILD (including idiopathic pulmonary fibrosis), COPD and asthma in animals
and humans. In one such embodiment, the peak lung ELF levels achieved following aerosol
administration to the lung will be between 0.1 mg/mL and about 50 mg/mL pirfenidone or
pyridone analog. In another embodiment, the peak lung wet tissue levels achieved following
aerosol administration to the lung will be between 0.004 mcg/gram lung tissue and about 500
mcg/gram lung tissue pirfenidone or pyridone analog.
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As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid suspension or
liquid nebulized, dry powder and/or metered-dose inhaled aerosol administration to supply
effective concentrations or amounts to produce and maintain threshold drug concentrations in
the blood and/or lung, which may be measured as drug levels in epithelial lining fluid (ELF),
sputum, lung tissue, bronchial lavage fluid (BAL), or by deconvolution of blood
concentrations through pharmacokinetic analysis that absorb to the pulmonary vasculature
producing drug levels sufficient for extra-pulmonary therapeutics, maintenance or
prophylaxis. One embodiment includes the use of aerosol administration, delivering high
concentration drug exposure in the pulmonary vasculature and subsequent tissues and
associated vasculature for treatment, maintenance and/or prophylaxis of, but not limited to
cardiac fibrosis, kidney fibrosis, hepatic fibrosis, heart or kidney toxicity, or multiple
sclerosis. In one such embodiment, the peak tissue-specific plasma levels (e.g., heart, kidney
and liver) or cerebral spinal fluid levels (e.g. central nervous system) achieved following
aerosol administration to the lung following oral inhalation or to the lung or nasal cavity
following intra-nasal administration will be between 0.1 mcg/mL and about 50 mcg/mL
pirfenidone or pyridone analog. In another embodiment, the peak lung wet tissue levels
achieved following aerosol administration to the lung will be between 0.004 mcg/gram lung
tissue and about 500 mcg/gram lung tissue pirfenidone or pyridone analog.
In another embodiment, a method is provided for acute or prophylactic treatment of a
patient through non-oral or non-nasal topical administration of pirfenidone or pyridone
analog (or a salt thereof) compound formulation to produce and maintain threshold drug
concentrations at a burn site. One embodiment includes the use of aerosol administration,
delivering high concentration drug exposure directly to the affected tissue for treatment or
prevention of scarring in skin. For example according to these and related embodiments, the
term aerosol may include a spray, mist, or other nucleated liquid or dry powder form.
In another embodiment, a method is provided for acute or prophylactic treatment of a
patient through non-oral or non-nasal topical administration of pirfenidone or pyridone
analog (or a salt thereof) compound formulation to produce and maintain threshold drug
concentrations in the eye. One embodiment includes the use of aerosol administration or
formulation drops to deliver high concentration drug exposure directly to the affected tissue
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for treatment or prevention of scarring following surgical glaucoma surgery (e.g., bleb
fibrosis). For example according to these and related embodiments, the term aerosol may
include a spray, mist, or other nucleated liquid or dry powder form. A drop may be simple
liquid or suspension formulation.
In another embodiment, a pyridone analog compound as provided herein (e.g.,
pirfenidone) formulation by inhalation, wherein the inhaled liquid aerosol (e.g., following
liquid nebulization or metered-dose administration) or dry powder aerosol has a mean particle
size from about 1 micron to 10 microns mass median aerodynamic diameter and a particle
size geometric standard deviation of less than or equal to about 3 microns. In another
embodiment, the particle size is 2 microns to about 5 microns mass median aerodynamic
diameter and a particle size geometric standard deviation of less than or equal to about 3
microns. In one embodiment, the particle size geometric standard deviation is less than or
equal to about 2 microns.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone) remains at the therapeutically effective concentration at
the site of pulmonary pathology, suspected pulmonary pathology, and/or site of pulmonary
absorption into the pulmonary vasculature for at least about 1 minute, at least about a 5
minute period, at least about a 10 min period, at least about a 20 min period, at least about a
min period, at least about a 1 hour period, at least a 2 hour period, at least about a 4 hour
period, at least an 8 hour period, at least a 12 hour period, at least a 24 hour period, at least a
48 hour period, at least a 72 hour period, or at least one week. The effective pirfenidone or
pyridone analog concentration is sufficient to cause a therapeutic effect and the effect may be
localized or broad-acting to or from the site of pulmonary pathology.
As a non-limiting example, in a preferred embodiment, a pyridone analog compound
as provided herein (e.g., pirfenidone or salt thereof) following inhalation administration
remains at the therapeutically effective concentration at the site of cardiac fibrosis, kidney
fibrosis, hepatic fibrosis, heart or kidney toxicity, or multiple sclerosis demylination for at
least about 1 minute, at least about a 5 minute period, at least about a 10 min period, at least
about a 20 min period, at least about a 30 min period, at least about a 1 hour period, at least a
2 hour period, at least about a 4 hour period, at least an 8 hour period, at least a 12 hour
period, at least a 24 hour period, at least a 48 hour period, at least a 72 hour period, or at least
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one week. The effective pirfenidone or pyridone analog concentration is sufficient to cause a
therapeutic effect and the effect may be localized or broad-acting to or from the site of
extrapulmonary pathology.
In some embodiments, delivery sites such as a pulmonary site, the a pirfenidone or
pyridone analog compound formulation as provided herein is administered in one or more
administrations so as to achieve a respirable delivered dose daily of pirfenidone or pyridone
analog of at least about 0.1 mg to about 50 mg, including all integral values therein such as
0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50 milligrams. In some
embodiments, a pirfenidone or pyridone analog compound formulation as provided herein is
administered in one or more administrations so as to achieve a respirable delivered dose daily
of pirfenidone or pyridone analog of at least about 0.1 mg to about 300 mg, including all
integral values therein such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50,
55, 60, 65, 70, 75, 80, 85, 90, 95, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150,
155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240,
245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 milligrams. The pirfenidone or
pyridone analog formulation is administered in the described respirable delivered dose in less
than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20
minutes, less than 15 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes,
in less than 3 minutes, in less than 2 minutes, in less than 1 minute, 10 inhalation breaths, 8
inhalation breaths, 6 inhalation breaths, 4 inhalation breaths, 3 inhalation breaths, 2 inhalation
breaths or 1 inhalation breath. In some embodiments, pirfenidone or pyridone analog
formulation is administered in the described respirable delivered dose using a breathing
pattern of 1 second inhalation and 2 seconds exhalation, 2 seconds inhalation and 2 seconds
exhalation, 3 seconds inhalation and 2 seconds exhalation, 4 seconds inhalation and 2
seconds exhalation, 5 seconds inhalation and 2 seconds exhalation, 6 seconds inhalation and
2 seconds exhalation, 7 seconds inhalation and 2 seconds exhalation, and 8 seconds
inhalation and 2 seconds exhalation.
In some embodiments, delivery sites such as the nasal cavity or sinus, pirfenidone or
pyridone analog (or salt thereof) compound formulation is administered in one or more
administrations so as to achieve a nasal cavity or sinus deposited dose daily of pirfenidone or
pyridone analog of at least about 0.1 mg to about 50 mg, including all integral values therein
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such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50 milligrams. In some
embodiments, delivery sites such as the nasal cavity or sinus, pirfenidone or pyridone analog
(or salt thereof) compound formulation is administered in one or more administrations so as
to achieve a nasal cavity or sinus deposited dose daily of pirfenidone or pyridone analog of at
least about 0.1 mg to about 300 mg, including all integral values therein such as 0.1, 0.2, 0.4,
0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 95, 100,
105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190,
195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280,
285, 290, 295, 300 milligrams. The pirfenidone or pyridone analog formulation is
administered in the described nasal or sinus deposited dose in less than 20 minutes, less than
minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, in less than 3
minutes, in less than 2 minutes, in less than 1 minute, 10 intranasal inhalation breaths, 8
intranasal inhalation breaths, 6 intranasal inhalation breaths, 4 intranasal inhalation breaths, 3
intranasal inhalation breaths, 2 intranasal inhalation breaths or 1 intranasal inhalation breath.
In some embodiments, pirfenidone or pyridone analog formulation is administered in the
described respirable delivered dose using a breathing pattern of 1 second inhalation and 2
seconds exhalation, 2 seconds inhalation and 2 seconds exhalation, 3 seconds inhalation and
2 seconds exhalation, 4 seconds inhalation and 2 seconds exhalation, 5 seconds inhalation
and 2 seconds exhalation, 6 seconds inhalation and 2 seconds exhalation, 7 seconds
inhalation and 2 seconds exhalation, and 8 seconds inhalation and 2 seconds exhalation.
In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human with ILD. In
some embodiments, the method further sub-classifies into idiopathic pulmonary fibrosis. In
some embodiments of the methods describe above, the human subject may be mechanically
ventilated.
In embodiments where a human is mechanically ventilated, aerosol administration
would be performed using an in-line device (by non-limiting example, the Nektar Aeroneb
Pro) or similar adaptor with device for liquid nebulization. Aerosol administration could also
be performed using an in-line adaptor for dry powder or metered-dose aerosol generation and
delivery.
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In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human requiring cardiac
fibrosis therapy. In some embodiments of the methods describe above, the human subject
may be mechanically ventilated.
In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human requiring kidney
fibrosis therapy. In some embodiments of the methods describe above, the human subject
may be mechanically ventilated.
In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human requiring hepatic
fibrosis therapy. In some embodiments of the methods describe above, the human subject
may be mechanically ventilated.
In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human requiring cardiac
or kidney toxicity therapy. In some embodiments of the methods describe above, the human
subject may be mechanically ventilated.
In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human requiring COPD
therapy. In some embodiments of the methods describe above, the human subject may be
mechanically ventilated.
In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human requiring asthma
therapy. In some embodiments of the methods describe above, the human subject may be
mechanically ventilated.
In some embodiments of the methods described above, the subject is a human. In
some embodiments of the methods described above, the subject is a human requiring multiple
sclerosis therapy. In some embodiments of the methods describe above, the human subject
may be mechanically ventilated.
In another embodiment, a pharmaceutical composition is provided that includes a
simple liquid pirfenidone or pyridone analog (or salt thereof) compound formulation with
non-encapsulating water soluble excipients as described above having an osmolality from
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about 50 mOsmol/kg to about 6000 mOsmol/kg. In one embodiment, the osmolality is from
about 50 mOsmol/kg to about 1000 mOsmol/kg. In one embodiment, the osmolality is from
about 400 mOsmol/kg to about 5000 mOsmol/kg. In other embodiments the osmolality is
from about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 mOsmol/kg to about 1000, 1100,
1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2600, 2800, 3000, 3200,
3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800m 5000, 5200, 5400, 5600, 5800 and 6000
mOsmol/kg. With respect to osmolality, and also elsewhere in the present application,
“about” when used to refer to a quantitative value means that a specified quantity may be
greater than or less than the indicated amount by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19 or 20 percent of the stated numerical value.
In another embodiment, a pharmaceutical composition is provided that includes a
simple liquid pirfenidone or pyridone analog (or salt thereof) compound formulation having a
permeant ion concentration between from about 30 mM to about 300 mM and preferably
between from about 50mM to 200 mM. In one such embodiment, one or more permeant ions
in the composition are selected from the group consisting of chloride and bromide.
In another embodiment, a pharmaceutical composition is provided that includes a
complex liquid pirfenidone or pyridone analog (or salt thereof) compound formulation
encapsulated or complexed with water soluble excipients such as lipids, liposomes,
cyclodextrins, microencapsulations, and emulsions) as described above having a solution
osmolality from about 50 mOsmol/kg to about 6000 mOsmol/kg. In one embodiment, the
osmolality is from about 50 mOsmol/kg to about 1000 mOsmol/kg. In one embodiment, the
osmolality is from about100 mOsmol/kg to about 500 mOsmol/kg. In one embodiment, the
osmolality is from about 400 mOsmol/kg to about 5000 mOsmol/kg.
In another embodiment, a pharmaceutical composition is provided that includes a
complex liquid pirfenidone or pyridone analog (or salt thereof) compound formulation having
a permeant ion concentration from about 30 mM to about 300 mM. In one such embodiment,
one or more permeant ions in the composition are selected from the group consisting of
chloride and bromide.
In another embodiment, a pharmaceutical composition is provided that includes a
complex liquid pirfenidone or pyridone analog (or salt thereof) compound formulation having
a permeant ion concentration from about 50 mM to about 200 mM. In one such embodiment,
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one or more permeant ions in the composition are selected from the group consisting of
chloride and bromide.
In another embodiment, a pharmaceutical composition is provided that includes a
simple liquid formulation of pirfenidone or pyridone analog (or salt thereof) compound
formulation having a prifenidone or pyridone analog to multivalent cation positive charge
molar ratio between about two pirfenidone or pyridone analog compounds to about 0.1 to
about 4 multivalent cation positive charges. By non-limiting example, two pirfenidone or
pyridone analog compounds to one magnesium ion (two cation positive charges), three
prifenidone or pyridone analog compounds to one magnesium ions, four pirfenidone or
pyridone analog compounds to one magnesium ions, and two pirfenidone or pyridone analog
compounds to two magnesium ions.
An unexpected finding was that divalent cations, by non-limiting example
magnesium, reduced pirfenidone dissolution time and increased pirfenidone aqueous
solubility in a molar ratio-dependent manner. This increased saturation solubility is enabling
to deliver predicted-sufficient quantities of inhaled liquid-nebulized pirfenidone to the lung.
By example, one pirfenidone molecules to three magnesium molecules exhibited a slower
dissolution time and reduced saturation solubility than one pirfenidone molecule to one
magnesium molecule. Moreover, one pirfenidone molecules to one magnesium molecule
exhibited a faster dissolution time and greater aqueous solubility than an equal-molar ratio of
pirfenidone to sodium.
In another embodiment, a pharmaceutical conmposition is provided that includes a
complex liquid formulation of pirfenidone or pyridone analog (or salt thereof) compound
formulation having a prifenidone or pyridone analog to to about 0.1 to about 4 multivalent
cation positive charges. By non-limiting example, two pirfenidone or pyridone analog
compounds to one magnesium ion (two cation positive charges), three prifenidone or
pyridone analog compounds to one magnesium ions, four pirfenidone or pyridone analog
compounds to one magnesium ions, and two pirfenidone or pyridone analog compounds to
two magnesium ions.
In another embodiment, a pharmaceutical composition is provided that includes a
complex liquid pirfenidone or pyridone analog (or salt thereof) compound formulation as a
low water-soluble stable nanosuspension alone or in co-crystal/co-precipitate complexes, or
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mixtures with low solubility lipids, such as lipid nanosuspensions) as described above having
a solution osmolality from about 50 mOsmol/kg to about 6000 mOsmol/kg. In one
embodiment, the osmolality is from about 100 mOsmol/kg to about 500 mOsmol/kg. In one
embodiment, the osmolality is from about 400 mOsmol/kg to about 5000 mOsmol/kg.
In another embodiment, a pharmaceutical composition is provided that includes a
complex suspension of a pirfenidone or pyridone analog (or salt thereof) compound
formulation having a permeant ion concentration from about 30 mM to about 300 mM. In
one such embodiment, one or more permeant ions in the composition are selected from the
group consisting of chloride and bromide.
In another embodiment, a pharmaceutical composition is provided that includes a
complex suspension of a pirfenidone or pyridone analog (or salt thereof) compound
formulation having a permeant ion concentration from about 50 mM to about 200 mM. In
one such embodiment, one or more permeant ions in the composition are selected from the
group consisting of chloride and bromide.
In another embodiment, a pharmaceutical composition is provided that includes a
complex suspension of pirfenidone or pyridone analog (or salt thereof) compound
formulation having a pirfenidone or pyridone analog to multivalent cation positive charge
molar ratio between about one pirfenidone or pyridone analog compounds to about 0.1 to
about 4 multivalent cation positive charges. By non-limiting example, two pirfenidone or
pyridone analog compounds to one magnesium ion (two cation positive charges), three
prifenidone or pyridone analog compounds to one magnesium ions, four pirfenidone or
pyridone analog compounds to one magnesium ions, and two pirfenidone or pyridone analog
compounds to two magnesium ions.
In other embodiments, a pirfenidone or pyridone analog (or salt thereof) compound
formulation as provided herein, or a pharmaceutical composition, is provided that includes a
taste-masking agent. As non-limiting examples, a taste-masking agent may include a sugar,
saccharin (e.g., sodium saccharin), sweetener or other compound or agent that beneficially
affects taste, after-taste, perceived unpleasant saltiness, sourness or bitterness, or that reduces
the tendency of an oral or inhaled formulation to irritate a recipient (e.g., by causing coughing
or sore throat or other undesired side effect, such as may reduce the delivered dose or
adversely influence patient compliance with a prescribed therapeutic regimen). Certain taste-
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masking agents may form complexes with a pirfenidone or pyridone analog (or salt thereof)
compound.
In certain preferred embodiments that relate to the pirfenidone or pyridone analog (or
salt thereof) compound formulations disclosed herein, the formulation comprises a
pirfenidone or pyridone analog (or salt thereof) compound and a taste-masking agent and
may be optimized with respect to a desired osmolality, and/or an optimized permeant ion
concentration. In certain such embodiments, the taste-masking agent comprises saccharin
(e.g., sodium saccharin), which according to non-limiting theory affords certain advantages
associated with the ability of this taste-masking agent to provide desirable taste effects even
when present in extremely low concentrations, such as may have little or no effect on the
detectable osmolality of a solution, thereby permitting the herein described formulations to
deliver aqueous solutions, organic or dry powder formulations in a well-tolerated manner. In
certain such embodiments, the taste-masking agent comprises a chelating agent (e.g., EDTA
or divalent cation such as magnesium), which according to non-limiting theory affords
certain advantages associated with the ability of this taste-masking agent to provide desirable
taste effects by masking taste-stimulating chemical moieties on pirfenidone of pyridone
analog. With divalent cations, inclusion as a taste-masking agent may also substitute as an
osmolality adjusting agent, and pending the salt form may also provide the permeant ion (e.g.
magnesium chloride), thereby permitting the herein described formulations to deliver
aqueous solutions, organic or dry powder formulations in a well-tolerated manner. Nonlimiting examples of these and related embodiments include a pirfenidone or pyridone analog
(or salt thereof) compound formulation for pulmonary delivery as described herein that
comprises an aqueous solution having a pH of from about 4 to about 8 and an osmolality of
from about 50 to about 1000 mOsmol/kg (e.g., adjusted with sodium chloride), the solution
comprising pirfenidone or pyridone analog (or salt thereof) compound and sodium saccharin
where the aqueous solution contains from about 0.1 mM to about 2.0 mM saccharin. A
related non-limiting example further comprises citrate (e.g., citric acid) in an aqueous
solution containing from about 1 mM to about 100 mM citrate. A related non-limiting
example further comprises or replace citrate with phosphate (e.g., sodium phosphate) in an
aqueous solution containing from about 0.0 mM to about 100 mM phosphate. Another related
non-limiting example further comprises or replace citrate with phosphate (e.g., sodium
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phosphate) in an aqueous solution containing from about 0.5 mM to about 100 mM
phosphate. By another non-limiting examples, these and related embodiments include a
pirfenidone or pyridone analog (or salt thereof) compound formulation for pulmonary
delivery as described herein that comprises an aqueous solution having a pH of from about 4
to about 8 and an osmolality of from about 50 to about 5000 mOsmol/kg (e.g., adjusted with
magnesium chloride), the solution comprising pirfenidone or pyridone analog (or salt thereof)
compound, wherein a divalent cation (e.g., berilium, magnesium, or calcium) serves both to
adjust osmolality and as a taste-masking agent. Where included as a taste-masking agent,
divalent cation (e.g., magnesium) is added stoichiometrically with pirfenidone or pyridone
analog. By example, 1 mol divalent ion to 2 mols pirfenidone or pyridone analog, 1.5 mols
divalent ion to 2 mols pirfenidone or pyridone analog, 2 mols divalent ion to 2 mols
pirfenidone or pyridone analog, 3 mols divalent ion to 2 mols pirfenidone or pyridone analog,
or 4 mols divalent ion to 2 mols pirfenidone or pyridone analog. Where osmolality required
further increase sodium chloride or additional divalent salt may be used. A related non15 limiting example further comprises citrate (e.g., citric acid) in an aqueous solution containing
from about 1 mM to about 100 mM citrate. A related non-limiting example citrate is
replaced with phosphate (e.g., sodium phosphate) in an aqueous solution containing from
about 0.0 mM to about 100 mM phosphate. In another related non-limiting example citrate is
replaced with phosphate (e.g., sodium phosphate) in an aqueous solution containing from
about 0.0 mM to about 100 mM phosphate.
In another embodiment, while the inclusion of the correct molar ratio of magnesium
to pirfenidone reduces dissolution time and increases saturation solubility to a level required
for sufficient liquid nebulization delivery to the lung, an unexpected finding was that this
formulation additionally requires a taste masking agent for acute tolerability upon inhalation
of a nebulized solution. To this end, between 0.1 and 1.0 micromolar saccharin enables the
use of this solubility-enabling formulation.
In another embodiment, a pharmaceutical composition may be protected from light to
avoid photodegradation. By non-limiting example, this may occur by light-protected vials,
ampoules, blisters, capsules, or other colored or light-protected primary packaging. By
another non-limiting example, this may occur by use of secondary packaging such as an
aluminum or other light-protected over-pouch, box or other secondary packaging.
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In another embodiment, a pharmaceutical composition may be protected from oxygen
to protect from oxidation. By non-limiting example, in solution this may occur by removing
oxygen from solution prior to or during compounding (e.g., sparging), and or controlled the
primary packaging head-space gas (e.g. using of inert gas such as argon or nitrogen in the
head space). Similarly, by another non-limiting example, controlling the included secondary
packaging gas (e.g. with inert gas) may also be required. For powder formulations this may
be controlled by use of insert gas in primary and/or secondary packaging. Meter-dose
inhaled products may benefit by the same means as described above for solution products.
In another embodiment, pirfenidone or pyridone analog present in a pharmaceutical
composition may be protected from hydrolysis by inclusion of a cationic metal ion. By nonlimiting example, acid hydrolysis of amide bonds decreases with an increased salt
concentration. Specifically, hydration number is important for this rate decrease, as
electrolyte hydration decreases the availability of free water for the reaction. Thus, the rate
decreases with increased salt and increased hydration number. The order of increasing
hydration number: potassium < sodium < lithium < magnesium. The rate decrease also
nearly parallels ionic strength. By non-limiting example, the addition of magnesium will
stabilize the 2-pyridone structure of pirfenidone. It is known that pirfenidone chelates Fe(III)
at a ratio of 3 pirfenidone molecules to 1 Fe(III). From this it follows that pirfenidone will
chelate magnesium at 2 pirfenidone molecules to 1 magnesium +2 charge. Therefore, for this
purpose the addition of magnesium or other cationic metal ion may be stoichiometric to the
amount of pirfenidone or pyridone analog. By non-limiting example, 2 pirfenidone
molecules to 0.1 magnesium molecules, 2 pirfenidone molecules to 0.25 magnesium
molecules, 2 pirfenidone molecules to 0.5 magnesium molecules, 2 pirfenidone molecules to
0.75 magnesium molecules, 2 pirfenidone molecules to 1 magnesium molecules, 2
pirfenidone molecules to 1.5 magnesium molecules, 2 pirfenidone molecules to 2 magnesium
molecules, 2 pirfenidone molecules to 3 magnesium molecules, 2 pirfenidone molecules to 4
magnesium molecules, 2 pirfenidone molecules to 5 magnesium molecules, 2 pirfenidone
molecules to 6 magnesium molecules, 2 pirfenidone molecules to 7 magnesium molecules, 2
pirfenidone molecules to 8 magnesium molecules, 2 pirfenidone molecules to 9 magnesium
molecules, 2 pirfenidone molecules to 10 magnesium molecules, 2 pirfenidone molecules to
12 magnesium molecules, 2 pirfenidone molecules to 14 magnesium molecules, 2
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pirfenidone molecules to 16 magnesium molecules, 2 pirfenidone molecules to 18
magnesium molecules, or 2 pirfenidone molecules to 20 magnesium molecules. Potassium,
sodium, lithium or iron may substitute for magnesium in these ratios and pharmaceutical
composition. Included in the above pharmaceutical composition is the maintenance of the
buffers described herein, at a pH from about 4.0 to about 8.0, and include MgCl2 or cationic
salt thereof at a level that provides an osmolality of 300 mOsmo/kg and 600 mOsmo/kg.
While 300 mOsmo/kg is discussed in the literature as important for acute tolerability upon
inhalation of this in a nebulized solution, 600 mOsmo/kg has been shown in unpublished
studies to be well tolerated with other drug solutions. However, a final solution osmolality up
to 6000 mOsmo/kg is contemplated. Unexpectantly, formulations described herein
demonstrate good tolerability at high osmolalities.
In another embodiment, a pharmaceutical composition of liquid pirfenidone or
pyridone analog may contain a solubility enhancing agent or co-solvent. By non-limiting
example, these may include ethanol, cetylpridinium chloride, glycerin, lecithin, propylene
glycol, polysorbate (including polysorbate 20, 40, 60, 80 and 85), sorbitan triolate, and the
like. By further example, cetylpridinium chloride may be used from about 0.01 mg/mL to
about 4 mg/mL pharmaceutical composition. Similarly, by another non-limiting example,
ethanol may be used from about 0.01% to about 30% pharmaceutical composition. Similarly,
by another non-limiting example, glycerin may be used from about 0.01% to about 25%
pharmaceutical composition. Similarly, by another non-limiting example, lecithin may be
used from about 0.01% to about 4% pharmaceutical composition. Similarly, by another nonlimiting example, propylene glycol may be used from about 0.01% to about 30%
pharmaceutical composition. Similarly, by another non-limiting example, polysorbates may
also be used from about 0.01% to about 10% pharmaceutical composition. Similarly, by
another non-limiting example, sorbitan triolate may be used from about 0.01% to about 20%
pharmaceutical composition.
In another embodiment, a pharmaceutical composition of liquid or dry powder
pirfenidone or pyridone analog may contain a chelated metal ion to assist in solubility and/or
dissolution of pirfenidone or pyridone analog. By non-limiting example, these may include
iron, magnesium, or calcium.
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In another embodiment, a pharmaceutical composition of liquid or dry powder
pirfenidone or pyridone analog may contain a chelated metal ion to assist in scavenging
reactive oxygen species. By non-limiting example, these may include iron, magnesium, or
calcium. By non-limiting example, for this purpose the addition of magnesium or other
cationic metal ion may be stoichiometric to the amount of pirfenidone or pyridone analog.
By non-limiting example, 2 pirfenidone molecules to 0.1 magnesium molecules, 2
pirfenidone molecules to 0.25 magnesium molecules, 2 pirfenidone molecules to 0.5
magnesium molecules, 2 pirfenidone molecules to 0.75 magnesium molecules, 2 pirfenidone
molecules to 1 magnesium molecules, 2 pirfenidone molecules to 1.5 magnesium molecules,
2 pirfenidone molecules to 2 magnesium molecules, 2 pirfenidone molecules to 3 magnesium
molecules, 2 pirfenidone molecules to 4 magnesium molecules, 2 pirfenidone molecules to 5
magnesium molecules, 2 pirfenidone molecules to 6 magnesium molecules, 2 pirfenidone
molecules to 7 magnesium molecules, 2 pirfenidone molecules to 8 magnesium molecules, 2
pirfenidone molecules to 9 magnesium molecules, 2 pirfenidone molecules to 10 magnesium
molecules, 2 pirfenidone molecules to 12 magnesium molecules, 2 pirfenidone molecules to
14 magnesium molecules, 2 pirfenidone molecules to 16 magnesium molecules, 2
pirfenidone molecules to 18 magnesium molecules, or 2 pirfenidone molecules to 20
magnesium molecules. Potassium, sodium, lithium or iron may substitute for magnesium in
these ratios and pharmaceutical composition. Included in the above pharmaceutical
composition is the maintenance of the buffers described herein, at a pH from about 4.0 to
about 8.0, and include MgCl2 or cationic salt thereof at a level that provides an osmolality of
300 mOsmo/kg and 600 mOsmo/kg. While 300 mOsmo/kg is discussed in the literature as
important for acute tolerability upon inhalation of this in a nebulized solution, 600 mOsmo/kg
has been shown in unpublished studies to be well tolerated with other drug solutions.
However, a final solution osmolality up to 5000 mOsmo/kg is contemplated.
In some embodiments, described herein is a pharmaceutical composition that
includes: pirfenidone; water; phosphate buffer or citrate buffer; and optionally sodium
chloride or magnesium chloride. In other embodiments, described herein is a pharmaceutical
composition that includes: pirfenidone; water; a buffer; and at least one additional ingredient
selected from sodium chloride, magnesium chloride, ethanol, propylene glycol, glycerol,
polysorbate 80, and cetylpyridinium bromide (or chloride). In some embodiments, the buffer
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is phosphate buffer. In other embodiments, the buffer is citrate buffer. In some
embodiments, the pharmaceutical composition includes 1 mg to 500 mg of pirfenidone, for
example, 5 mg, 10 mg, 15 mg, 25 mg, 37.5 mg, 75 mg, 100 mg, 115 mg, 150 mg, 190 mg,
220 mg, or 500 mg. In some embodiments, the osmolality of the pharmaceutical composition
described herein is between about 50 mOsmo/kg to 6000 mOsmo/kg. In some embodiments,
the pharmaceutical composition optionally includes saccharin (e.g. sodium salt). Nonlimiting examples of pharmaceutical compositions described herein include any one of the
pharmaceutical compositions described in Tables 1-1 to Table 1-11 of Example 1.
Solutions of pirfenidone should remain protected from light as the API in solution is
subject to degradation
In another embodiment, a pharmaceutical composition is provided that includes a
simple dry powder pirfenidone or pyridone analog (or salt thereof) compound alone in dry
powder form with or without a blending agent such as lactose.
In another embodiment, the pharmaceutical composition used in a liquid, dry powder
or meter-dose inhalation device is provided such that pirfenidone or pyridone analog is not in
a salt form.
In another embodiment, a pharmaceutical composition is provided that includes a
complex dry powder pirfenidone or pyridone analog (or salt thereof) compound formulation
in co-crystal/co-precipitate/spray dried complex or mixture with low water soluble
excipients/salts in dry powder form with or without a blending agent such as lactose.
In another embodiment, a system is provided for administering a pirfenidone or
pyridone analog (or salt thereof) compound that includes a container comprising a solution of
a pirfenidone or pyridone analog (or salt thereof) compound formulation and a nebulizer
physically coupled or co-packaged with the container and adapted to produce an aerosol of
the solution having a particle size from about 1 microns to about 5 microns mean mass
aerodynamic diameter, volumetric mean diameter (VMD) or mass median diameter (MMD)
and a particle size geometric standard deviation of less than or equal to about 2.5 microns
mean mass aerodynamic diameter. In one embodiment, the particle size geometric standard
deviation is less than or equal to about 3.0 microns. In one embodiment, the particle size
geometric standard deviation is less than or equal to about 2.0 microns.
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In another embodiment, a system is provided for administering a pirfenidone or
pyridone analog (or salt thereof) compound that includes a container comprising a dry
powder of a pirfenidone or pyridone analog (or salt thereof) compound and a dry powder
inhaler coupled to the container and adapted to produce a dispersed dry powder aerosol
having a particle size from about 1 microns to about 5 microns mean mass aerodynamic and a
particle size standard deviation of less than or equal to about 3.0 microns. In one
embodiment, the particle size standard deviation is less than or equal to about 2.5 microns. In
one embodiment, the particle size standard deviation is less than or equal to about 2.0
microns.
In another embodiment, a kit is provided that includes a container comprising a
pharmaceutical formulation comprising a pirfenidone or pyridone analog (or salt thereof)
compound and an aerosolizer adapted to aerosolize the pharmaceutical formulation (e.g., in
certain preferred embodiments, a liquid nebulizer) and deliver it to the lower respiratory tract,
for instance, to a pulmonary compartment such as alveoli, alveolar ducts and/or bronchioles,
following intraoral administration. The formulation may also be delivered as a dry powder or
through a metered-dose inhaler.
In another embodiment, a kit is provided that includes a container comprising a
pharmaceutical formulation comprising a pirfenidone or pyridone analog (or salt thereof)
compound and an aerosolizer adapted to aerosolize the pharmaceutical formulation (e.g., in
certain preferred embodiments, a liquid nebulizer) and deliver it to a nasal cavity following
intranasal administration. The formulation may also be delivered as a dry powder or through
a metered-dose inhaler.
It should be understood that many carriers and excipients may serve several functions,
even within the same formulation.
Contemplated pharmaceutical compositions provide a therapeutically effective
amount of pirfendione or pyridone analog compound enabling, for example, once-a-day,
twice-a-day, three times a day, etc. administration. In some embodiments, pharmaceutical
compositions for inhaled delivery provide an effective amount of pirfendione or pyridone
analog compound enabling once-a-day dosing. In some embodiments, pharmaceutical
compositions for inhaled delivery provide an effective amount of pirfendione or pyridone
analog compound enabling twice-a-day dosing. In some embodiments, pharmaceutical
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compositions for inhaled delivery provide an effective amount of pirfendione or pyridone
analog compound enabling three times-a-day dosing.
It is to be understood that both the foregoing general description and the following
detailed description are exemplary and explanatory only and are not restrictive of the
invention, as claimed.
Certain Terminology
The term “mg” refers to milligram.
The term “mcg” refers to microgram.
The term “microM” refers to micromolar.
The term “QD” refers to once a day dosing.
The term “BID” refers to twice a day dosing.
The term “TID” refers to three times a day dosing.
The term “QID” refers to four times a day dosing.
As used herein, the term “about” is used synonymously with the term
“approximately.” Illustratively, the use of the term “about” with regard to a certain
therapeutically effective pharmaceutical dose indicates that values slightly outside the cited
values, .e.g., plus or minus 0.1% to 10%, which are also effective and safe.
As used herein, the terms “comprising,” “including,” “such as,” and “for example” are
used in their open, non-limiting sense.
The terms “administration” or “administering” and “delivery” or “delivery” refer to a
method of giving to a mammal a dosage of a therapeutic or prophylactic formulation, such as
a pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, for
example as an anti-inflammatory, anti-fibrotic and/or anti-demylination pharmaceutical
composition, or for other purposes. The preferred delivery method or method of
administration can vary depending on various factors, e.g., the components of the
pharmaceutical composition, the desired site at which the formulation is to be introduced,
delivered or administered, the site where therapeutic benefit is sought, or the proximity of the
initial delivery site to the downstream diseased organ (e.g., aerosol delivery to the lung for
absorption and secondary delivery to the heart, kidney, liver, central nervous system or other
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diseased destination). In some embodiments, pharmaceutical compositions described herein
are administered by pulmonary administration.
The terms “pulmonary administration” or “inhalation” or “pulmonary delivery” or
“oral inhalation” or “intranasal inhalation” and other related terms refer to a method of giving
to a mammal a dosage of a therapeutic or prophylactic formulation, such as a pirfenidone or
pyridone analog (or salt thereof) compound formulation described herein, by a route such that
the desired therapeutic or prophylactic agent is delivered to the lungs of a mammal. Such
delivery to the lung may occur by intranasal administration, oral inhalation administration.
Each of these routes of administration may occur as inhalation of an aerosol of formulations
described herein. In some embodiments, pulmonary administration occurs by passively
delivering an aerosol described herein by mechanical ventilation.
The terms “intranasal inhalation administration” and “intranasal inhalation delivery”
refer to a method of giving to a mammal a dosage of a pirfenidone or pyridone analog (or salt
thereof) compound formulation described herein, by a route such that the formulation is
targeting delivery and absorption of the therapeutic formulation directly in the lungs of the
mammal through the nasal cavity. In some embodiments, intranasal inhalation administration
is performed with a nebulizer.
The terms “intranasal administration” and “intranasal delivery” refer to a method of
giving to a mammal a dosage of a therapeutic or prophylactic formulation, such as a
pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, by a
route such that the desired therapeutic or prophylactic agent is delivered to the nasal cavity or
diseased organs downstream (e.g., aerosol delivery to the nasal cavity for absorption and
secondary delivery to the central nervous system or other diseased destination). Such
delivery to the nasal cavity may occur by intranasal administration, wherein this route of
administration may occur as inhalation of an aerosol of formulations described herein,
injection of an aerosol of formulations described herein, gavage of a formulation described
herein, or passively delivered by mechanical ventilation.
The terms “intraoccular administration” and “intraoccular delivery” refer to a method
of giving to a mammal a dosage of a therapeutic or prophylactic formulation, such as a
pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, by a
route such that the desired therapeutic or prophylactic agent is delivered to the eye. Such
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delivery to the eye may occur by direct administration to the eye. This route of
administration may occur as spray of an aerosol of formulations described herein, injection of
an aerosol of formulations described herein, or drops of a formulation described herein.
“Oral administration” or “orally” or “oral” is a route of administration where a
substance (e.g. a pharmaceutical composition) is taken through the mouth. In some
embodiments, when it is used without any further descriptors, it refers to administration of a
substance through the mouth and directly into the gastrointestinal tract. Oral administration
generally includes a number of forms, such as tablets, pills, capsules, and solutions.
The terms “oral inhalation administration” or “oral inhalation delivery” or “oral
inhalation” refer to a method of giving to a mammal a dosage of a pirfenidone or pyridone
analog (or salt thereof) compound formulation described herein, through the mouth for
delivery and absorption of the formulation directly to the lungs of the mammal. In some
embodiments, oral inhalation administration is carried out by the use of a nebulizer.
The term “abnormal liver function” may manifest as abnormalities in levels of
biomarkers of liver function, including alanine transaminase, aspartate transaminase,
bilirubin, and/or alkaline phosphatase, and may be an indicator of drug-induced liver injury.
See FDA Draft Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical
Evaluation, October 2007.
"Grade 2 liver function abnormalities" include elevations in alanine transaminase
(ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyl
transferase (GGT) greater than 2.5-times and less than or equal to 5-times the upper limit of
normal (ULN). Grade 2 liver function abnormalities also include elevations of bilirubin levels
greater than 1.5-times and less than or equal to 3-times the ULN.
“Gastrointestinal adverse events” include but are not limited to any one or more of the
following: dyspepsia, nausea, diarrhea, gastroesophageal reflux disease (GERD) and
vomiting.
A “carrier” or “excipient” is a compound or material used to facilitate administration
of the compound, for example, to increase the solubility of the compound. Solid carriers
include, e.g., starch, lactose, dicalcium phosphate, sucrose, and kaolin. Liquid carriers
include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil,
peanut and sesame oils. In addition, various adjuvants such as are commonly used in the art
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may be included. These and other such compounds are described in the literature, e.g., in the
Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various
components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.)
(1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed.,
Pergamon Press.
A “diagnostic” as used herein is a compound, method, system, or device that assists in
the identification and characterization of a health or disease state. The diagnostic can be used
in standard assays as is known in the art.
“Patient” or “subject” are used interchangeably and refer to a mammal.
The term “mammal” is used in its usual biological sense. In some embodiments, a
mammal is a human.
The term “ex vivo” refers to experimentation or manipulation done in or on living
tissue in an artificial environment outside the organism.
The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable
excipient” includes any and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the like. The use of such
media and agents for pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the active ingredient, its use
in the therapeutic compositions is contemplated. Supplementary active ingredients can also
be incorporated into the compositions.
The term “pharmaceutically acceptable salt” refers to salts that retain the biological
effectiveness and properties of the compounds disclosed herein and, which are not
biologically or otherwise undesirable. In many cases, the compounds described herein are
capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl
groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids. Inorganic acids from which salts can be
derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like. Organic acids from which salts can be derived include, for
example, acetic acid, propionic acid, naphtoic acid, oleic acid, palmitic acid, pamoic (emboic)
acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic
acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, glucoheptonic acid, glucuronic
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acid, lactic acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic
bases. Inorganic bases from which salts can be derived include, for example, sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,
aluminum, and the like; particularly preferred are the ammonium, potassium, sodium,
calcium and magnesium salts. Organic bases from which salts can be derived include, for
example, primary, secondary, and tertiary amines, substituted amines including naturally
occurring substituted amines, cyclic amines, basic ion exchange resins, and the like,
specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine,
tripropylamine, histidine, arginine, lysine, benethamine, N-methyl-glucamine, and
ethanolamine. Other acids include dodecylsufuric acid, naphthalene-1,5-disulfonic acid,
naphthalenesulfonic acid, and saccharin.
The term “pH-reducing acid” refers to acids that retain the biological effectiveness
and properties of the compounds described herein and, which are not biologically or
otherwise undesirable. Pharmaceutically acceptable pH-reducing acids include, for example,
inorganic acids such as, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like. Also by nonlimiting example, pH-reducing acids may also
include organic acids such as citric acid, acetic acid, propionic acid, naphtoic acid, oleic acid,
palmitic acid, pamoic (emboic) acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid,
glucoheptonic acid, glucuronic acid, lactic acid, lactobioic acid, tartaric acid, benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like.
According to certain herein disclosed embodiments a pirfenidone or a pyridone
analog compound formulation may comprise an “acidic excipient” that is typically present as
an acidic excipient aqueous solution. Examples of may include acid salts such as phosphate,
sulphate, nitrate, acetate, formate, citrate, tartrate, propionate and sorbate, organic acids such
as carboxylic acids, sulfonic acids, phosphonic acids, phosphinic acids, phosphoric
monoesters, and phosphoric diesters, and/or other organic acids that contain from 1 to 12
carbon atoms, citric acid, acetic acid, formic acid, propionic acid, butyric acid, benzoic acid,
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mono-, di-, and trichloroacetic acid, salicylic acid, trifluoroacetic acid, benzenesulfonic acid,
toluenesulfonic acid, methylphosphonic acid, methylphosphinic acid, dimethylphosphinic
acid, and phosphonic acid monobutyl ester.
A “buffer” refers to a compound that functions to regulate pH. In certain related
embodiments the pH buffer is present under conditions and in sufficient quantity to maintain
a pH that is “about” a recited pH value. “About” such a pH refers to the functional presence
of that buffer, which, as is known in the art, may be a consequence of a variety of factors
including pKa value(s) of the buffer, buffer concentration, working temperature, effects of
other components of the composition on pKa (i.e., the pH at which the buffer is at
equilibrium between protonated and deprotonated forms, typically the center of the effective
buffering range of pH values), and other factors.
Hence, “about” in the context of pH may be understood to represent a quantitative
variation in pH that may be more or less than the recited value by no more than 0.5 pH units,
more preferably no more than 0.4 pH units, more preferably no more than 0.3 pH units, still
more preferably no more than 0.2 pH units, and most preferably no more than 0.1-0.15 pH
units. As also noted above, in certain embodiments a substantially constant pH (e.g., a pH
that is maintained within the recited range for an extended time period) may be from about
pH 4.0 to about pH 8.0, from about pH 4.0 to about pH 7.0, or from about pH 4.0 to about pH
6.8, or any other pH or pH range as described herein, which in preferred embodiments may
be from about pH 4.0 to about pH 8.0 for a pirfenidone or pyridone analog compound
formulation, and greater than about pH 8.0 for a pirfenidone or pyridone analog compound
aqueous solution.
Therefore the pH buffer typically may comprise a composition that, when present
under appropriate conditions and in sufficient quantity, is capable of maintaining a desired
pH level as may be selected by those familiar with the art, for example, buffers comprising
citrate, formate, malate, formate, pyridine, piperazine, succinate, histidine, maleate, bis-Tris,
pyrophosphate, PIPES, ACES, histidine, MES, cacodylic acid, H2CO3 / NaHCO3 and N-(2-
Acetamido)iminodiacetic acid (ADA) or other buffers for maintaining, preserving,
enhancing, protecting or otherwise promoting desired biological or pharmacological activity
of a pirfenidone or pyridone analog compound, based on the disclosure herein. Suitable
buffers may include those in Table 1 or known to the art (see, e.g., Calbiochem®
106
Biochemicals & Immunochemicals Catalog 2004/2005, pp. 68-69 and catalog pages cited
therein, EMD Biosciences, La Jolla, CA).
Non-limiting examples of buffers that may be used according to certain embodiments
disclosed herein, include but are not limited to formate (pKa 3.77), Citric acid (pKa2 4.76),
Malate (pKa2 5.13), Pyridine (pKa 5.23), Piperazine ((pKa1) 5.33), Succinate ((pKa2)
.64), Histidine (pKa 6.04), Maleate ((pKa2) 6.24), Citric acid ((pKa3) 6.40), Bis-Tris
(pKa 6.46), Pyrophosphate ((pKa3) 6.70), PIPES (pKa 6.76), ACES (pKa 6.78), Histidine
(pKa 6.80), MES (pKa 6.15), Cacodylic acid (pKa 6.27), H2CO3 / NaHCO3 (pKa1) ( 6.37),
ADA (N-(2-Acetamido)iminodiacetic acid) (pKa 6.60). In some embodiments,
pharmaceutical compositions disclosed herein include a citrate buffer or a phosphate buffer.
In some embodiments, pharmaceutical compositions disclosed herein include a citrate buffer.
In some embodiments, pharmaceutical compositions disclosed herein include a phosphate
buffer.
“Solvate” refers to the compound formed by the interaction of a solvent and
pirfenidone or a pyridone analog compound, a metabolite, or salt thereof. Suitable solvates
are pharmaceutically acceptable solvates including hydrates.
By “therapeutically effective amount” or “pharmaceutically effective amount” is
meant pirfenidone or a pyridone analog compound, as disclosed herein, which has a
therapeutic effect. The doses of pirfenidone or a pyridone analog compound which are useful
in treatment are therapeutically effective amounts. Thus, as used herein, a therapeutically
effective amount means those amounts of pirfenidone or a pyridone analog compound which
produce the desired therapeutic effect as judged by clinical trial results and/or model animal
pulmonary fibrosis, cardiac fibrosis, kidney fibrosis, hepatic fibrosis, heart or kidney toxicity,
multiple sclerosis, COPD or asthma. In particular embodiments, the pirfenidone or pyridone
analog compounds are administered in a pre-determined dose, and thus a therapeutically
effective amount would be an amount of the dose administered. This amount and the amount
of the pirfenidone or pyridone analog compound can be routinely determined by one of skill
in the art, and will vary, depending on several factors, such as the therapeutic or prophylactic
effect for fibrotic, inflammatory or demylination injury occurs, and how distant that disease
site is from the initial respiratory location receiving the initial inhaled aerosol dose. This
amount can further depend upon the patient’s height, weight, sex, age and medical history.
107
For prophylactic treatments, a therapeutically effective amount is that amount which would
be effective to prevent a fibrotic, inflammatory or demylination injury.
A “therapeutic effect” relieves, to some extent, one or more of the symptoms
associated with inflammation, fibrosis and/or demylination. This includes slowing the
progression of, or preventing or reducing additional inflammation, fibrosis and/or
demylination. For IPF, a “therapeutic effect” is defined as a patient-reported improvement in
quality of life and/or a statistically significant increase in or stabilization of exercise tolerance
and associated blood-oxygen saturation, reduced decline in baseline forced vital capacity,
decreased incidence in acute exacerbations, increase in progression-free survival, increased
time-to-death or disease progression, and/or reduced lung fibrosis. For cardiac fibrosis, a
"therapeutic effect" is defined as a patient-reported improvement in quality of life and/or a
statistically significant improvement in cardiac function, reduced fibrosis, reduced cardiac
stiffness, reduced or reversed valvular stenosis, reduced incidence of arrhythmias and/or
reduced atrial or ventricular remodeling. For kidney fibrosis, a "therapeutic effect" is defined
as a patient-reported improvement in quality of life and/or a statistically significant
improvement in glomular filtration rate and associated markers. For hepatic fibrosis, a
“therapeutic effect” is defined as a patient-reported improvement in quality of life and/or a
statistically significant lowering of elevated aminotransferases (e.g., AST and ALT), alkaline
phosphatases, gamma-glutamyl transferase, bilirubin, prothrombin time, globulins, as well as
reversal of thromobocytopenia, leukopenai and neutropenia and coagulation defects. Further
a potential reversal of imaging, endoscopic or other pathological findings. For COPD, a
"therapeutic effect" is defined as a patient-reported improvement in quality of life and/or a
statistically significant improved exercise capacity and associated blood-oxygen saturation,
FEV1 and/or FVC, a slowed or halted progression in the same, progression-free survival,
increased time-to-death or disease progression, and/or reduced incidence or acute
exacerbation. For asthma, a "therapeutic effect" is defined as a patient-reported improvement
in quality of life and/or a statistically significantly improved exercise capacity, improved
FEV1 and/or FVC, and/or reduced incidence or acute exacerbation. For multiple sclerosis, a
"therapeutic effect" is defined as a patient-reported improvement in quality of life and/or a
statistically significantly improved Scripps Neurological Rating Scale score, improvement in
108
bladder dysfunction, improved Disability Status Socres, MRI lesion count, and/or an slowed
or halted progression of disease.
“Treat,” “treatment,” or “treating,” as used herein refers to administering a
pharmaceutical composition for therapeutic purposes. In some embodiments, treating refers
to alleviating, abating or ameliorating at least one symptom of a disease or condition,
preventing any additional symptoms from arising, arresting the progression of at least one
current symptom of the disease or condition, relieving at least one of the symptoms of a
disease or condition, causing regression of the disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the disease or condition. In
some embodiments, the compositions described herein are used for prophylactic treatment.
The term “prophylactic treatment” refers to treating a patient who is not yet diseased but who
is susceptible to, or otherwise at risk of, a particular disease, or who is diseased but whose
condition does not worsen while being treated with the pharmaceutical compositions
described herein. The term “therapeutic treatment” refers to administering treatment to a
patient already suffering from a disease. Thus, in preferred embodiments, treating is the
administration to a mammal (either for therapeutic or prophylactic purposes) of
therapeutically effective amounts of pirfenidone or a pyridone analog compound.
“Treat,” “treatment,” or “treating,” as used herein refers to administering a
pharmaceutical composition for prophylactic and/or therapeutic purposes. The term
“prophylactic treatment” refers to treating a patient who is not yet diseased, but who is
susceptible to, or otherwise at risk of, a particular disease. The term “therapeutic treatment”
refers to administering treatment to a patient already suffering from a disease. Thus, in
preferred embodiments, treating is the administration to a mammal (either for therapeutic or
prophylactic purposes) of therapeutically effective amounts of pirfenidone or a pyridone
analog compound.
The term “dosing interval” refers to the time between administrations of the two
sequential doses of a pharmaceutical’s during multiple dosing regimens.
The “respirable delivered dose” is the amount of aerosolized pirfenidone or a
pyridone analog compound particles inhaled during the inspiratory phase of the breath
simulator that is equal to or less than 5 microns.
109
“Lung Deposition” as used herein, refers to the fraction of the nominal dose of an
active pharmaceutical ingredient (API) that is deposited on the inner surface of the lungs.
“Nominal dose,” or “loaded dose” refers to the amount of drug that is placed in the
nebuluzer prior to administration to a mammal. The volume of solution containing the
nominal dose is referred to as the “fill volume.”
“Enhanced pharmacokinetic profile” means an improvement in some pharmacokinetic
parameter. Pharmacokinetic parameters that may be improved include, AUClast, AUC(0-∞)
Tmax, and optionally a Cmax. In some embodiments, the enhanced pharmacokinetic profile
may be measured quantitatively by comparing a pharmacokinetic parameter obtained for a
nominal dose of an active pharmaceutical ingredient (API) administered with one type of
inhalation device with the same pharmacokinetic parameter obtained with oral administration
of a composition of the same active pharmaceutical ingredient (API).
"Blood plasma concentration" refers to the concentration of an active pharmaceutical
ingredient (API) in the plasma component of blood of a subject or patient population.
“Respiratory condition,” as used herein, refers to a disease or condition that is
physically manifested in the respiratory tract, including, but not limited to, pulmonary
fibrosis, chronic obstructive pulmonary disease (COPD), bronchitis, chronic bronchitis,
emphysema, or asthma.
"Nebulizer," as used herein, refers to a device that turns medications, compositions,
formulations, suspensions, and mixtures, etc. into a fine mist or aerosol for delivery to the
lungs. Nebulizers may also be referred to as atomizers.
"Drug absorption" or simply "absorption" typically refers to the process of movement
of drug from site of delivery of a drug across a barrier into a blood vessel or the site of action,
e.g., a drug being absorbed in the pulmonary capillary beds of the alveoli.
Pirfenidone and Pyridone Analog Compounds
As also noted elsewhere herein, in preferred embodiments the pyridone compound for
use in a pyridone compound formulation as described herein comprises pirfenidone (5-
methylphenyl(1H)-pyridone) or a salt thereof. Although various embodiments are
described with the use of pirfenidone, it is noted that other pyridone analog compounds, or
salts thereof, may be used in place of pirfenidone.
110
Pirfenidone is also known as 5-methylphenyl(1H)-pyridone and has the
structure:
“Pyridone analog” or “pyridone compound” refers to compounds that have the same
type of biological activity and effectiveness as pirfenidone. Such pyridone analog
compounds are those that upon administration to a mammal produce anti-inflammatory, anti10 fibrotic and/or anti-demylination activity for therapeutic or prophylactic purposes. In some
embodiments, a pyridone analog is a compound that has a substituted 2-(1H)pyridone or 3-
(1H)pyridone core structure. In some embodiments, a pyridone analog is a compound that
has a substituted 2-(1H)pyridone core structure.
1-Phenyl(1H)pyridone, 5-methyl(4-methylphenyl)(1H)-pyridone, 5-methyl15 1-(4-hydroxyphenyl)(1H)-pyridone, 5-methyl(4-methoxyphenyl)(1H)-pyridone, 5-
Methyl(2'-pyridyl)(1H)pyridone, 6-Methylphenyl(1H)pyridone, 6-Methyl
phenyl(1H)pyridone, 5-Methylp-tolyl(1H)pyridone, 5-Methylphenyl(2'-
thienyl)(1H)pyridone, 5-Methyl(2'-naphthyl)- 3-(1H)pyridone, 5-Methyl(2'-
naphthyl)(1H)pyridone, 5-Methylphenyl(1H)pyridone, 5-Methylp-tolyl
(1H)pyridone, 5-Methyl(1'naphthyl)(1H)pyridone, 5-Methyl(5'-quinolyl)
(1H)pyridone, 5-Ethylphenyl(1H)pyridone, 5-Ethylphenyl(1H)pyridone, 5-
Methyl(5'-quinolyl)(1H)pyridone, 5-Methyl(4'- methoxyphenyl)(1H)pyridone, 5-
Methyl(4'-quinolyl)(1H)pyridone, 4-Methylphenyl(1H)pyridone, 5-Methyl(4'-
pyridyl)(1H)pyridone, 5-Methyl(3'-pyridyl)(1H)pyridone, 3-Methylphenyl
(1H)pyridone, 5-Methyl(4'-methoxyphenyl)(1H)pyridone, 5-Methyl(2'-Thienyl)
(1H)pyridone, 5-Methyl(2'-pyridyl) (1H)pyridone, 1,3-Diphenyl(1H)pyridone, 1,3-
Diphenylmethyl (1H)pyridone, 5-Methyl(2'-quinolyl) (1H)pyridone, 5-Methyl
(3'- trifluoromethylphenyl)(1H)pyridone, 1-Phenyl(1H)pyridone, 1-(2'-Furyl)methyl3- (1H)-pyridone, 3-Ethylphenyl(1H)pyridone, 1-(4'-Chlorophenyl)methyl30 (1H)pyridone, 5-Methyl(3'-pyridyl)3-(1H)pyridone, 5-Methyl(3-nitrophenyl)
(1H)pyridone, 3-(4'-Chlorophenyl)Methylphenyl(1H)pyridone, 5-Methyl(2'-
N
O
111
Thienyl) (1H)pyridone, 5-Methyl(2'-thiazolyl) (1H)pyridone, 3,6-Dimethyl
phenyl (1H)pyridone, 1-(4'Chlorophenyl)Methyl- 2-(1H)pyridone, 1-(2'-Imidazolyl)
Methyl- 2-(1H)pyridone, 1-(4'-Nitrophenyl) (1H)pyridone, 1-(2'-Furyl)Methyl
(1H)pyridone, 1-Phenyl(4'-chlorophenyl)- 2-(1H)pyridone.
In some embodiments, a pyridone analog compound is a compound described in US
patent publication no. US20090005424; US patent publication no. 20070092488; US Patent
8,022,087; US Patent 6,090,822; US Patent 5,716,632; US Patent 5,518,729; US Patent
,310,562; US Patent 4,052,509; US Patent 4,042,699; US Patent 3,839,346; or US Patent
3,974,281.
In some embodiments, a pyridone analog is a deuterated pirfenidone compound,
where 1 or more hydrogen atoms of pirfenidone are replced with deuterium.
According to certain other distinct embodiments of the compositions and methods
described herein, the pyridone compound is selected from the group consisting of bis(2-
hydroxyethyl)azanium; 2-(3,5-diiodooxopyridinyl)acetate, propyl 2-(3,5-diiodo
oxopyridinyl)acetate, 2-[3-[4-(3-chlorophenyl)piperazinyl]propyl] [1,2,4]triazolo[4,3-
a]pyridinone hydrochloride, 2-[3-[4-(3-chlorophenyl)piperazinyl]propyl]-
[1,2,4]triazolo[4,3-a]pyridinone, 3-anilinophenylpropanone, 2-[3-[4-(3-
chlorophenyl)piperazinyl]propyl]-[1,2,4]triazolo[4,3-a]pyridinone hydrochloride, 2-[3-
[4-(3-chlorophenyl)piperazinyl]propyl]-[1,2,4]triazolo[4,3 a]pyridinone, 2S)amino20 3-(3-hydroxyoxopyridinyl)propanoic acid, 2-[3-[4 (3-chlorophenyl)piperazin
yl]propyl]-[1,2,4]triazolo[4,3-a]pyridinone, 2-[3-[4-(3-chlorophenyl)piperazin
yl]propyl]-[1,2,4]triazolo[4,3-a]pyridinone hydrochloride, 2-[3-[4-(3-
chlorophenyl)piperazinyl]propyl]-[1,2,4]triazolo[4,3-a]pyridinone hydrochloride, (2S)-
2-[(3-hydroxyoxopyridinyl)amino] propanoic acid, 2-[3-[4-(3 chlorophenyl)piperazin25 1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridinone hydrochloride, 2-amino(3-hydroxy
oxopyridinyl)propanoic acid, 2-[3-[4-(3chlorophenyl)piperazin yl]propyl]-
[1,2,4]triazolo[4,3-a]pyridinone hydrochloride, propyl 2-(3,5-diiodooxopyridin
yl)acetate, 2-(3,5-diiodooxopyridinyl)acetic acid; 2-(2 hydroxyethylamino)ethanol,
(2S)amino(3-hydroxyoxopyridinyl)propanoic acid, (2R)amino(3-hydroxy30 4-oxopyridinyl)propanoic acid, 2-amino(3-hydroxyoxopyridinyl)propanoic acid,
-cyanomethyl-N-[4 (methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
112
dihydropyridinecarboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]nitrooxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-(1-butoxyvinyl)methyl-N-
[4-(methylsulfonyl)benzyl]ox o[3-(trifluoromethyl) phenyl]-1,2-dihydropyridine
carbox amide, 5-acetylmethyl-N-[4-(methyl sulfonyl)benzyl]oxo[3-(t
rifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-[(1E)-Nmethoxyethanimidoyl]methyl-N-[4-(methylsulfonyl )benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyri dinecarboxamide, 5-[(1E)-Nhydroxyethanimidoyl]methyl-N-[4-(methylsulfonyl )benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyri dinecarboxamide, 6-methyl-N-[4-
(methylsulfonyl)benzyl]oxo(pyridinyle thynyl)[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridine carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]oxo(2-
pyridiny lethyl)[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine carboxamide, 6-
methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-(trifluorom ethyl)phenyl]vinyl-1,2-
dihydropyridinecarboxamide, ethyl 2-methyl({[4(methylsulfonyl)benzyl]amino}
carbonyl)oxo [3-(trifluoromethyl)phenyl]-1,6-dihydropyridinecarboxy late, 5-(4-
methanesulfonyl-benzylcarbamoyl)methyloxo(3-trifluoromethyl-phenyl)-1,6-
dihydro-pyridinecarboxylic acid, 6-methyloxo(3-trifluoromethyl-phenyl)-1,2-
dihydro-pyri dine-3,5-dicarboxylic acid 5-dimethylamide 3-(4-methanesulfonylbenzylamide), 6-methyloxo(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-
dicarboxylic acid 5-amide 3-(4-methanesulfonyl-benzylamide), 6-methyloxo(3-
trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-methanesulfonylbenzylamide)5-methylamide, 6-methyloxo(3-trifluoromethyl-phenyl)-1,2-dihydropyridine-3,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-methyl-amide]3-(4-methanesulfonylbenzy lamide), 6-methyloxo(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-
dicarboxylic acid 3-(4-methanesulfonyl-benzylamide)5-(methyl-propyl-amide), 6-methyl
oxo(pyrrolidinecarbonyl)(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-
dicarboxylic acid 3-(4-methanesulfonyl-benzylamide), 6-methyloxo(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-[(2-dimethylamino-ethyl)-methylamide]3-(4-methanesulfonyl -benzylamide), 5-((2R)hydroxymethyl-pyrrolidine
carbonyl)methyloxo(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridinecarboxylic
acid 3-(4-methanesulfonyl-benzylamide), 5-(3-hydroxy-pyrrolidinecarbonyl)methyl
113
oxo(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-
methanesulfonyl-benzylamide), N 3 -[(1,1-dioxido-2,3-dihydrobenzothienyl)methyl]-N
,N 5 ,6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
dicarboxamide, 5-(N 1 -acetyl-hydrazinocarbonyl)methyloxo(3-trifluo romethylphenyl)-1,2-dihydro-pyridinecarboxylic acid 4-methanesulfonyl-benzylamide, 5-[N 1 5 -(2-
cyano-acetyl)-hydrazinocarbonyl]methyloxo (3-trifluoromethyl-phenyl) -1,2-
dihydro-pyridinecarboxylic acid 4-methanesulfonyl-benzylamide, 5-{[2-
(aminocarbonothioyl)hydrazino]carbonyl}methyl-N-[4- (methylsulfonyl)benzyl]oxo
[3-(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-hydrazinocarbonyl
methyloxo(3-trifluoromethyl-phen yl)-1,2-dihydro-pyridine carboxylic acid 4-
methanesulfonyl-benzylamide, 5-({2-[(ethylamino)carbonyl]hydrazino}carbonyl)methylN-[ 4-(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl ]-1,2-dihydropyridine
carboxamide, 5-({2-[(N,N-dimethylamino)carbonyl]hydrazino}carbonyl)methyl-N-[4-
(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl )phenyl]-1,2-dihydropyridine
carboxamide, 5-(3,3-dimethyl-ureido)methyloxo(3-trifluoromethyl- phenyl)-1,2-
dihydro-pyridine carboxylic acid 4-methanesulfonyl-benzylamide, 6-methyl(3-methylureido)oxo(3-trifluoromethyl-phen yl)-1,2-dihydro-pyridinecarboxylic acid 4-
methanesulfonyl-benzylamide, 6-methyloxo(3-trifluoromethyl-phenyl)ureido-1,2-
dih ydro-pyridinecarboxylic acid 4-methanesulfonyl-benzylamide, 5-aminomethyl
oxo(3-trifluoromethyl-phenyl)-1,2-dihy dro-pyridinecarboxylic acid 4-
methanesulfonyl-benzylamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]oxopropionyl
[3 -(trifluoromethyl) phenyl]-1,2-dihydropyridinecarboxamide, 5-formylmethyl-N-[4-
(methyl sulfonyl)benzyl]oxo[3-(t rifluoromethyl)phenyl]-1,2-dihydropyridine
carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]oxo(3-oxobutyl)-1 -[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-acetyl-N-[4-
(isopropylsulfonyl)benzyl]methyloxo[3 -(trifluoromethyl)phenyl]-1,2-
dihydropyridinecarboxamide, 5-acetyl(3-cyano-phenyl)methyloxo-1,2-dihydropyrid inecarboxylic acid 4-methanesulfonyl-benzylamide, 5-acetyl(3-chloro-phenyl)
methyloxo-1,2-dihydro-pyridinecarboxylic acid 4-methanesulfonyl-benzylamide, 5-
acetylmethyloxom-tolyl-1,2-dihydro-pyridinecarboxylic acid 4-methanesulfonylbenzylamide, 5-(1-hydroxyethyl)methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-
114
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-(1-azidoethyl)methyl-N-
[4-(methylsulfonyl) benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine
carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl](1-morpholinyleth yl)oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridine- 3-carboxamide, 5-(1-hydroxypropyl)
methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridinecarb oxamide, 5-(1-hydroxyethyl)-N-[4-(isopropylsulfonyl) benzyl]
methyloxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, N-[4-
(cyclopropylsulfonyl)benzyl]formylmethyloxo 1-[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridinecarboxamide, 5-[(E)-(methoxyimino) methyl]methyl-N-[4-
(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridi ne
carboxamide, 5-(hydroxymethyl)methyl-N-[4-(methyl sulfonyl)benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarbox amide, 5-[(dimethylamino)methyl]
methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridine- 3-carboxamide, 6-methyl[(methylamino)methyl]-N-[4-
(methylsulfonyl)benzyl ]oxo 1-[3-(trifluoromethyl) phenyl]-1,2-dihydropyridine
carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl](morpholinylmethy l)oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-{[(2-
furylmethyl)amino]methyl}methyl-N-[4-(methylsulfon yl)benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropy ridinecarboxamide, 5-
[(cyclopropylamino)methyl]methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-{[(2-hydroxypropyl)
amino]methyl}methyl-N-[4-(methylsulf onyl)benzyl]oxo[3-(trifluoromethyl)
phenyl]-1,2-dihydropyridinecarboxamide, 5-[(cyclopentylamino) methyl]methyl-N-[4-
(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine
carboxamide, 5-{[(2-hydroxyethyl)(methyl)amino]methyl}methyl-N-[4-(met
hylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine
carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]oxo(pyrrolidinylmethyl)[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-
{[methoxy(methyl)amino]methyl}methyl-N-[4-(methylsulfonyl) benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-
{[(cyanomethyl)amino]methyl}methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-
115
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-{[(cyclopropylmethyl
)amino]methyl}methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)
phenyl]-1,2-dihydropyridinecarboxamide, 5-[(3-hydroxypyrrolidinyl)methyl]methylN-[4-(methylsu lfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihyd ropyridine
carboxamide, 5-(2-hydroxyethoxy)-N-[4-(isopropylsulfonyl)benzyl]methyl oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 2-methyl({[4-
(methylsulfonyl)benzyl]amino} carbonyl)oxo[3-(trifluoromethyl) phenyl]-1,6-
dihydropyridinyl acetate, 5-methoxymethyl-N-[4-(methylsulfonyl) benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-(3-methoxypropoxy)
methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridinecar boxamide, 2-methyl({[4-(methylsulfonyl)benzyl]amino}carbonyl)-
6-oxo[3-(trifluoromethyl)phenyl]-1,6-dihydropyridinyl methanesulfonate, 5-ethoxy
methyl-N-[4-(methylsulfonyl) benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridinecarboxamide, 5-(2-hydroxyethoxy)methyl-N-[4-
(methylsulfonyl)benzyl]oxo[3-(trifluoro methyl)phenyl]-1,2-dihydropyridine
carboxamide, 5-(cyanomethoxy)methyl-N-[4-(methylsulfonyl)benzyl]oxo [3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 2-({2-methyl({[4-
(methylsulfonyl) benzyl]amino}carbonyl)-6 -oxo[3-(trifluoromethyl)phenyl]-1,6-
dihydropyridinyl}oxy)ethyl acetate, 5-[2-(dimethylamino)oxoethoxy]methyl-N-[4-
(methylsulfo nyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine
carboxamide, 5-(2-aminoethoxy)-N-[4-(isopropylsulfonyl)benzyl]methyl-2 -oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-(acetylamino)methyl-N-
[4-(methylsulfonyl) benzyl]oxo- 1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine
carboxamide, N-[4-(isopropylsulfonyl)benzyl]methyl[3-(methylamino)p ropoxy]
oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyrid inecarboxamide, 5-(1-methoxyethyl)-
6-methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridinecarboxamide, 5-(2-bromomethoxyethyl)methyl-N-[4-
(methylsulfonyl)ben zyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine
carboxamide, 5-(1-isopropoxyethyl)methyl-N-[4-(methylsulfonyl)benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-(N 1 30 -isobutyrylhydrazinocarbonyl)methyloxo(3-tri fluoromethyl-phenyl)-1,2-dihydro-pyridine
116
carboxylic acid 4-methanesulfonyl-benzylamide, N 5 -methoxymethyl-N 3 -[4-
(methylsulfonyl)benzyl]oxo[3-(trifluoromethy l)phenyl]-1,2-dihydro pyridine-3,5-
dicarboxamide, N 5 -methoxy-N 5 ,6-dimethyl-N 3 -[4-(methylsulfonyl) benzyl]oxo[3-
(trifluoromethy l)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, 5-[(2,5-dimethyl-2,5-
dihydro-1H-pyrrolyl)carbonyl]methyl-N-[4-(methyl sulfonyl)benzyl]oxo[3-
(trifluoromethyl) phenyl]-1,2-dihydropyridinecarboxamide, 6-methyl-N 3 -[4-
(methylsulfonyl)benzyl]oxo-N 5 -pyrrolidinyl[3-(trifluoromethyl)phenyl]-1,2-dih
ydropyridine-3,5-dicarboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]oxo(piperidin1-ylcarbonyl)[3-(trifluoromethyl) phenyl]-1,2-dihydropyridine carboxamide, 6-methylN 3 -[4-(methylsulfonyl) benzyl]-N 5 10 -morpholinyloxo[3-(trifluoromethyl) phenyl]-1,
2-dihydro pyridine-3,5-dicarboxamide, 6-methyl[(4-methylpiperidinyl)carbonyl]-N-[4-
(methylsu lfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihyd ropyridine
carboxamide, 6-methyl-N 3 -[4-(methylsulfonyl)benzyl]oxo-N 5 -piperidinyl[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 -(tert-butyl)-N 5 ,6-
dimethyl-N 3 15 -[4-(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 5 -butyl-N 5 ,6-dimethyl-N 3 -[4-
(methylsulfonyl)benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
dicarboxamide, N 5 -ethyl-N 5 -isopropylmethyl-N 3 -[4-(methylsulfonyl) benzyl]oxo
[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, 5-[N 1 -(formyl20 hydrazinocarbonyl]methyloxo(3-triflu oromethyl-phenyl)-1,2-dihydro-pyridine
carboxylic acid 4-methanesulfonyl-benzylamide, N 1 -[5-(4-methanesulfonylbenzylcarbamoyl)methyloxo(3-trifluoromethyl-phenyl) -1,6-dihydro-pyridine
carbonyl]-hydrazinecarboxylic acid ethyl ester, 5-({2-[(ethylamino)carbonothioyl]
hydrazino}carbonyl)methy l-N-[4-(methylsulfonyl) benzyl]oxo[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridinecarboxamide, 5-(isoxazolidinylcarbonyl)-
6-methyl-N-[4-(methylsulfonyl) benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-
dihydropyridinecarboxamide, 6-methyloxo(3-trifluoromethyl-phenyl)-1,2-dihydropyridine-3,5-dicarboxylic acid 5-(methoxy-methyl-amide)3-[4-(propanesulfonyl)-
benzylamide], 6-methyloxo(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-
dicarboxylic acid 3-(4-ethanesulfonyl-benzylamide)5-(methoxy-methyl-amide), 6-methyl
oxo(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-
117
cyclopropanesulfonyl-benzylamide)5-(methoxy-methyl-amide), 6-methyloxo(3-
trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-
amide]3-(4-methanesulfonyl-benzylamide, 5-(isoxazolidinecarbonyl)methyloxo
(3-trifluorome thyl-phenyl)1,2-dihydro-pyridine carboxylic acid 4-ethanesulfonyl5 benzylamide, 5-(isoxazolidinecarbonyl)methyloxo(3-trifluorome thylphenyl)
1,2dihydropyridinecarboxylic acid 4-cyclopropane sulfonylbenzylamide, 5-(Nhydroxycarbamimidoyl)methyloxo(3-trifluoro methyl-phenyl)-1,2-dihydro-pyridine
carboxylic acid 4-methanesulfonyl-benzylamide, N 3 -(cyclohexylmethyl)-N 5 ,N 5 ,6-
trimethyloxo[3-(trifluoro methyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N 5
,N 5 ,6-trimethyloxo-N 3 10 -(pyridinylmethyl)[3-(trifluoromethyl)-phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-N 3 -(2-morpholinylethyl)oxo1-[3-(trifluoromethyl)- phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethylN 3 -(3-morpholinylpropyl)oxo[3-(trifluoromethyl) -phenyl]-1,2-dihydropyridine3,5-dicarboxamide, N 3 -benzyl-N 5 ,N 5 ,6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-
d ihydro-pyridine-3,5-dicarboxamide, N 3 -[2-(1H-indolyl)ethyl]-N 5 ,N 5 15 ,6-trimethyl
oxo[3-(trifluoromethyl)-phenyl]-1,2- dihydro pyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-
trimethyloxo-N 3 -(1-phenylethyl)[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
dicarboxamide, N 5 ,N 5 ,6-trimethyloxo-N 3 -(2-phenylethyl)[3-
(trifluoromethyl)phenyl]-1,2-dih ydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl
oxo-N 3 20 -[(2R)phenylcyclopropyl][3-(trifluoromethyl)-phe nyl]-1,2-dihydropyridine3,5-dicarboxamide, N 3 -(2,3-dihydro-1H-indenyl)-N 5 ,N 5 ,6-trimethyloxo[3-
(trifluoromethyl)-phenyl]-1,2- dihydropyridine-3,5-dicarboxamide, N 3 -[2-(1,3-benzodioxol5-yl)ethyl]-N 5 ,N 5 ,6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine3,5-dicarboxamide, 5-{[4-(2-hydroxyethyl)piperazinyl]carbonyl}-N,N,2-trimethyloxo1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3 –carboxamide, N 3 25 -[(1-ethylpyrrolidin2-yl)methyl]-N 5 ,N 5 ,6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-N 3 -[3-(2-methylpiperidinyl)propyl]oxo[3-
(triflu oromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-N 3 -
(1-naphthylmethyl) oxo[3-(trifluoromethyl)phenyl ]-1,2-dihydropyridine-3,5-
dicarboxamide, N 3 -(1,3-benzodioxolylmethyl)-N 5 ,N 5 30 ,6-trimethyloxo[3-
(trifluoromethyl) phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N 3 -(3,4-difluorobenzyl)-
118
N 5 ,N 5 , 6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-
dicarboxamide, N 3 -(2-chlorofluorobenzyl)-N 5 ,N 5 ,6-trimethyloxo[3-
(trifluoromethyl)-phenyl]-1,2- dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl
oxo-N 3 -(2-thienylmethyl)[3-(trifluoromethyl)phenyl]-1,2-dihydro pyridine-3,5-
dicarboxamide, N 3 -(3,4-dichlorobenzyl)-N 5 ,N 5 5 ,6-trimethyloxo[3-
(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N 3 -[2-(2,4-
dichlorophenyl)ethyl]-N 5 ,N 5 ,6-trimethyloxo[3-(trifluoromethyl)-phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 3 -(2-cyclohexenylethyl)-N 5 ,N 5 ,6-trimethyl
oxo[3-(trifluoromethyl)-phenyl]-1,2- dihydropyridine-3,5-dicarboxamide, N 3 -[1-(4-
chlorophenyl)ethyl]-N 5 ,N 5 10 ,6-trimethyloxo[3-(trifluoromethyl)-phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyloxo-N 3 -[3-(2-oxopyrrolidin
yl)propyl][3-(trifluoromethy l)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-
trimethyloxo-N 3 -(pyridinylmethyl)[3-(trifluoromethyl)phenyl]-1, 2-
dihydropyridine-3,5-dicarboxamide, N,N,2-trimethyloxo[(4-phenylpiperazin
yl)carbonyl]-1 -[3-(trifluoromethyl) phenyl]-1,6-dihydropyridinecarboxamide, N,N,2-
trimethyloxo[(4-pyridinylpiperazinyl)carbo nyl][3-(trifluoromethyl)phenyl]-
1,6-dihydropyridinecar boxamide, N 3 -(2,3-dihydrobenzofuranylmethyl)-N 5 ,N 5 ,6-
trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide,
methyl 4-{[({5-[(dimethylamino)carbonyl]methyloxo[3-(trifluoromethyl)phenyl]-
1,2-dihydropyridinyl}carbonyl)amino]me thyl}benzoate, 5-{[3-(dimethylamino)
pyrrolidinyl]carbonyl}-N,N,2-trimeth yloxo[3-(trifluoromethyl)phenyl]-1,6-
dihydropyridinecarboxamide, N 5 ,N 5 ,6-trimethyloxo-N 3 -[2-(2-thienyl)ethyl][3-
(trifluoromethyl)phenyl]-1, 2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl
oxo-N 3 -(4-phenoxybenzyl)[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-
dicarboxamide, N 5 ,N 5 ,6-trimethyloxo-N 3 25 -(3-thienylmethyl)[3-
(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N 3 -[2-(4-tertbutylphenyl)ethyl]-N 5 ,N 5 ,6-trimethyloxo[3-(trifluoromethyl)-phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 3 -{2-[4-(aminosulfonyl)phenyl]ethyl}-N 5 ,N 5 ,6-
trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N 5
,N 5 ,6-trimethyloxo-N 3 30 -[4-(1H-pyrazolyl)benzyl][3-(trifluoromethyl)-phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyloxo-N 3 -phenoxy[3-
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(trifluoromethyl)phenyl]-1,2-dihydro-pyr idine -3,5-dicarboxamide, N 3 -(2,3-dihydro-1,4-
benzodioxinylmethyl)-N 5 ,N 5 ,6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-d
ihydropyridine-3,5-dicarboxamide, N 3 -[(6-fluoro-4H-1,3-benzodioxinyl)methyl]-N 5 ,N 5
,6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N
3 -(1-benzothienylmethyl)-N 5 ,N 5 5 ,6-trimethyloxo[3-(trifluoromethyl)-phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyloxo-N 3 -[2-(tetrahydro-2Hpyranyl)ethyl][3-(trifluorome thyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5
,N 5 ,6-trimethyl-N 3 -[(1-methyl-1H-pyrazolyl)methyl]oxo[3-(triflu
oromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyloxo-N 3 -
[(1-phenyl-1H-pyrazolyl)methyl][3-(trifluoromet hyl)phenyl]-1,2-dihydropyridine-3,5-
dicarboxamide, N 3 -[(5-methoxyoxo-4H-pyranyl)methyl]-N 5 ,N 5 ,6-trimethyloxo
[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N 3 -(3-azepan
ylpropyl)-N 5 ,N 5 ,6-trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-
dicarboxamide, N 3 -(4-cyanobenzyl)-N 5 ,N 5 ,6-trimethyloxo[3-
(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, N 5 ,N 5 15 ,6-trimethyl
oxo-N 3 -[3-(5-oxo-4,5-dihydro-1H-pyrazolyl)propyl][3-(t rifluoromethyl)phenyl]-1,2-
dihydropyridine-3,5-dicarboxamide, N 3 -{[(2R)ethylpyrrolidinyl]methyl}-N 5 ,N 5 ,6-
trimethyloxo[3-(trifluoromethyl)phenyl]-1,2-d ihydropyridine-3,5-dicarboxamide, 5-
cyclopropylmethyl-N-[4-(methylsulfonyl)benzyl]oxo [3-(trifluoromethyl) phenyl]-
1,2-dihydropyridinecarboxamide, 6-methyl(2-methyl-1,3-dioxolanyl)-N-[4-
(methylsulfonyl )benzyl]oxo[3-(trifluoromethyl)phenyl]-1,2-dihydro pyridine
carboxamide, 5-(4,5-dihydro-oxazolyl)methyloxo(3-trifluoromethyl-phenyl)-1,2-
dihydro-pyridinecarboxylic acid 4-methanesulfonyl-benzylamide, 5-cyclopropyl
methyl-N-{[5-(methylsulfonyl)pyridinyl]methyl}oxo[3-(trifluoromethyl)phenyl]-
1,2-dihydropyridinecarboxamide, 2-amino(3-hydroxyoxopyridinyl)propanoic
acid, (2S)amino(3-hydroxyoxopyridinyl)propanoic acid, 2-amino(3-hydroxy4-oxopyridinyl)propanoic acid, (2S)amino(3-hydroxyoxopyridinyl)propanoic
acid, 2-amino(3-hydroxyoxopyridinyl)propanoic acid, 2-amino(3-hydroxy
oxopyridinyl)propanoic acid, propyl 2-(3,5-diiodooxopyridinyl)acetate, (2S)
azaniumyl(3-hydroxyoxopyridinyl)propanoate, propyl 2-(3,5-diiodooxopyridin
yl)acetate, 2-(4-aminophenyl)ethanol, 4-hydroxy(3-methylanilino)-1H-pyrimidinone, 6-
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cyclohexylhydroxymethylpyridinone, 1,6-dimethyloxopyridinylpyridine
carbonitrile, (2-oxo-1H-pyridinyl) acetate, 3-methyl(2,4,6-trimethylphenyl)butanone,
-methylphenylpyridinone, 6-cyclohexylhydroxymethylpyridinone, 2-
aminoethanol; 6-cyclohexylhydroxymethylpyridinone, 4-[(3,5-diiodooxopyridin5 1-yl)methyl]benzoic acid, 2-aminoethanol; 3-[(6-hydroxymethyloxo-1H-pyridin
yl)imino]-
-methylpyridine-2,6-dione, 5-ethyl[(5-ethylmethoxymethylpyridin
yl)methylamino]methyl-1H-pyridinone, 6-cyclohexylhydroxymethyl pyridin
one, 5-(2,5-dihydroxyphenyl)-1H-pyridinone, 6-(4,4-dimethyloxofuranyl)-1H10 pyridinone, N'-(6-oxo-1H-pyridinyl)-N,N-dipropyl methanimidamide, [6-oxo
[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy(hydroxyl methyl)oxanyl]pyridinyl]acetic acid,
-(2,5-dihydroxyphenyl)-1H-pyridinone, 3-[(6-hydroxymethyloxo-1H-pyridin
yl)imino]methylpyridine-2,6 -dione, 5-(4-cyanophenyl)methyloxo-1H-pyridine
carbonitrile, 3,3-diethyl[(piperazinylamino)methyl]pyridine-2,4-dione, 5-ethyl[(5-
ethylmethoxymethylpyridinyl)methylamino]methyl-1H-pyridinone and
pharmaceutically acceptable salts thereof.
In some embodiments, the pirfendione or pyridone analog compound is used in
compositions and methods described herein in free-base or free-acid form. In other
embodiments, the pirfendione or pyridone analog compound is used as pharmaceutically
acceptable salts. In some embodiments, pharmaceutically acceptable salts are obtained by
reacting the compound with an acid or with a base. The type of pharmaceutical acceptable
salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base
form of the compound with a pharmaceutically acceptable: (1) acid such as, for example,
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,
trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic
acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octenecarboxylic acid,
glucoheptonic acid, 4,4’-methylenebis-(3-hydroxyenecarboxylic acid), 3-
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phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid,
gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; or (2)
base, where an acidic proton present in the parent compound is replaced by a metal ion, e.g.,
an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium,
or calcium), or an aluminum ion. In some cases, the pirfendione or pyridone analog
compound is reacted with an organic base, such as, but not limited to, ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,
tris(hydroxymethyl)methylamine or with an amino acid such as, but not limited to, arginine,
lysine, and the like.
Advantages of Inhaled Aerosol and Topical (Non-Oral) Drug Delivery
Inhalation therapy of aerosolized pirfenidone or a pyridone analog compound enables
direct deposition of the sustained-release or active substance in the respiratory tract (be that
intra-nasal or pulmonary) for therapeutic action at that site of deposition or systemic
absorption to regions immediately down stream of the vascular absorption site. In the case of
central nervous system (CNS) deposition, intra-nasal inhalation aerosol delivery deposits
pirfenidone or a pyridone analog compound directly upstream of the CNS compartment.
Similar to the intra-nasal and pulmonary applications described above, treatment or
prevention of organs outside the respiratory tract requires absorption to the systemic vascular
department for transport to these extra-respiratory sites. In the case of treating or preventing
fibrotic or inflammatory diseases associated with the heart, liver and kidney, deposition of
drug in the respiratory tract, more specifically the deep lung will enable direct access to these
organs through the left atrium to either the carotid arteries or coronary arteries. Similarly, in
the case of treating CNS disorder (e.g., multiple sclerosis), deposition of drug in the
respiratory tract (as defined above) or nasal cavity, more specifically the absorption from the
nasal cavity to the nasal capillary beds for immediate access to the brain and CNS. This
direct delivery will permit direct dosing of high concentration pirfenidone or a pyridone
analog compound in the absence of unnecessary systemic exposure. Similarly, this route
permits titration of the dose to a level that may be critical for these indications.
Pharmaceutical Compositions
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For purposes of the method described herein, a pyridone analog compound, most
preferably pirfenidone may be administered using a liquid nebulization, dry powder or
metered-dose inhaler. In some embodiments, pirfenidone or a pyridone analog compound
disclosed herein is produced as a pharmaceutical composition suitable for aerosol formation,
dose for indication, deposition location, pulmonary or intra-nasal delivery for pulmonary,
intranasal/sinus, or extra-respiratory therapeutic action, good taste, manufacturing and storage
stability, and patient safety and tolerability.
In some embodiments, the isoform content of the manufactured pyridone analog
compound, most preferably pirfenidone may be optimized for drug substance and drug
product stability, dissolution (in the case of dry powder or suspension formulations) in the
nose and/or lung, tolerability, and site of action (be that lung, nasal/sinus, or regional tissue).
Manufacture
In some embodiments, pirfenidone drug product (DP) includes pirfenidone at a
concentration of about 1 mg/mL to about 100 mg/mL in aqueous buffer (citrate or phosphate
pH = 4 to 8), plus optional added salts (NaCl and/or MgCl2 and/or MgSO4). In some
embodiments, the pirfenidone drug product also includes co-solvent(s) (by non-limiting
example ethanol, propylene glycol, and glycerin) and/or surfactant(s) (by non-limiting
example Tween 80, Tween 60, lecithin, Cetylpyridinium, and Tween 20). In some
embodiments, the formulation also includes a taste-masking agent (by non-limiting example
sodium saccharin).
To achieve pirfenidone concentrations above 3 mg/mL, manufacturing process are
described. In one embodiment, the manufacturing process includes high temperature
pirfenidone aqueous dissolution, followed by co-solvent and/or surfactant and/or salt
addition, and subsequent cooling to ambient temperature. In this process, added co-solvent
and/or surfactant and/or salt stabilize the high-temperature-dissolved pirfenidone during the
cooling process and provide a stable, high-concentration, ambient-temperature formulation of
pirfenidone. In some embodiments, the processing temperature is 30o
C, 35o
C, 40o
C, 45o
C,
50o
C, 55o
C, 60o
C, 65o
C, 70o
C, 75o
C, 80o
C, 85o
C, 90o
C, 95o
C, 100o
C or other pressureenabled increased temperature. In some embodiments, the process includes addition of
surfactant and/or co-solvent and/or salt at the highest temperature or incrementally-lower
temperature as the solution is cooled. In some embodiments, addition of surfactant and/or co-
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solvent and/or salt occurs all at once or incrementally during a maintained temperature or as
the solution is cooled. The time by which the solution is maintained at the highest
temperature is from 0 minutes to 24 hours. The time by which the solution is cooled from the
highest temperature is from 0 minutes to 24 hours. In some embodiments, the solution is
protected from light. In some embodiments, the solution is sparged to remove or lower the
oxygen concentration. In some embodiments, the head space of the reaction container
includes an inert gas or mixture of inert gases. Inert gases include, but are not limited to,
nitrogen and argon. In some embodiments, the pirfenidone drug product includes cosolvent(s) in the concentration range of 0% to 100% in otherwise buffered aqueous solution.
In some embodiments, the pirfenidone drug product includes co-solvent(s) at a concentration
of about 1% to about 25%. Co-solvents include, but are not limited to, ethanol, glycerin or
propylene glycol. In some embodiments, the pirfenidone drug product includes surfactant(s)
in the concentration range of 0% to 100% in otherwise buffered aqueous solution. In some
embodiments, the pirfenidone drug product includes surfactant(s) at a concentration of about
0.1% to about 10%. Surfactants include, but are not limited to Tween 20, Tween 60, Tween
80, Cetylpyridinium Bromide, or Lecithin. In some embodiments, the pirfenidone drug
product includes a buffer. In some embodiments, the buffer includes salt and/or acid forms
of agents such as citrate, phosphate or formate at a concentration between 0 mM to 1000 mM.
In some embodiments, the buffer includes salt and/or acid forms of agents such as citrate,
phosphate or formate at a concentration between about 1 mM and about 50 mM. In some
embodiments, the pirfenidone drug product includes a salt. In some embodiments, the salt is
present at a concentration between 0% to 100%. In some embodiments, the salt is present at
a concentration between about 0.1% and about 5%. In some embodiments, the salt is sodium
chloride, magnesium chloride, magnesium sulfate or barium chloride. In some embodiments,
a sweetening agent is added to the pirfenidone drug product. In some embodiments, the
sweetening agent is saccharin or a salt thereof. In some embodiments, the sweetening agent
is present at a concentration between about 0.01 mM and about 10 mM. In some
embodiments, the pH of the buffered solution will be between about 2.0 and about 10.0.
In another embodiment, the manufacturing process includes excess co-solvent and/or
surfactant and/or cation addition to a super-saturated pirfenidone aqueous solution. Upon
dissolution in the excess co-solvent and/or surfactant and/or cation aqueous solution, the
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formulation is diluted to reduce co-solvent and/or surfactant and/or cation concentrations to
within the concentration range generally-recognized as safe and/or non-toxic and/or nonirritable.
In some embodiments, the manufacturing process is as described in Example 5.
Administration
The pyridone analog compound, most preferably pirfenidone as disclosed herein can
be administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide
treatment for the disease states previously described. Generally, for example, a daily aerosol
dose of pirfenidone in a pirfenidone compound formulation may be from about 0.001 mg to
about 6.6 mg pirfenidone/kg of body weigh per dose. Thus, for administration to a 70 kg
person, the dosage range would be about 0.07 mg to about 463 mg pirfenidone per dose or up
to about 0.280 mg to about 1852 mg pirfenidone day. The amount of active compound
administered will, of course, be dependent on the subject and disease state being treated, the
severity of the affliction, the manner and schedule of administration, the location of the
disease (e.g., whether it is desired to effect intra-nasal or upper airway delivery, pharyngeal
or laryngeal delivery, bronchial delivery, pulmonary delivery and/or pulmonary delivery with
subsequent systemic or central nervous system absorption), and the judgment of the
prescribing physician; for example, a likely dose range for aerosol administration of
pirfenidone in preferred embodiments, or in other embodiments of pyridone analog
compound, would be about 0.28 to 1852 mg per day.
Another unexpected observation is that inhalation delivery of aerosol pirfenidone to
the lung exhibits less metabolism of pirfenidone observed with oral administration. Thus,
oral or intranasal inhalation of pirfenidone or pyridone analog will permit maximum levels of
active substance to the pulmonary tissue in the absence of substantial metabolism to inactive
agents.
Inhibitors of CYP enzymes reduce pirfenidone metabolism resulting in elevated blood
levels and associated toxicity. As many products effecting CYP enzymes are useful to
fibrosis patients, permitting their use would be beneficial. While the oral route is already at
the maximum permissible dose (which provides only moderate efficacy), any inhibition of
the enzymes described above elevates pirfenidone blood levels and increases the rate and
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severity of the toxic events described herein. Because oral and intranasal inhalation delivery
of pirfenidone or pyridone analogs can achieve effective tissue levels with much less drug
than that required by the oral product, resulting blood levels are significantly lower and
consequences associated with CYP enzyme inhibitory properties described herein are
removed. Thus, permitting use of these CYP inhibitory enzyme products currently
contraindicated with the oral medicine.
The primary metabolite of pirfenidone is 5-carboxy-pirfenidone. Following oral or
intravenous administration, this metabolite appears quickly at at high concetrations in blood.
-carboxy-pirfenidone does not appear to have anti-fibrotic or anti-inflammatory activity, its
high blood levels occur at the loss of pirfenidone blood concentrations. Thus, while the oral
product is dosed at the highest possible level, once pirfenidone enters the blood it is rapidly
metabolized to a non-active species further reducing the drugs potential to achieve sufficient
lung levels required for substantital efficacy. Because oral and intranasal inhalation delivery
of pirfenidone or pyridone analogs can achieve effective lung tissue levels directly extra-lung
metabolism is not a factor.
Administration of the pyridone analog compound, most preferably pirfenidone as
disclosed herein, such as a pharmaceutically acceptable salt thereof, can be via any of the
accepted modes of administration for agents that serve similar utilities including, but not
limited to, aerosol inhalation such as nasal and/or oral inhalation of a mist or spray containing
liquid particles, for example, as delivered by a nebulizer.
Pharmaceutically acceptable compositions thus may include solid, semi-solid, liquid
and aerosol dosage forms, such as, e.g., powders, liquids, suspensions, complexations,
liposomes, particulates, or the like. Preferably, the compositions are provided in unit dosage
forms suitable for single administration of a precise dose. The unit dosage form can also be
assembled and packaged together to provide a patient with a weekly or monthly supply and
can also incorporate other compounds such as saline, taste masking agents, pharmaceutical
excipients, and other active ingredients or carriers.
The pyridone analog compound, most preferably pirfenidone as disclosed herein, such
as a pharmaceutically acceptable salt thereof, can be administered either alone or more
typically in combination with a conventional pharmaceutical carrier, excipient or the like
(e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose,
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sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, magnesium
chloride, magnesium sulfate, calcium chloride, lactose, sucrose, glucose and the like). If
desired, the pharmaceutical composition can also contain minor amounts of nontoxic
auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH
buffering agents and the like (e.g., citric acid, ascorbic acid, sodium phosphate, potassium
phosphate, sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate,
triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the
intended mode of administration, the pharmaceutical formulation will contain about 0.005%
to 95%, preferably about 0.1% to 50% by weight of a compound described herein. Actual
methods of preparing such dosage forms are known, or will be apparent, to those skilled in
this art; for example, see Remington’s Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pennsylvania.
In one preferred embodiment, the compositions will take the form of a unit dosage
form such as vial containing a liquid, solid to be suspended, dry powder, lyophilisate, or other
composition and thus the composition may contain, along with the active ingredient, a diluent
such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium
stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin,
cellulose, cellulose derivatives or the like.
Liquid pharmaceutically administrable compositions can, for example, be prepared by
dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical
adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the
like) to form a solution or suspension. Solutions to be aerosolized can be prepared in
conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms
suitable for dissolution or suspension in liquid prior to aerosol production and inhalation.
The percentage of active compound contained in such aerosol compositions is highly
dependent on the specific nature thereof, as well as the activity of the compound and the
needs of the subject. However, percentages of active ingredient of 0.01% to 90% in solution
are employable, and will be higher if the composition is a solid, which will be subsequently
diluted to the above percentages. In some embodiments, the composition will comprise
0.25%-50.0% of the active agent in solution.
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Pirfenidone or pyridone analog compound formulations can be separated into two
groups; those of simple formulation and complex formulations providing taste-masking for
improved tolerability, pH-optimized for stability and tolerability, immediate or sustainedrelease, and/or area-under-the-curve (AUC) shape-enhancing properties. Simple
formulations can be further separated into three groups. 1. Simple formulations may include
water-based liquid formulations for nebulization. By non-limiting example water-based
liquid formulations may consist of pirfenidone or pyridone analog compound alone or with
non-encapsulating water soluble excipients. 2. Simple formulations may also include
organic-based liquid formulations for nebulization or meter-dose inhaler. By non-limiting
example organic-based liquid formulations may consist of pirfenidone or pyridone analog
compound or with non-encapsulating organic soluble excipients. 3. Simple formulations
may also include dry powder formulations for administration with a dry powder inhaler. By
non-limiting example dry powder formulations may consist of pirfenidone or pyridone analog
compound alone or with either water soluble or organic soluble non-encapsulating excipients
with or without a blending agent such as lactose. Complex formulations can be further
separated into five groups. 1. Complex formulations may include water-based liquid
formulations for nebulization. By non-limiting example water-based liquid complex
formulations may consist of pirfenidone or pyridone analog compound encapsulated or
complexed with water-soluble excipients such as lipids, liposomes, cyclodextrins,
microencapsulations, and emulsions. 2. Complex formulations may also include organicbased liquid formulations for nebulization or meter-dose inhaler. By non-limiting example
organic-based liquid complex formulations may consist of pirfenidone or pyridone analog
compound encapsulated or complexed with organic-soluble excipients such as lipids,
microencapsulations, and reverse-phase water-based emulsions. 3. Complex formulations
may also include low-solubility, water-based liquid formulations for nebulization. By nonlimiting example low-solubility, water-based liquid complex formulations may consist of
pirfenidone or pyridone analog compound as a low-water soluble, stable nanosuspension
alone or in co-crystal/co-precipitate excipient complexes, or mixtures with low solubility
lipids, such as lipid nanosuspensions. 4. Complex formulations may also include low30 solubility, organic-based liquid formulations for nebulization or meter-dose inhaler. By nonlimiting example low-solubility, organic-based liquid complex formulations may consist of
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pirfenidone or pyridone analog compound as a low-organic soluble, stable nanosuspension
alone or in co-crystal/co-precipitate excipient complexes, or mixtures with low solubility
lipids, such as lipid nanosuspensions. 5. Complex formulations may also include dry powder
formulations for administration using a dry powder inhaler. By non-limiting example,
complex dry powder formulations may consist of pirfenidone or pyridone analog compound
in co-crystal/co-precipitate/spray dried complex or mixture with low-water soluble
excipients/salts in dry powder form with or without a blending agent such as lactose.
Specific methods for simple and complex formulation preparation are described herein.
Aerosol Delivery
Pirfenidone or pyridone analog compounds as described herein are preferably directly
administered as an aerosol to a site of pulmonary pathology including pulmonary fibrosis,
COPD or asthma. The aerosol may also be delivered to the pulmonary compartment for
absorption into the pulmonary vasculature for therapy or prophylaxis of extra-pulmonary
pathologies such as fibrosis and inflammatory diseases of the heart, kidney and liver, or
pulmonary or intra-nasal delivery for extra-pulmonary or extra-nasal cavity demylination
diseases associated with the central nervous system.
Several device technologies exist to deliver either dry powder or liquid aerosolized
products. Dry powder formulations generally require less time for drug administration, yet
longer and more expensive development efforts. Conversely, liquid formulations have
historically suffered from longer administration times, yet have the advantage of shorter and
less expensive development efforts. Pirfenidone or pyridone analog compounds disclosed
herein range in solubility, are generally stable and have a range of tastes. In one such
embodiment, pirfenidone or pyridone analog compounds are water soluble at pH 4 to pH 8,
are stable in aqueous solution and have limited to no taste. Such a pyridone includes
pirfenidone.
Accordingly, in one embodiment, a particular formulation of the pirfenidone or
pyridone analog compound disclosed herein is combined with a particular aerosolizing device
to provide an aerosol for inhalation that is optimized for maximum drug deposition at a site of
infection, pulmonary arterial hypertension, pulmonary or intra-nasal site for systemic
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absorption for extra-nasal and/or extra-pulmonary indications, and maximal tolerability.
Factors that can be optimized include solution or solid particle formulation, rate of delivery,
and particle size and distribution produced by the aerosolizing device.
Particle Size and Distribution
The distribution of aerosol particle/droplet size can be expressed in terms of either:
- the mass median aerodynamic diameter (MMAD) — the droplet size at which half of
the mass of the aerosol is contained in smaller droplets and half in larger droplets;
- volumetric mean diameter (VMD);
- mass median diameter (MMD);
- the fine particle fraction (FPF) —the percentage of particles that are <5 μm in
diameter.
These measures have been used for comparisons of the in vitro performance of
different inhaler device and drug combinations. In general, the higher the fine particle
fraction, the higher the proportion of the emitted dose that is likely to deposit the lung.
Generally, inhaled particles are subject to deposition by one of two mechanisms:
impaction, which usually predominates for larger particles, and sedimentation, which is
prevalent for smaller particles. Impaction occurs when the momentum of an inhaled particle
is large enough that the particle does not follow the air stream and encounters a physiological
surface. In contrast, sedimentation occurs primarily in the deep lung when very small
particles which have traveled with the inhaled air stream encounter physiological surfaces as
a result of random diffusion within the air stream.
For pulmonary administration, the upper airways are avoided in favor of the middle
and lower airways. Pulmonary drug delivery may be accomplished by inhalation of an
aerosol through the mouth and throat. Particles having a mass median aerodynamic diameter
(MMAD) of greater than about 5 microns generally do not reach the lung; instead, they tend
to impact the back of the throat and are swallowed and possibly orally absorbed. Particles
having diameters of about 1 to about 5 microns are small enough to reach the upper- to midpulmonary region (conducting airways), but are too large to reach the alveoli. Smaller
particles, i.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region.
Particles having diameters smaller than about 0.5 microns can also be deposited in the
alveolar region by sedimentation, although very small particles may be exhaled. Measures of
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particle size can be referred to as volumetric mean diameter (VMD), mass median diameter
(MMD), or MMAD. These measurements may be made by impaction (MMD and MMAD)
or by laser (VMD). For liquid particles, VMD, MMD and MMAD may be the same if
environmental conditions are maintained, e.g., standard humidity. However, if humidity is
not maintained, MMD and MMAD determinations will be smaller than VMD due to
dehydration during impator measurements. For the purposes of this description, VMD,
MMD and MMAD measurements are considered to be under standard conditions such that
descriptions of VMD, MMD and MMAD will be comparable. Similarly, dry powder particle
size determinations in MMD and MMAD are also considered comparable.
In some embodiments, the particle size of the aerosol is optimized to maximize the
pirfenidone or pyridone analog compound deposition at the site of pulmonary pathology
and/or extra-pulmonary, systemic or central nervous system distribution, and to maximize
tolerability (or in the later case, systemic absorption). Aerosol particle size may be expressed
in terms of the mass median aerodynamic diameter (MMAD). Large particles (e.g., MMAD
>5 µm) may deposit in the upper airway because they are too large to navigate the curvature
of the upper airway. Small particles (e.g., MMAD < 2 µm) may be poorly deposited in the
lower airways and thus become exhaled, providing additional opportunity for upper airway
deposition. Hence, intolerability (e.g., cough and bronchospasm) may occur from upper
airway deposition from both inhalation impaction of large particles and settling of small
particles during repeated inhalation and expiration. Thus, in one embodiment, an optimum
particle size is used (e.g., MMAD = 2-5 µm) in order to maximize deposition at a mid-lung
and to minimize intolerability associated with upper airway deposition. Moreover,
generation of a defined particle size with limited geometric standard deviation (GSD) may
optimize deposition and tolerability. Narrow GSD limits the number of particles outside the
desired MMAD size range. In one embodiment, an aerosol containing one or more
compounds disclosed herein is provided having a MMAD from about 2 microns to about 5
microns with a GSD of less than or equal to about 2.5 microns. In another embodiment, an
aerosol having an MMAD from about 2.8 microns to about 4.3 microns with a GSD less than
or equal to 2 microns is provided. In another embodiment, an aerosol having an MMAD
from about 2.5 microns to about 4.5 microns with a GSD less than or equal to 1.8 microns is
provided.
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In some embodiments, the pirfenidone or pyridone analog compound that is intended
for respiratory delivery (for either systemic or local distribution) can be administered as
aqueous formulations, as suspensions or solutions in halogenated hydrocarbon propellants, or
as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing
either hydraulic or ultrasonic atomization. Propellant-based systems may use suitable
pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler
devices (DPIs), which are capable of dispersing the drug substance effectively. A desired
particle size and distribution may be obtained by choosing an appropriate device.
Lung Deposition as used herein, refers to the fraction of the nominal dose of an active
pharmaceutical ingredient (API) that is bioavailable at a specific site of pharmacologic
activity upon administration of the agent to a patient via a specific delivery route. For
example, a lung deposition of 30% means 30% of the active ingredient in the inhalation
device just prior to administration is deposited in the lung. Likewise, a lung deposition of
60% means 60% of the active ingredient in the inhalation device just prior to administration
is deposited in the lung, and so forth. Lung deposition can be determined using methods of
scintigraphy or deconvolution. In some embodiments, described herein are methods and
inhalation systems for the treatment or prophylaxis of a respiratory condition in a patient,
comprising administering to the patient a nominal dose of pirfenidone or a pyridone analog
compound with a liquid nebulizer. In some embodiments, the liquid nebulizer is a high
effieciency liquid nebulizer. In some embodiments a lung deposition of pirfenidone or a
pyridone analog compound of at least about 7%, at least about 10%, at least about 15%, at
least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least
about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%,
based on the nominal dose of pirfenidone or a pyridone analog compound is acheived.
There are two main methods used to measure aerosol deposition in the lungs. First, γscintigraphy is performed by radiolabeling the drug with a substance like 99m-technetium,
and scanning the subject after inhalation of the drug. This technique has the advantage of
being able to quantify the proportion of aerosol inhaled by the patient, as well as regional
distribution in the upper airway and lungs. Second, since most of the drug deposited in the
lower airways will be absorbed into the bloodstream, pharmacokinetic techniques are used to
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measure lung deposition. This technique can assess the total amount of ICSs that interacts
with the airway epithelium and is absorbed systemically, but will miss the small portion that
may be expectorated or swallowed after mucociliary clearance, and cannot tell us about
regional distribution. Therefore, γ-scintigraphy and pharmacokinetic studies are in many
cases considered complementary.
In some embodiments, administration of the pirfenidone or pyridone analog
compound with a liquid nebulizer provides a GSD of emitted droplet size distribution of
about 1.0 μm to about 2.5 μm, about 1.2 μm to about 2.0 μm, or about 1.0 μm to about 2.0
μm. In some embodiments, the MMAD is about 0.5μm to about 5 μm, or about 1 to about 4
μm or less than about 5 μm. In some embodiments, the VMD is about 0.5μm to about 5 μm,
or about 1 to about 4 μm or less than about 5 μm.
Fine Particle Fraction (FPF) describes the efficiency of a nebulizer inhalation device.
FPF represents the percentage of the delivered aerosol dose, or inhaled mass, with droplets of
diameter less than 5.0 μm. Droplets of less than 5.0 μm in diameter are considered to
penetrate to the lung. In some embodiments, administration of an aqueous inhalation
pirfenidone or pyridone analog solution with a liquid nebulizer provides a RDD of at least
about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about
75%, or at least about 80%.
The Delivered Dose (DD) of drug to a patient is the certain portion of volume of
liquid filled into the nebulizer, i.e. the fill volume, which is emitted from the mouthpiece of
the device. The difference between the nominal dose and the DD is the amount of volume
lost primarily to residues, i.e. the amount of fill volume remaining in the nebulizer after
administration, or is lost in aerosol form during expiration of air from the patient and
therefore not deposited in the patient’s body. In some embodiments, the DD of the nebulized
formaulations described herein is at least about 30%, at least about 35%, at least about 40%,
at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about
65%, at least about 70%, or at least about 80%.
The Respirable Delivered Dose (RDD) is an expression of the delivered mass of drug
contained within emitted droplets from a nebulizer that are small enough to reach and deposit
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on the surface epithelium of the patients lung. The RDD is determined by multiplying the
DD by the FPF.
In one embodiment, described herein an aqueous droplet containing pirfenidone or
pyridone analog compound, wherein the aqueous droplet has a diameter less than about 5.0
μm. In some embodiments, the aqueous droplet has a diameter less than about 5.0 μm, less
than about 4.5 μm, less than about 4.0 μm, less than about 3.5 μm, less than about 3.0 μm,
less than about 2.5 μm, less than about 2.0 μm, less than about 1.5 μm, or less than about 1.0
μm. In some embodiments, the aqueous droplet further comprises one or more colsolvents.
In some embodiments, the one or more cosolvents are selected from ethanol and propylene
glycol. In some embodiments, the aqueous droplet further comprises a buffer. In some
embodiments, the buffer is a citrate buffer or a phosphate buffer. In some embodiments, the
dioplet was produced from a liquid nebulizer and an aqueous solution of pirfenidone or
pyridone analog compound as described herein. In some embodiments, the aqueous droplet
was produced from an aqueous solution that has concentration of pirfenidone or pyridone
analog compound between about 0.1 mg/mL and about 60 mg/mL and an osmolality from
about 50 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the osmolality is
greater than about 100 mOsmol/kg. In some embodiments, the osmolality is greater than
about 400 mOsmol/kg. In some embodiments, the osmolality is greater than about 1000
mOsmol/kg. In some embodiments, the osmolality is greater than about 2000 mOsmol/kg.
In some embodiments, the osmolality is greater than about 3000 mOsmol/kg. In some
embodiments, the osmolality is greater than about 4000 mOsmol/kg. In some embodiments,
the osmolality is greater than about 5000 mOsmol/kg.
Also described are aqueous aerosols comprising a plurality of aqueous droplets of
pirfenidone or pyridone analog compound as described herein. In some embodiments, the at
least about 30% of the aqueous droplets in the aerosol have a diameter less than about 5 μm.
In some embodiments, at least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at
least about 75%, at least about 80%, at least about 85%, or at least about 90% of the aqueous
droplets in the aerosol have a diameter less than about 5 μm. In some embodiments, the
aqueous aerosols are produced with a liquid nebulizer. In some embodiments, the aqueous
aerosols are produced with a high efficiency liquid nebulizer.
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Liquid Nebulizer
In one embodiment, a nebulizer is selected on the basis of allowing the formation of
an aerosol of a pirfenidone or pyridone analog compound disclosed herein having an MMAD
predominantly between about 1 to about 5 microns. In one embodiment, the delivered
amount of pirfenidone or pyridone analog compound provides a therapeutic effect for
pulmonary pathology and/or extra-pulmonary, systemic, tissue or central nervous system
distribution.
Previously, two types of nebulizers, jet and ultrasonic, have been shown to be able to
produce and deliver aerosol particles having sizes between 2 and 4 micron. These particle
sizes have been shown as being optimal for middle airway deposition. However, unless a
specially formulated solution is used, these nebulizers typically need larger volumes to
administer sufficient amount of drug to obtain a therapeutic effect. A jet nebulizer utilizes air
pressure breakage of an aqueous solution into aerosol droplets. An ultrasonic nebulizer
utilizes shearing of the aqueous solution by a piezoelectric crystal. Typically, however, the
jet nebulizers are only about 10% efficient under clinical conditions, while the ultrasonic
nebulizer is only about 5% efficient. The amount of pharmaceutical deposited and absorbed
in the lungs is thus a fraction of the 10% in spite of the large amounts of the drug placed in
the nebulizer. The amount of drug that is placed in the nebuluzer prior to administration to
the mammal is generally referred to the “nominal dose,” or “loaded dose.” The volume of
solution containing the nominal dose is referred to as the “fill volume.” Smaller particle sizes
or slow inhalation rates permit deep lung deposition. Both middle-lung and alveolar
deposition may be desired as described herein depending on the indication, e.g., middle
and/or alveolar deposition for pulmonary fibrosis and systemic delivery. Exemplary
disclosure of compositions and methods for formulation delivery using nebulizers can be
found in, e.g., US 2006/0276483, including descriptions of techniques, protocols and
characterization of aerosolized mist delivery using a vibrating mesh nebulizer.
Accordingly, in one embodiment, a vibrating mesh nebulizer is used to deliver in
preferred embodiments an aerosol of the pirfenidone compound as disclosed herein, or in
other embodiments, a pyridone analog compound as disclosed herein. A vibrating mesh
nebulizer comprises a liquid storage container in fluid contact with a diaphragm and
inhalation and exhalation valves. In one embodiment, about 1 to about 6 ml of the
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pirfenidone compound formulation (or in another related embodiment, of a pyridone analog
compound formulation) is placed in the storage container and the aerosol generator is
engaged producing atomized aerosol of particle sizes selectively between about 1 and about 5
micron. In one embodiment, about 1 to about 10 mL of the pirfenidone compound
formulation (or in another related embodiment, of a pyridone analog compound formulation)
is placed in the storage container and the aerosol generator is engaged producing atomized
aerosol of particle sizes selectively between about 1 and about 5 micron. In one embodiment,
about the volume of the pirfenidone compound formulation (or in another related
embodiment, of a pyridone analog compound formulation) that is originally placed in the
storage container and the aerosol generator is replaced to increase the administered dose size.
In some embodiments a pirfenidone or pyridone analog compound formulation as
disclosed herein, is placed in a liquid nebulization inhaler and prepared in dosages to deliver
from about 34 mcg to about 463 mg from a dosing solution of about 0.5 to about 6 ml with
MMAD particles sizes between about 1 to about 5 micron being produced.
In some embodiments a pirfenidone or pyridone analog compound formulation as
disclosed herein, is placed in a liquid nebulization inhaler and prepared in dosages to deliver
from about 34 mcg to about 463 mg from a dosing solution of about 0.5 to about 7 ml with
MMAD particles sizes between about 1 to about 5 micron being produced.
By non-limiting example, a nebulized pirfenidone or pyridone analog compound may
be administered in the described respirable delivered dose in less than about 20 min, less than
about 15 min, less than about 10 min, less than about 7 min, less than about 5 min, less than
about 3 min, or less than about 2 min.
By non-limiting example, a nebulized pirfenidone or pyridone analog compound may
be administered in the described respirable delivered dose using a breath-actuated nebulizer
in less than about 20 min, less than about 10 min, less than about 7 min, less than about 5
min, less than about 3 min, or less than about 2 min.
By non-limiting example, in other circumstances, a nebulized pirfenidone or pyridone
analog compound may achieve improved tolerability and/or exhibit an area-under-the-curve
(AUC) shape-enhancing characteristic when administered over longer periods of time. Under
these conditions, the described respirable delivered dose in more than about 2 min, preferably
more than about 3 min, more preferably more than about 5 min, more preferably more than
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about 7 min, more preferably more than about 10 min, and in some cases most preferable
from about 10 to about 20 min.
As disclosed herein, there is provided a pyridone analog compound formulation
composition comprising a pirfenidone compound aqueous solution having a pH from about
4.0 to about pH 8.0 where the pirfenidone compound is present at a concentration from about
34 mcg/mL to about 463 mg/mL pirfenidone. In certain other embodiments the pirfenidone
compound formulation is provided as an aqueous solution having a pH of from about 4.0 to
about 8.0, the solution comprising a pirfenidone compound at a concentration of from about
34 mcg/mL to about 463 mg/mL pirfenidone; and citrate buffer or phosphate buffer at a
concentration of from about 0 mM to about 50 mM. In certain other embodiments the
pirfenidone compound formulation is provided as an aqueous solution having a pH of from
about 4.0 to about 8.0, the solution comprising a pirfenidone compound at a concentration of
from about 34 mcg/mL to about 463 mg/mL pirfenidone; and a buffer that has a pKa between
4.7 and 6.8 and that is present at a concentration sufficient to maintain or maintain after
titration with acid or base a pH from about 4.0 to about 8.0 for a time period sufficient to
enable marketable product shelf-life storage.
In some embodiments, described herein is a pharmaceutical composition that
includes: pirfenidone; water; phosphate buffer or citrate buffer; and optionally sodium
chloride or magnesium chloride. In other embodiments, described herein is a pharmaceutical
composition that includes: pirfenidone; water; a buffer; and at least one additional ingredient
selected from sodium chloride, magnesium chloride, ethanol, propylene glycol, glycerol,
polysorbate 80, and cetylpyridinium bromide (or chloride). In some embodiments, the buffer
is phosphate buffer. In other embodiments, the buffer is citrate buffer. In some
embodiments, the pharmaceutical composition includes 1 mg to 500 mg of pirfenidone, for
example, 5 mg, 10 mg, 15 mg, 25 mg, 37.5 mg, 75 mg, 100 mg, 115 mg, 150 mg, 190 mg,
220 mg, or 500 mg. In some embodiments, the osmolality of the pharmaceutical composition
described herein is between about 50 mOsmo/kg to 6000 mOsmo/kg. In some embodiments,
the osmolality of the pharmaceutical composition described herein is between about 50
mOsmo/kg to 5000 mOsmo/kg. In some embodiments, the pharmaceutical composition
optionally includes saccharin (e.g. sodium salt). In some embodiments, such a pharmaceutical
composition is placed in a liquid nebulization inhaler to deliver from about 1 mg to about 500
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mg from a dosing solution of about 0.5 to about 6 mL with MMAD particles sizes between
about 1 to about 5 micron being produced. In some embodiments, such a pharmaceutical
composition is placed in a liquid nebulization inhaler to deliver from about 1 mg to about 500
mg from a dosing solution of about 0.5 to about 7 mL with MMAD particles sizes between
about 1 to about 5 micron being produced. In some embodiments such a nebulized
pharmaceutical composition may deliver between about 0.0001 mg and about 25 mg
pirfenidone or pryridone analog in aerosol particles with a MMAD between 1 and 5 microns
in each inhaled breath. In some embodiments, 1 mg pirfenidone or pyridone analog delivered
in 10 breaths over 1 minute, whereby 50% of the inhaled particles are between 1 and 5
microns, 0.05 mg pirfenidone or pyridine analog will be delivered in each breath. In some
embodiments, 1 mg pirfenidone or pyridone analog delivered in 15 breaths per minute over
minutes, whereby 50% of the inhaled particles are between 1 and 5 microns, 0.0033 mg
pirfenidone or pyridone analog will be delivered in each breath. In some embodiments, 1 mg
pirfenidone or pyridone analog delivered in 20 breaths per minute over 20 minutes, whereby
50% of the inhaled particles are between 1 and 5 microns, 0.00125 mg pirfenidone or
pyridone analog will be delivered in each breath. In some embodiments, 200 mg pirfenidone
or pyridone analog delivered in 10 breaths over 1 minute, whereby 50% of the inhaled
particles are between 1 and 5 microns, 10 mg pirfenidone or pyridone analog will be
delivered in each breath. In some embodiments, 200 mg pirfenidone or pyridone analog
delivered in 15 breaths per minute over 10 minutes, whereby 50% of the inhaled particles are
between 1 and 5 microns, 0.67 mg pirfenidone or pyridone analog will be delivered in each
breath. By another non-limiting example, In some embodiments, 200 mg pirfenidone or
pyridone analog delivered in 20 breaths per minute over 20 minutes, whereby 50% of the
inhaled particles are between 1 and 5 microns, 0.25 mg pirfenidone or pyridone analog will
be delivered in each breath. In some embodiments, 500 mg pirfenidone or pyridine analog
delivered in 10 breaths over 1 minute, whereby 50% of the inhaled particles are between 1
and 5 microns, 25 mg pirfenidone or pyridone analog will be delivered in each breath. In
some embodiments, 500 mg pirfenidone or pyridone analog delivered in 15 breaths per
minute over 10 minutes, whereby 50% of the inhaled particles are between 1 and 5 microns,
1.67 mg pirfenidone or pyridone analog will be delivered in each breath. In some
embodiments, 500 mg pirfenidone or pyridone analog delivered in 20 breaths per minute over
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minutes, whereby 50% of the inhaled particles are between 1 and 5 microns, 0.625 mg
pirfenidone or pyridone analog will be delivered in each breath.
In some embodiments, a nebulized pirfenidone or pyridone analog compound may be
administered in the described respirable delivered dose in less than about 20 min, less than
about 10 min, less than about 7 min, less than about 5 min, less than about 3 min, or less than
about 2 min.
For aqueous and other non-pressurized liquid systems, a variety of nebulizers
(including small volume nebulizers) are available to aerosolize the formulations.
Compressor-driven nebulizers incorporate jet technology and use compressed air to generate
the liquid aerosol. Such devices are commercially available from, for example, Healthdyne
Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.;
Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak,
Inc. Ultrasonic nebulizers rely on mechanical energy in the form of vibration of a
piezoelectric crystal to generate respirable liquid droplets and are commercially available
from, for example, Omron Heathcare, Inc., Boehringer Ingelheim, and DeVilbiss Health
Care, Inc. Vibrating mesh nebulizers rely upon either piezoelectric or mechanical pulses to
respirable liquid droplets generate. Other examples of nebulizers for use with pirfenidone or
pyridone analogs described herein are described in U.S. Patent Nos. 4,268,460; 4,253,468;
4,046,146; 3,826,255; 4,649,911; 4,510,929; 4,624,251; 5,164,740; 5,586,550; 5,758,637;
6,644,304; 6,338,443; 5,906,202; 5,934,272; 5,960,792; 5,971,951; 6,070,575; 6,192,876;
6,230,706; 6,349,719; 6,367,470; 6,543,442; 6,584,971; 6,601,581; 4,263,907; 5,709,202;
,823,179; 6,192,876; 6,644,304; 5,549,102; 6,083,922; 6,161,536; 6,264,922; 6,557,549;
and 6,612,303 all of which are hereby incorporated by reference in their entirety.
Any known inhalation nebulizer suitable to provide delivery of a medicament as
described herein may be used in the various embodiments and methods described herein.
Such nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, pulsating membrane
nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers
comprising a vibration generator and an aqueous chamber (e.g., Pari eFlow®).
Commercially available nebulizers suitable for use in the present invention can include the
Aeroneb®, MicroAir®, Aeroneb® Pro, and Aeroneb® Go, Aeroneb® Solo, Aeroneb®
Solo/Idehaler combination, Aeroneb® Solo or Go Idehaler-Pocket® combination, PARI LC-
139
Plus®, PARI LC-Star®, PARI Sprint®, eFlow and eFlow Rapid®, Pari Boy® N and Pari
Duraneb® (PARI, GmbH), MicroAir® (Omron Healthcare, Inc.), Halolite® (Profile
Therapeutics Inc.), Respimat® (Boehringer Ingelheim), Aerodose® (Aerogen, Inc, Mountain
View, CA), Omron Elite® (Omron Healthcare, Inc.), Omron Microair® (Omron Healthcare,
Inc.), Mabismist II® (Mabis Healthcare, Inc.), Lumiscope® 6610, (The Lumiscope
Company, Inc.), Airsep Mystique®, (AirSep Corporation), Acorn-1 and Acorn-II (Vital
Signs, Inc.), Aquatower® (Medical Industries America), Ava-Neb® (Hudson Respiratory
Care Incorporated), Cirrus® (Intersurgical Incorporated), Dart® (Professional Medical
Products), Devilbiss® Pulmo Aide (DeVilbiss Corp.), Downdraft® (Marquest), Fan Jet®
(Marquest), MB-5 (Mefar), Misty Neb® (Baxter), Salter 8900 (Salter Labs), Sidestream®
(Medic-Aid), Updraft-II® (Hudson Respiratory Care), Whisper Jet® (Marquest Medical
Products), Aiolos® (Aiolos Medicnnsk Teknik), Inspiron® (Intertech Resources, Inc.),
Optimist® (Unomedical Inc.), Prodomo®, Spira® (Respiratory Care Center), AERx® and
AERx EssenceTM (Aradigm), Respirgard II®, Sonik® LDI Nebulizer (Evit Labs), Swirler W
Radioaerosol System (AMICI, Inc.), Maquet SUN 145 ultrasonic, Schill untrasonic, compare
and compare Elite from Omron, Monoghan AeroEclipse BAN, Transneb, DeVilbiss 800,
AerovectRx, Porta-Neb®, Freeway FreedomTM, Sidestream, Ventstream and I-neb produced
by Philips, Inc.. By further non-limiting example, U.S. Patent No. 6,196,219, is hereby
incorporated by reference in its entirety.
Any of these and other known nebulizers suitable to provide delivery of a aqueous
inhalation medicament as described herein may be used in the various embodiments and
methods described herein. In some embodiments, the nebulizers are available from, e.g., Pari
GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne,
Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep,
Luminscope, Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd.
(Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland,
UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplies
(London, UK), Intersurgical (Berkshire, UK), Lifecare Hospital Supplies (Leies, UK), MedicAid Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK),
and many others.
140
Other nebulizers suitable for use in the methods and systems describe herein can
include, but are not limited to, jet nebulizers (optionally sold with compressors), ultrasonic
nebulizers, and others. Exemplary jet nebulizers for use herein can include Pari LC
plus/ProNeb, Pari LC plus/ProNeb Turbo, Pari LCPlus/Dura Neb 1000 & 2000 Pari LC
plus/Walkhaler, Pari LC plus/Pari Master, Pari LC star, Omron CompAir XL Portable
Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron compare Elite
Compressor Nebulizer System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC Plus or
Pari LC Star nebulizer with Proneb Ultra compressor, Pulomo- aide, Pulmo-aide LT, Pulmoaide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traveler, DeVilbiss
646, Whisper Jet, AcornII, Misty-Neb, Allied aerosol, Schuco Home Care, Lexan Plasic
Pocet Neb, SideStream Hand Held Neb, Mobil Mist, Up-Draft, Up-DraftII, T Up-Draft, ISONEB, Ava-Neb, Micro Mist, and PuImoMate.
Exemplary ultrasonic nebulizers suitable to provide delivery of a medicament as
described herein can include MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir,
Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic
Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana Ultrasonic
Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer.
Other nebulizers for use herein include 5000 Electromagnetic Neb, 5001 Electromagnetic
Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer
System, Aerodose Inhaler, and AeroEclipse Breath Actuated Nebulizer. Exemplary
nebulizers comprising a vibrating mesh or plate with multiple apertures are described by R.
Dhand in New Nebuliser Technology—Aerosol Generation by Using a Vibrating Mesh or
Plate with Multiple Apertures, Long-Term Healthcare Strategies 2003, (July 2003), p. 1-4
and Respiratory Care, 47: 1406-1416 (2002), the entire disclosure of each of which is hereby
incorporated by reference.
Additional nebulizers suitable for use in the presently described invention include
nebulizers comprising a vibration generator and an aqueous chamber. Such nebulizers are
sold commercially as, e.g., Pari eFlow, and are described in U.S. Patent Nos. 6,962,151,
,518,179, 5,261,601, and 5,152,456, each of which is specifically incorporated by reference
herein.
141
The parameters used in nebulization, such as flow rate, mesh membrane size, aerosol
inhalation chamber size, mask size and materials, valves, and power source may be varied as
applicable to provide delivery of a medicament as described herein to maximize their use
with different types and aqueous inhalation mixtures.
In some embodiments, the drug solution is formed prior to use of the nebulizer by a
patient. In other embodiments, the drug is stored in the nebulizer in liquid form, which may
include a suspension, solution, or the like. In other embodiments, the drug is store in the
nebulizer in solid form. In this case, the solution is mixed upon activation of the nebulizer,
such as described in U.S. Patent No. 6,427,682 and PCT Publication No. WO 03/035030,
both of which are hereby incorporated by reference in their entirety. In these nebulizers, the
solid drug, optionally combined with excipients to form a solid composition, is stored in a
separate compartment from a liquid solvent.
The liquid solvent is capable of dissolving the solid composition to form a liquid
composition, which can be aerosolized and inhaled. Such capability is, among other factors,
a function of the selected amount and, potentially, the composition of the liquid. To allow
easy handling and reproducible dosing, the sterile aqueous liquid may be able to dissolve the
solid composition within a short period of time, possibly under gentle shaking. In some
embodiments, the final liquid is ready to use after no longer than about 30 seconds. In some
cases, the solid composition is dissolved within about 20 seconds, and advantageously, within
about 10 seconds. As used herein, the terms “dissolve(d)”, “dissolving”, and “dissolution”
refer to the disintegration of the solid composition and the release, i.e., the dissolution, of the
active compound. As a result of dissolving the solid composition with the liquid solvent a
liquid composition is formed in which the active compound is contained in the dissolved
state. As used herein, the active compound is in the dissolved state when at least about 90
wt.-% are dissolved, and more preferably when at least about 95 wt.-% are dissolved.
With regard to basic separated-compartment nebulizer design, it primarily depends on
the specific application whether it is more useful to accommodate the aqueous liquid and the
solid composition within separate chambers of the same container or primary package, or
whether they should be provided in separate containers. If separate containers are used, these
are provided as a set within the same secondary package. The use of separate containers is
especially preferred for nebulizers containing two or more doses of the active compound.
142
There is no limit to the total number of containers provided in a multi-dose kit. In one
embodiment, the solid composition is provided as unit doses within multiple containers or
within multiple chambers of a container, whereas the liquid solvent is provided within one
chamber or container. In this case, a favorable design provides the liquid in a metered-dose
dispenser, which may consist of a glass or plastic bottle closed with a dispensing device, such
as a mechanical pump for metering the liquid. For instance, one actuation of the pumping
mechanism may dispense the exact amount of liquid for dissolving one dose unit of the solid
composition.
In another embodiment for multiple-dose separated-compartment nebulizers, both the
solid composition and the liquid solvent are provided as matched unit doses within multiple
containers or within multiple chambers of a container. For instance, two-chambered
containers can be used to hold one unit of the solid composition in one of the chambers and
one unit of liquid in the other. As used herein, one unit is defined by the amount of drug
present in the solid composition, which is one unit dose. Such two-chambered containers
may, however, also be used advantageously for nebulizers containing only one single drug
dose.
In one embodiment of a separated-compartment nebulizer, a blister pack having two
blisters is used, the blisters representing the chambers for containing the solid composition
and the liquid solvent in matched quantities for preparing a dose unit of the final liquid
composition. As used herein, a blister pack represents a thermoformed or pressure-formed
primary packaging unit, most likely comprising a polymeric packaging material that
optionally includes a metal foil, such as aluminum. The blister pack may be shaped to allow
easy dispensing of the contents. For instance, one side of the pack may be tapered or have a
tapered portion or region through which the content is dispensable into another vessel upon
opening the blister pack at the tapered end. The tapered end may represent a tip.
In some embodiments, the two chambers of the blister pack are connected by a
channel, the channel being adapted to direct fluid from the blister containing the liquid
solvent to the blister containing the solid composition. During storage, the channel is closed
with a seal. In this sense, a seal is any structure that prevents the liquid solvent from
contacting the solid composition. The seal is preferably breakable or removable; breaking or
removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the
143
other chamber and dissolve the solid composition. The dissolution process may be improved
by shaking the blister pack. Thus, the final liquid composition for inhalation is obtained, the
liquid being present in one or both of the chambers of the pack connected by the channel,
depending on how the pack is held.
According to another embodiment, one of the chambers, preferably the one that is
closer to the tapered portion of the blister pack communicates with a second channel, the
channel extending from the chamber to a distal position of the tapered portion. During
storage, this second channel does not communicate with the outside of the pack but is closed
in an air-tight fashion. Optionally, the distal end of the second channel is closed by a
breakable or removable cap or closure, which may e.g., be a twist-off cap, a break-off cap, or
a cut-off cap.
In one embodiment, a vial or container having two compartments is used, the
compartment representing the chambers for containing the solid composition and the liquid
solvent in matched quantities for preparing a dose unit of the final liquid composition. The
liquid composition and a second liquid solvent may be contained in matched quantities for
preparing a dose unit of the final liquid composition (by non-limiting example in cases where
two soluble excipients or the pirfenidone or pyridone analog compound and excipient are
unstable for storage, yet desired in the same mixture for administration.
In some embodiments, the two compartments are physically separated but in fluid
communication such as when so the vial or container are connected by a channel or breakable
barrier, the channel or breakable barrier being adapted to direct fluid between the two
compartments to enable mixing prior to administration. During storage, the channel is closed
with a seal or the breakable barrier intact. In this sense, a seal is any structure that prevents
mixing of contents in the two compartments. The seal is preferably breakable or removable;
breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to
enter the other chamber and dissolve the solid composition or in the case of two liquids
permit mixing. The dissolution or mixing process may be improved by shaking the container.
Thus, the final liquid composition for inhalation is obtained, the liquid being present in one or
both of the chambers of the pack connected by the channel or breakable barrier, depending on
how the pack is held.
144
The solid composition itself can be provided in various different types of dosage
forms, depending on the physicochemical properties of the drug, the desired dissolution rate,
cost considerations, and other criteria. In one of the embodiments, the solid composition is a
single unit. This implies that one unit dose of the drug is comprised in a single, physically
shaped solid form or article. In other words, the solid composition is coherent, which is in
contrast to a multiple unit dosage form, in which the units are incoherent.
Examples of single units which may be used as dosage forms for the solid
composition include tablets, such as compressed tablets, film-like units, foil-like units,
wafers, lyophilized matrix units, and the like. In a preferred embodiment, the solid
composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called
wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also
enables the rapid dissolution of the active compound.
On the other hand, for some applications the solid composition may also be formed as
a multiple unit dosage form as defined above. Examples of multiple units are powders,
granules, microparticles, pellets, beads, lyophilized powders, and the like. In one
embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized
system comprises a multitude of powder particles, and due to the lyophilization process used
in the formation of the powder, each particle has an irregular, porous microstructure through
which the powder is capable of absorbing water very rapidly, resulting in quick dissolution.
Another type of multiparticulate system which is also capable of achieving rapid drug
dissolution is that of powders, granules, or pellets from water-soluble excipients which are
coated with the drug, so that the drug is located at the outer surface of the individual particles.
In this type of system, the water-soluble low molecular weight excipient is useful for
preparing the cores of such coated particles, which can be subsequently coated with a coating
composition comprising the drug and, preferably, one or more additional excipients, such as a
binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or
other excipients used in pharmaceutical coating compositions.
In another embodiment, the solid composition resembles a coating layer that is coated
on multiple units made of insoluble material. Examples of insoluble units include beads
made of glass, polymers, metals, and mineral salts. Again, the desired effect is primarily
rapid disintegration of the coating layer and quick drug dissolution, which is achieved by
145
providing the solid composition in a physical form that has a particularly high surface-tovolume ratio. Typically, the coating composition will, in addition to the drug and the watersoluble low molecular weight excipient, comprise one or more excipients, such as those
mentioned above for coating soluble particles, or any other excipient known to be useful in
pharmaceutical coating compositions.
To achieve the desired effects, it may be useful to incorporate more than one watersoluble low molecular weight excipient into the solid composition. For instance, one
excipient may be selected for its drug carrier and diluent capability, while another excipient
may be selected to adjust the pH. If the final liquid composition needs to be buffered, two
excipients that together form a buffer system may be selected.
In one embodiment, the liquid to be used in a separated-compartment nebulizer is an
aqueous liquid, which is herein defined as a liquid whose major component is water. The
liquid does not necessarily consist of water only; however, in one embodiment it is purified
water. In another embodiment, the liquid contains other components or substances,
preferably other liquid components, but possibly also dissolved solids. Liquid components
other than water which may be useful include propylene glycol, glycerol, and polyethylene
glycol. One of the reasons to incorporate a solid compound as a solute is that such a
compound is desirable in the final liquid composition, but is incompatible with the solid
composition or with a component thereof, such as the active ingredient.
Another desirable characteristic for the liquid solvent is that it is sterile. An aqueous
liquid would be subject to the risk of considerable microbiological contamination and growth
if no measures were taken to ensure sterility. In order to provide a substantially sterile liquid,
an effective amount of an acceptable antimicrobial agent or preservative can be incorporated
or the liquid can be sterilized prior to providing it and to seal it with an air-tight seal. In one
embodiment, the liquid is a sterilized liquid free of preservatives and provided in an
appropriate air-tight container. However, according to another embodiment in which the
nebulizer contains multiple doses of the active compound, the liquid may be supplied in a
multiple-dose container, such as a metered-dose dispenser, and may require a preservative to
prevent microbial contamination after the first use.
High Efficiency Liquid Nebulizers
146
High efficiency liquid nebulizers are inhalation devices that are adapted to deliver a
large fraction of a loaded dose to a patient. Some high efficiency liquid nebulizers utilize
microperforated membranes. In some embodiments, the high efficiency liquid nebulizer also
utilizes one or more actively or passively vibrating microperforated membranes. In some
embodiments, the high efficiency liquid nebulizer contains one or more oscillating
membranes. In some embodiments, the high efficiency liquid nebulizer contains a vibrating
mesh or plate with multiple apertures and optionally a vibration generator with an aerosol
mixing chamber. In some such embodiments, the mixing chamber functions to collect (or
stage) the aerosol from the aerosol generator. In some embodiments, an inhalation valve is
also used to allow an inflow of ambient air into the mixing chamber during an inhalation
phase and is closed to prevent escape of the aerosol from the mixing chamber during an
exhalation phase. In some such embodiments, the exhalation valve is arranged at a
mouthpiece which is removably mounted at the mixing chamber and through which the
patient inhales the aerosol from the mixing chamber. In yet some other embodiments, the
high efficiency liquid nebulizer contains a pulsating membrane. In some embodiments, the
high efficiency liquid nebulizer is continuously operating.
In some embodiments, the high efficiency liquid nebulizer contains a vibrating
microperforated membrane of tapered nozzles against a bulk liquid will generate a plume of
droplets without the need for compressed gas. In these embodiments, a solution in the
microperforated membrane nebulizer is in contact with a membrane, the opposite side of
which is open to the air. The membrane is perforated by a large number of nozzle orifices of
an atomizing head. An aerosol is created when alternating acoustic pressure in the solution is
built up in the vicinity of the membrane causing the fluid on the liquid side of the membrane
to be emitted through the nozzles as uniformly sized droplets.
Some embodiments the high efficiency liquid nebulizers use passive nozzle
membranes and a separate piezoelectric transducer that are in contact with the solution. In
contrast, some high efficiency liquid nebulizers employ an active nozzle membrane, which
use the acoustic pressure in the nebulizer to generate very fine droplets of solution via the
high frequency vibration of the nozzle membrane.
Some high efficiency liquid nebulizers contain a resonant system. In some such high
efficiency liquid nebulizers, the membrane is driven by a frequency for which the amplitude
147
of the vibrational movement at the center of the membrane is particularly large, resulting in a
focused acoustic pressure in the vicinity of the nozzle; the resonant frequency may be about
100kHz. A flexible mounting is used to keep unwanted loss of vibrational energy to the
mechanical surroundings of the atomizing head to a minimum. In some embodiments, the
vibrating membrane of the high efficiency liquid nebulizer may be made of a nickelpalladium alloy by electroforming.
In some embodiments, the high efficiency liquid nebulizer (i) achieves lung
deposition of at least about 5%, at least about 6%, at least about 7%, at least about 8%, at
least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%,
at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least
about 75%, at least about 80%, or at least about 85%, based on the nominal dose of the
pirfenidone or pyridone analog compound administered to the mammal.
In some embodiments, the high efficiency liquid nebulizer (ii) provides a Geometric
Standard Deviation (GSD) of emitted droplet size distribution of the solution administered
with the high efficiency liquid nebulizer of about 1.0 μm to about 2.5 μm, about 1.2 μm to
about 2.5 μm, about 1.3 μm to about 2.0 μm, at least about 1.4 μm to about 1.9 μm, at least
about 1.5 μm to about 1.9 μm, about 1.5 μm, about 1.7 μm, or about 1.9 μm.
In some embodiments, the high efficiency liquid nebulizer (iii) provides a mass
median aerodynamic diameter (MMAD) of droplet size of the solution emitted with the high
efficiency liquid nebulizer of about 1 μm to about 5 μm, about 2 to about 4 μm, or about 2.5
to about 4.0 μm. In some embodiments, the high efficiency liquid nebulizer (iii) provides a
volumetric mean diameter (VMD) 1 μm to about 5 μm, about 2 to about 4 μm, or about 2.5
to about 4.0 μm. In some embodiments, the high efficiency liquid nebulizer (iii) provides a
mass median diameter (MMD) 1 μm to about 5 μm, about 2 to about 4 μm, or about 2.5 to
about 4.0 μm.
In some embodiments, the high efficiency liquid nebulizer (iv) provides a fine particle
fraction (FPF= % ≤ 5 microns) of droplets emitted from the high efficiency nebulizer of at
least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about
80%, at least about 85%, or at least about 90%.
148
In some embodiments, the high efficiency liquid nebulizer (v) provides an output rate
of at least 0.1 mL/min, at least 0.2 mL/min, at least 0.3 mL/min, at least 0.4 mL/min, at least
0.5 mL/min, at least 0.6 mL/min, at least 0.8 mL/min, or at least 1.0 mL/min.
In some embodiments, the high efficiency liquid nebulizer (vi) delivers at least about
20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%,at least about 55%, at least about 60%, at least about 65%, at
least about 70%, at least about 75%, or at least about 80% of the fill volume to the mammal.
In some embodiments, the high efficiency liquid nebulizer provides an RDD of at
least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at
least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about
%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at
least about 80%, or at least about 85%.
In some embodiments, the high efficiency liquid nebulizer is characterized as
providing one or more of (i), (ii), (iii) (iv), (v), or (vi). In some embodiments, the high
efficiency liquid nebulizer is characterized as providing at least one, at least two, at least
three, at least four, at least five, or all six of (i), (ii), (iii) (iv), (v), or (vi).
Additional features of a high efficiency liquid nebulizer with perforated membranes
are disclosed in U.S. Pat. Nos. 6,962,151, 5,152,456, 5,261,601, and 5,518,179, US
6,983,747, each of which is hereby incorporated by reference in its entirety. Other
embodiments of the high efficiency liquid nebulizers contain oscillatable membranes.
Features of these high efficiency liquid nebulizers are disclosed in 7,252,085; 7,059, 320;
6,983,747, each of which is hereby incorporated by reference in its entirety.
Commercial high efficiency liquid nebulizers are available from: PARI (Germany)
under the trade name eFlow®; Nektar Therapeutics (San Carlos, CA) under the trade names
AeroNeb® Go and AeroNeb® Pro, and AeroNeb® Solo, Respironics (Murrysville, CA) under
the trade names I-Neb®, Omron (Bannockburn, IL) under the trade name Micro-Air®, and
Activaero (Germany) under the trade name Akita®. Commercial High Efficiency Nebulizers
are also available from Aerogen (Galaway, Ireland) utilizing the OnQ® nebulizer technology.
Meter Dose Inhaler (MDI)
149
A propellant driven inhaler (pMDI) releases a metered dose of medicine upon each
actuation. The medicine is formulated as a suspension or solution of a drug substance in a
suitable propellant such as a halogenated hydrocarbon. pMDIs are described in, for example,
Newman, S. P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224 (Butterworths,
London, England, 1984).
In some embodiments, the particle size of the drug substance in an MDI may be
optimally chosen. In some embodiments, the particles of active ingredient have diameters of
less than about 50 microns. In some embodiments, the particles have diameters of less than
about 10 microns. In some embodiments, the particles have diameters of from about 1
micron to about 5 microns. In some embodiments, the particles have diameters of less than
about 1 micron. In one advantageous embodiment, the particles have diameters of from
about 2 microns to about 5 microns.
By non-limiting example, metered-dose inhalers (MDI), the pirfenidone or pyridone
analog compound disclosed herein are prepared in dosages to deliver from about 34 mcg to
about 463 mg from a formulation meeting the requirements of the MDI. The pirfenidone or
pyridone analog compound disclosed herein may be soluble in the propellant, soluble in the
propellant plus a co-solvent (by non-limiting example ethanol), soluble in the propellant plus
an additional moiety promoting increased solubility (by non-limiting example glycerol or
phospholipid), or as a stable suspension or micronized, spray-dried or nanosuspension.
By non-limiting example, a metered-dose pirfenidone or pyridone analog compound
may be administered in the described respirable delivered dose in 10 or fewer inhalation
breaths, more preferably in 8 or fewer inhalation breaths, more preferably in 6 or fewer
inhalation breaths, more preferably in 8 or fewer inhalation breaths, more preferably in 4 or
fewer inhalation breaths, more preferably in 2 or fewer inhalation breaths.
The propellants for use with the MDIs may be any propellants known in the art.
Examples of propellants include chlorofluorocarbons (CFCs) such as
dichlorodifluoromethane, trichlorofluorometbane, and dichlorotetrafluoroethane;
hydrofluoroalkanes (HFAs); and carbon dioxide. It may be advantageous to use HFAs
instead of CFCs due to the environmental concerns associated with the use of CFCs.
Examples of medicinal aerosol preparations containing HFAs are presented in U.S. Patent
Nos. 6,585,958; 2,868,691 and 3,014,844, all of which are hereby incorporated by reference
150
in their entirety. In some embodiments, a co-solvent is mixed with the propellant to facilitate
dissolution or suspension of the drug substance.
In some embodiments, the propellant and active ingredient are contained in separate
containers, such as described in U.S. Patent No. 4,534,345, which is hereby incorporated by
reference in its entirety.
In some embodiments, the MDI used herein is activated by a patient pushing a lever,
button, or other actuator. In other embodiments, the release of the aerosol is breath activated
such that, after initially arming the unit, the active compound aerosol is released once the
patient begins to inhale, such as described in U.S. Patent Nos. 6,672,304; 5,404,871;
5,347,998; 5,284,133; 5,217,004; 5,119,806; 5,060,643; 4,664,107; 4,648,393; 3,789,843;
3,732,864; 3,636,949; 3,598,294; 3,565,070; 3,456,646; 3,456,645; and 3,456,644, each of
which is hereby incorporated by reference in its entirety. Such a system enables more of the
active compound to get into the lungs of the patient. Another mechanism to help a patient get
adequate dosage with the active ingredient may include a valve mechanism that allows a
patient to use more than one breath to inhale the drug, such as described in U.S. Patent Nos.
4,470,412 and 5,385,140, both of which are hereby incorporated by reference in their
entirety.
Additional examples of MDIs known in the art and suitable for use herein include
U.S. Patent Nos. 6,435,177; 6,585,958; 5,642,730; 6,223,746; 4,955,371; 5,404,871;
5,364,838; and 6,523,536, all of which are hereby incorporated by reference in their entirety.
Dry Powder Inhaler (DPI)
There are two major designs of dry powder inhalers. One design is the metering
device in which a reservoir for the drug is placed within the device and the patient adds a
dose of the drug into the inhalation chamber. The second is a factory-metered device in
which each individual dose has been manufactured in a separate container. Both systems
depend upon the formulation of drug into small particles of mass median diameters from
about 1 to about 5 micron, and usually involve co-formulation with larger excipient particles
(typically 100 micron diameter lactose particles). Drug powder is placed into the inhalation
chamber (either by device metering or by breakage of a factory-metered dosage) and the
inspiratory flow of the patient accelerates the powder out of the device and into the oral
cavity. Non-laminar flow characteristics of the powder path cause the excipient-drug
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aggregates to decompose, and the mass of the large excipient particles causes their impaction
at the back of the throat, while the smaller drug particles are deposited deep in the lungs.
As with liquid nebulization and MDIs, particle size of the pirfenidone or pyridone
analog compound aerosol formulation may be optimized. If the particle size is larger than
about 5 micron MMAD then the particles are deposited in upper airways. If the particle size
of the aerosol is smaller than about 1 micron then it is delivered into the alveoli and may get
transferred into the systemic blood circulation.
By non-limiting example, in dry powder inhalers, the pirfenidone or pyridone analog
compound disclosed herein are prepared in dosages to disperse and deliver from about 34
mcg to about 463 mg from a dry powder formulation.
By non-limiting example, a dry powder pirfenidone or pyridone analog compound
may be administered in the described respirable delivered dose in 10 or fewer inhalation
breaths, more preferably in 8 or fewer inhalation breaths, more preferably in 6 or fewer
inhalation breaths, more preferably in 8 or fewer inhalation breaths, more preferably in 4 or
fewer inhalation breaths, more preferably in 2 or fewer inhalation breaths.
In some embodiments, a dry powder inhaler (DPI) is used to dispense the pirfenidone
or pyridone analog compound described herein. DPIs contain the drug substance in fine dry
particle form. Typically, inhalation by a patient causes the dry particles to form an aerosol
cloud that is drawn into the patient’s lungs. The fine dry drug particles may be produced by
any technique known in the art. Some well-known techniques include use of a jet mill or
other comminution equipment, precipitation from saturated or super saturated solutions, spray
drying, in situ micronization (Hovione), or supercritical fluid methods. Typical powder
formulations include production of spherical pellets or adhesive mixtures. In adhesive
mixtures, the drug particles are attached to larger carrier particles, such as lactose
monohydrate of size about 50 to about 100 microns in diameter. The larger carrier particles
increase the aerodynamic forces on the carrier/drug agglomerates to improve aerosol
formation. Turbulence and/or mechanical devices break the agglomerates into their
constituent parts. The smaller drug particles are then drawn into the lungs while the larger
carrier particles deposit in the mouth or throat. Some examples of adhesive mixtures are
described in U.S. Patent No. 5,478,578 and PCT Publication Nos. WO 95/11666, WO
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87/05213, WO 96/23485, and WO 97/03649, all of which are incorporated by reference in
their entirety. Additional excipients may also be included with the drug substance.
There are three common types of DPIs, all of which may be used with the pirfenidone
or pyridone analog compounds described herein. In a single-dose DPI, a capsule containing
one dose of dry drug substance/excipients is loaded into the inhaler. Upon activation, the
capsule is breached, allowing the dry powder to be dispersed and inhaled using a dry powder
inhaler. To dispense additional doses, the old capsule must be removed and an additional
capsule loaded. Examples of single-dose DPIs are described in U.S. Patent Nos. 3,807,400;
3,906,950; 3,991,761; and 4,013,075, all of which are hereby incorporated by reference in
their entirety. In a multiple unit dose DPI, a package containing multiple single dose
compartments is provided. For example, the package may comprise a blister pack, where
each blister compartment contains one dose. Each dose can be dispensed upon breach of a
blister compartment. Any of several arrangements of compartments in the package can be
used. For example, rotary or strip arrangements are common. Examples of multiple unit
does DPIs are described in EPO Patent Application Publication Nos. 0211595A2,
0455463A1, and 0467172A1, all of which are hereby incorporated by reference in their
entirety. In a multi-dose DPI, a single reservoir of dry powder is used. Mechanisms are
provided that measure out single dose amounts from the reservoir to be aerosolized and
inhaled, such as described in U.S. Patent Nos. 5,829,434; 5,437,270; 2,587,215; 5,113,855;
5,840,279; 4,688,218; 4,667,668; 5,033,463; and 4,805,811 and PCT Publication No. WO
92/09322, all of which are hereby incorporated by reference in their entirety.
In some embodiments, auxiliary energy in addition to or other than a patient’s
inhalation may be provided to facilitate operation of a DPI. For example, pressurized air may
be provided to aid in powder de-agglomeration, such as described in U.S. Patent Nos.
3,906,950; 5,113,855; 5,388,572; 6,029,662 and PCT Publication Nos. WO 93/12831, WO
90/07351, and WO 99/62495, all of which are hereby incorporated by reference in their
entirety. Electrically driven impellers may also be provided, such as described in U.S. Patent
Nos. 3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT Publication No. WO 98/03217, all
of which are hereby incorporated by reference in their entirety. Another mechanism is an
electrically powered tapping piston, such as described in PCT Publication No. WO 90/13327,
which is hereby incorporated by reference in its entirety. Other DPIs use a vibrator, such as
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described in U.S. Patent Nos. 5,694,920 and 6,026,809, both of which are hereby
incorporated by reference in their entirety. Finally, a scraper system may be employed, such
as described in PCT Publication No. WO 93/24165, which is hereby incorporated by
reference in its entirety.
Additional examples of DPIs for use herein are described in U.S. Patent Nos.
4,811,731; 5,113,855; 5,840,279; 3,507,277; 3,669,113; 3,635,219; 3,991,761; 4,353,365;
4,889,144, 4,907,538; 5,829,434; 6,681,768; 6,561,186; 5,918,594; 6,003,512; 5,775,320;
,740,794; and 6,626,173, all of which are hereby incorporated by reference in their entirety.
In some embodiments, a spacer or chamber may be used with any of the inhalers
described herein to increase the amount of drug substance that gets absorbed by the patient,
such as is described in U.S. Patent Nos. 4,470,412; 4,790,305; 4,926,852; 5,012,803;
,040,527; 5,024,467; 5,816,240; 5,027,806; and 6,026,807, all of which are hereby
incorporated by reference in their entirety. For example, a spacer may delay the time from
aerosol production to the time when the aerosol enters a patient’s mouth. Such a delay may
improve synchronization between the patient’s inhalation and the aerosol production. A
mask may also be incorporated for infants or other patients that have difficulty using the
traditional mouthpiece, such as is described in U.S. Patent Nos. 4,809,692; 4,832,015;
,012,804; 5,427,089; 5,645,049; and 5,988,160, all of which are hereby incorporated by
reference in their entirety.
Dry powder inhalers (DPIs), which involve deaggregation and aerosolization of dry
powder particles, normally rely upon a burst of inspired air that is drawn through the unit to
deliver a drug dosage. Such devices are described in, for example, U.S. Pat. No. 4,807,814,
which is directed to a pneumatic powder ejector having a suction stage and an injection stage;
SU 628930 (Abstract), describing a hand-held powder disperser having an axial air flow tube;
Fox et al., Powder and Bulk Engineering, pages 33-36 (March 1988), describing a venturi
eductor having an axial air inlet tube upstream of a venturi restriction; EP 347 779, describing
a hand-held powder disperser having a collapsible expansion chamber, and U.S. Pat. No.
,785,049, directed to dry powder delivery devices for drugs.
Commercial examples of dry powder inhalers that can be used with the pirfenidone or
pyridone analog compound formulations described herein include the Aerolizer, Turohaler,
Handihaler and Discus.
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Solution/Dispersion Formulations
In one embodiment, aqueous formulations containing soluble or nanoparticulate drug
particles are provided. For aqueous aerosol formulations, the drug may be present at a
concentration from about 34 mcg/mL to about 463 mg/mL. In some embodiments the drug is
present at a concentration from about 1 mg/mL to about 463 mg/mL, or about 1 mg/mL to
about 400 mg/mL, or about 0.1 mg/mL to about 360 mg/mL, or about 1 mg/mL to about 300
mg/mL, or about 1 mg/mL to about 200 mg/mL, about 1 mg/mL to about 100 mg/mL, or
about 1 mg/mL to about 50 mg/mL, or about 5 mg/mL to about 50 mg/mL, or about 10
mg/mL to about 50 mg/mL, or about 15 mg/mL to about 50 mg/mL, or about 20 mg/mL to
about 50 mg/mL. Such formulations provide effective delivery to appropriate areas of the
lung, with the more concentrated aerosol formulations having the additional advantage of
enabling large quantities of drug substance to be delivered to the lung in a very short period
of time. In one embodiment, a formulation is optimized to provide a well tolerated
formulation. Accordingly, in one embodiment, pirfenidone or pyridone analog compound
disclosed herein are formulated to have good taste, pH from about 4.0 to about 8.0,
osmolarity from about 100 to about 5000 mOsmol/kg. In some embodiments, the osmolarity
is from about 100 to about 1000 mOsmol/kg. In some embodiments, the osmolarity is from
about 200 to about 500 mOsmol/kg. In some embodiments, the permeant ion concentration is
from about 30 to about 300 mM.
In some embodiments, described herein is an aqueous pharmaceutical composition
comprising pirfenidone or pyridone analog compound, water and one or more additional
ingredients selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents,
chelating agents, anti-oxidants, salts, and buffers. It should be understood that many
excipients may serve several functions, even within the same formulation.
In some embodiments, pharmaceutical compositions described herein do not include
any thickening agents.
In some embodiments, the concentration of pirfenidone or pyridone analog compound
in the aqueous pharmaceutical composition is between about 0.1 mg/mL and about 100
mg/mL. In some embodiments, the concentration of pirfenidone or pyridone analog
compound in the pharmaceutical composition is between about 1 mg/mL and about 100
mg/mL, between about 10 mg/mL and about 100 mg/mL between about 20 mg/mL and about
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100 mg/mL, between about 25 mg/mL and about 100 mg/mL, between about 30 mg/mL and
about 100 mg/mL, between about 15 mg/mL and about 50 mg/mL, between about 20 mg/mL
and about 50 mg/mL, between about 25 mg/mL and about 50 mg/mL, or between about 30
mg/mL and about 50 mg/mL.
In some embodiments, the pH is between about pH 4.0 and about pH 8.0. In some
embodiments, the pH is between about pH 5.0 and about pH 8.0. In some embodiments, the
pH is between about pH 6.0 and about pH 8.0. In some embodiments, the pH is between
about pH 6.5 and about pH 8.0.
In some embodiments, the aqueous pharmaceutical composition includes one or more
co-solvents. In some embodiments, the aqueous pharmaceutical composition includes one or
more co-solvents, where the total amount of co-solvents is from about 1% to about 50% v/v
of the total volume of the composition. In some embodiments, the aqueous pharmaceutical
composition includes one or more co-solvents, where the total amount of co-solvents is from
about 1% to about 50% v/v, from about 1% to about 40% v/v, from about 1% to about 30%
v/v, or from about 1% to about 25% v/v, of the total volume of the composition. Co-solvents
include, but are not limited to, ethanol, propylene glycol and glycerol. In some embodiments,
the aqueous pharmaceutical composition includes ethanol at about 1% v/v to about 25%. In
some embodiments, the aqueous pharmaceutical composition includes ethanol at about 1%
v/v to about 15%. In some embodiments, the aqueous pharmaceutical composition includes
ethanol at about 1% v/v, 2% v/v, 3% v/v, 4% v/v, 5% v/v, 6% v/v, 7% v/v, 8% v/v, 9% v/v,
% v/v, 11% v/v, 12% v/v, 13% v/v, 14% v/v, 15% v/v, 16% v/v, 17% v/v, 18% v/v, 19%
v/v, 20% v/v, 21% v/v, 22% v/v, 23% v/v, 24% v/v, or 25% v/v. In some embodiments, the
aqueous pharmaceutical composition includes glycerol at about 1% v/v to about 25%. In
some embodiments, the aqueous pharmaceutical composition includes glycerol at about 1%
v/v to about 15%. In some embodiments, the aqueous pharmaceutical composition includes
glycerol at about 1% v/v, 2% v/v, 3% v/v, 4% v/v, 5% v/v, 6% v/v, 7% v/v, 8% v/v, 9% v/v,
% v/v, 11% v/v, 12% v/v, 13% v/v, 14% v/v, 15% v/v, 16% v/v, 17% v/v, 18% v/v, 19%
v/v, 20% v/v, 21% v/v, 22% v/v, 23% v/v, 24% v/v, or 25% v/v. In some embodiments, the
aqueous pharmaceutical composition includes propylene glycol at about 1% v/v to about
50%. In some embodiments, the aqueous pharmaceutical composition includes propylene
glycol at about 1% v/v to about 25%. In some embodiments, the aqueous pharmaceutical
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composition includes propylene glycol at about 1% v/v, 2% v/v, 3% v/v, 4% v/v, 5% v/v, 6%
v/v, 7% v/v, 8% v/v, 9% v/v, 10% v/v, 11% v/v, 12% v/v, 13% v/v, 14% v/v, 15% v/v, 16%
v/v, 17% v/v, 18% v/v, 19% v/v, 20% v/v, 21% v/v, 22% v/v, 23% v/v, 24% v/v, or 25% v/v.
In some embodiments, the aqueous pharmaceutical composition includes ethanol at
about 1% v/v to about 25% and propylene glycol at about 1% v/v to about 50%. In some
embodiments, the aqueous pharmaceutical composition includes ethanol at about 1% v/v to
about 15% and propylene glycol at about 1% v/v to about 30%. In some embodiments, the
aqueous pharmaceutical composition includes ethanol at about 1% v/v to about 8% and
propylene glycol at about 1% v/v to about 16%. In some embodiments, the aqueous
pharmaceutical composition includes ethanol and twice as much propylene glycol, based on
volume.
In some embodiments, the aqueous pharmaceutical composition includes a buffer. In
some embodiments, the buffer is a citrate buffer or a phosphate buffer. In some embodiments,
the buffer is a citrate buffer. In some embodiments, the buffer is a phosphate buffer.
In some embodiments, the aqueous pharmaceutical composition consists essentially of
pirfenidone or pyridone analog compound, water, ethanol and/or propylene glycol, a buffer to
maintain the pH at about 4 to 8 and optionally one or more ingredients selected from salts,
surfactants, and sweeteners (taste-maksing agents). In some embodiments, the one or more
salts are selected from tonicity agents. In some embodiments, the one or more salts are
selected from sodium chloride and magnesium chloride.
In some embodiments, the aqueous pharmaceutical composition consists essentially of
pirfenidone or pyridone analog compound at a concentration of about 10 mg/mL to about
50mg/mL, water, one or two coslovents (ethanol at a concentration of about 1% v/v to about
% v/v and/or propylene glycol at a concentration of about 1% v/v to about 50% v/v), a
buffer to maintain the pH at about 4 to 8 and optionally one or more ingredients selected from
salts, surfactants, and sweeteners (taste-maksing agents).
In one embodiment, the solution or diluent used for preparation of aerosol
formulations has a pH range from about 4.0 to about 8.0. This pH range improves
tolerability. When the aerosol is either acidic or basic, it can cause bronchospasm and cough.
Although the safe range of pH is relative and some patients may tolerate a mildly acidic
aerosol, while others will experience bronchospasm. Any aerosol with a pH of less than
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about 4.0 typically induces bronchospasm. Aerosols having pH greater than about 8.0 may
have low tolerability because body tissues are generally unable to buffer alkaline aerosols.
Aerosols with controlled pH below about 4.0 and over about 8.0 typically result in lung
irritation accompanied by severe bronchospasm cough and inflammatory reactions. For these
reasons as well as for the avoidance of bronchospasm, cough or inflammation in patients, the
optimum pH for the aerosol formulation was determined to be between about pH 4.0 to about
pH 8.0.
By non-limiting example, compositions may also include a buffer or a pH adjusting
agent, typically a salt prepared from an organic acid or base. Representative buffers include
organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid,
succinic acid, acetic acid, or phthalic acid, Tris, tromethamine, hydrochloride, or phosphate
buffers.
Many patients have increased sensitivity to various chemical tastes, including bitter,
salt, sweet, metallic sensations. To create well-tolerated drug products, by non-limiting
example taste masking may be accomplished through the addition of taste-masking
excipients, adjusted osmolality, and sweeteners.
Many patients have increased sensitivity to various chemical agents and have high
incidence of bronchospastic, asthmatic or other coughing incidents. Their airways are
particularly sensitive to hypotonic or hypertonic and acidic or alkaline conditions and to the
presence of any permanent ion, such as chloride. Any imbalance in these conditions or a
presence of chloride above certain value leads to bronchospastic or inflammatory events
and/or cough which greatly impair treatment with inhalable formulations. Both these
conditions prevent efficient delivery of aerosolized drugs into the endobronchial space.
In some embodiments, the osmolality of aqueous solutions of the pirfenidone or
pyridone analog compound disclosed herein are adjusted by providing excipients. In some
cases, a certain amount of chloride or another anion is needed for successful and efficacious
delivery of aerosolized pirfenidone or pyridone analog compound.
In some embodiments, the osmolality of aqueous solutions of the pirfenidone or
pyridone analog compound disclosed herein is greater than 100 mOsmol/kg. In some
embodiments, the osmolality of aqueous solutions of the pirfenidone or pyridone analog
compound disclosed herein is greater than 300 mOsmol/kg. In some embodiments, the
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osmolality of aqueous solutions of the pirfenidone or pyridone analog compound disclosed
herein is greater than 1000 mOsmol/kg. In some embodiments, aerosol delivery of aqueous
solutions with high osmolality (i.e. greater than about 300 mOsmol/kg) have high incidence
of bronchospastic, asthmatic or other coughing incidents. In some embodiments, aerosol
delivery of the aqueous solutions having high osmolality (i.e. greater than about 300
mOsmol/kg) as described do not increase the incidence of bronchospastic, asthmatic or other
coughing incidents.
In some embodiments, the osmolality of aqueous solutions of the pirfenidone or
pyridone analog compound disclosed herein are are greater than 100 mOsmol/kg above by
providing excipients. In some cases, a certain amount of chloride or another anion is needed
for successful and efficacious delivery of aerosolized pirfenidone or pyridone analog
compound
In some embodiments, the formulation for an aerosol pirfenidone or pyridone analog
compound may comprise from about 34 mcg to about 463 mg pirfenidone or pyridone analog
compound per about 1 to about 5 ml of dilute saline (between 1/10 to 2/1 normal saline).
Accordingly, the concentration of a pirfenidone or pyridone analog compound solution may
be greater than about 34 mcg/ml, greater than about 463 mcg/ml, greater than about 1 mg/ml,
greater than about 2 mg/mL, greater than about 3.0 mg/mL, greater than about 3.7 mg/mL,
greater than about 10 mg/mL, greater than about 37 mg/mL, greater than about 50 mg/ml,
greater than about 100 mg/mL, or greater than 463 mg/mL.
In some embodiments, solution osmolality is from about 100 mOsmol/kg to about
6000 mOsmol/kg. In some embodiments, solution osmolality is from about 100 mOsmol/kg
to about 5000 mOsmol/kg. In some other embodiments, the solution osmolality is from about
400 mOsmol/kg to about 5000 mOsmol/kg.
In one embodiments, permeant ion concentration is from about 25 mM to about 400
mM. In various other embodiments, permeant ion concentration is from about 30 mM to
about 300 mM; from about 40 mM to about 200 mM; and from about 50 mM to about 150
mM.
Solid Particle Formulations
In some embodiments, solid drug nanoparticles are provided for use in generating dry
aerosols or for generating nanoparticles in liquid suspension. Powders comprising
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nanoparticulate drug can be made by spray-drying aqueous dispersions of a nanoparticulate
drug and a surface modifier to form a dry powder which consists of aggregated drug
nanoparticles. In one embodiment, the aggregates can have a size of about 1 to about 2
microns which is suitable for deep lung delivery. The aggregate particle size can be
increased to target alternative delivery sites, such as the upper bronchial region or nasal
mucosa by increasing the concentration of drug in the spray-dried dispersion or by increasing
the droplet size generated by the spray dryer.
Alternatively, an aqueous dispersion of drug and surface modifier can contain a
dissolved diluent such as lactose or mannitol which, when spray dried, forms respirable
diluent particles, each of which contains at least one embedded drug nanoparticle and surface
modifier. The diluent particles with embedded drug can have a particle size of about 1 to
about 2 microns, suitable for deep lung delivery. In addition, the diluent particle size can be
increased to target alternate delivery sites, such as the upper bronchial region or nasal mucosa
by increasing the concentration of dissolved diluent in the aqueous dispersion prior to spray
drying, or by increasing the droplet size generated by the spray dryer.
Spray-dried powders can be used in DPIs or pMDIs, either alone or combined with
freeze-dried nanoparticulate powder. In addition, spray-dried powders containing drug
nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate
aqueous dispersions having respirable droplet sizes, where each droplet contains at least one
drug nanoparticle. Concentrated nanoparticulate dispersions may also be used in these
embodiments of the invention.
Nanoparticulate drug dispersions can also be freeze-dried to obtain powders suitable
for nasal or pulmonary delivery. Such powders may contain aggregated nanoparticulate drug
particles having a surface modifier. Such aggregates may have sizes within a respirable
range, e.g., about 1 to about 5 microns MMAD.
Freeze dried powders of the appropriate particle size can also be obtained by freeze
drying aqueous dispersions of drug and surface modifier, which additionally contain a
dissolved diluent such as lactose or mannitol. In these instances the freeze dried powders
consist of respirable particles of diluent, each of which contains at least one embedded drug
nanoparticle.
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Freeze-dried powders can be used in DPIs or pMDIs, either alone or combined with
spray-dried nanoparticulate powder. In addition, freeze-dried powders containing drug
nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate
aqueous dispersions that have respirable droplet sizes, where each droplet contains at least
one drug nanoparticle.
One embodiment described herein is directed to a process and composition for
propellant-based systems comprising nanoparticulate drug particles and a surface modifier.
Such formulations may be prepared by wet milling the coarse drug substance and surface
modifier in liquid propellant, either at ambient pressure or under high pressure conditions.
Alternatively, dry powders containing drug nanoparticles may be prepared by spray-drying or
freeze-drying aqueous dispersions of drug nanoparticles and the resultant powders dispersed
into suitable propellants for use in conventional pMDIs. Such nanoparticulate pMDI
formulations can be used for either nasal or pulmonary delivery. For pulmonary
administration, such formulations afford increased delivery to the deep lung regions because
of the small (e.g., about 1 to about 2 microns MMAD) particle sizes available from these
methods. Concentrated aerosol formulations can also be employed in pMDIs.
Another embodiment is directed to dry powders which contain nanoparticulate
compositions for pulmonary or nasal delivery. The powders may consist of respirable
aggregates of nanoparticulate drug particles, or of respirable particles of a diluent which
contains at least one embedded drug nanoparticle. Powders containing nanoparticulate drug
particles can be prepared from aqueous dispersions of nanoparticles by removing the water
via spray-drying or lyophilization (freeze drying). Spray-drying is less time consuming and
less expensive than freeze-drying, and therefore more cost-effective. However, certain drugs,
such as biologicals benefit from lyophilization rather than spray-drying in making dry powder
formulations.
Conventional micronized drug particles used in dry powder aerosol delivery having
particle diameters of from about 1 to about 5 microns MMAD are often difficult to meter and
disperse in small quantities because of the electrostatic cohesive forces inherent in such
powders. These difficulties can lead to loss of drug substance to the delivery device as well
as incomplete powder dispersion and sub-optimal delivery to the lung. Many drug
compounds, particularly proteins and peptides, are intended for deep lung delivery and
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systemic absorption. Since the average particle sizes of conventionally prepared dry powders
are usually in the range of from about 1 to about 5 microns MMAD, the fraction of material
which actually reaches the alveolar region may be quite small. Thus, delivery of micronized
dry powders to the lung, especially the alveolar region, is generally very inefficient because
of the properties of the powders themselves.
The dry powder aerosols which contain nanoparticulate drugs can be made smaller
than comparable micronized drug substance and, therefore, are appropriate for efficient
delivery to the deep lung. Moreover, aggregates of nanoparticulate drugs are spherical in
geometry and have good flow properties, thereby aiding in dose metering and deposition of
the administered composition in the lung or nasal cavities.
Dry nanoparticulate compositions can be used in both DPIs and pMDIs. As used
herein, "dry" refers to a composition having less than about 5% water.
In one embodiment, compositions are provided containing nanoparticles which have
an effective average particle size of less than about 1000 nm, more preferably less than about
400 nm, less than about 300 nm, less than about 250 nm, or less than about 200 nm, as
measured by light-scattering methods. By "an effective average particle size of less than
about 1000 nm" it is meant that at least 50% of the drug particles have a weight average
particle size of less than about 1000 nm when measured by light scattering techniques.
Preferably, at least 70% of the drug particles have an average particle size of less than about
1000 nm, more preferably at least 90% of the drug particles have an average particle size of
less than about 1000 nm, and even more preferably at least about 95% of the particles have a
weight average particle size of less than about 1000 nm.
For aqueous aerosol formulations, the nanoparticulate pirfenidone or pyridone analog
compound agent may be present at a concentration of about 34 mcg/mL up to about 463
mg/mL. For dry powder aerosol formulations, the nanoparticulate agent may be present at a
concentration of about 34 mg/g up to about 463 mg/g, depending on the desired drug dosage.
Concentrated nanoparticulate aerosols, defined as containing a nanoparticulate drug at a
concentration of about 34 mcg/mL up to about 463 mg/mL for aqueous aerosol formulations,
and about 34 mg/g up to about 463 mg/g for dry powder aerosol formulations, are specifically
provided. Such formulations provide effective delivery to appropriate areas of the lung or
nasal cavities in short administration times, i.e., less than about 3-15 seconds per dose as
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compared to administration times of up to 4 to 20 minutes as found in conventional
pulmonary nebulizer therapies.
Nanoparticulate drug compositions for aerosol administration can be made by, for
example, (1) nebulizing a dispersion of a nanoparticulate drug, obtained by either grinding or
precipitation; (2) aerosolizing a dry powder of aggregates of nanoparticulate drug and surface
modifier (the aerosolized composition may additionally contain a diluent); or (3) aerosolizing
a suspension of nanoparticulate drug or drug aggregates in a non-aqueous propellant. The
aggregates of nanoparticulate drug and surface modifier, which may additionally contain a
diluent, can be made in a non-pressurized or a pressurized non-aqueous system.
Concentrated aerosol formulations may also be made via such methods.
Milling of aqueous drug to obtain nanoparticulate drug may be performed by
dispersing drug particles in a liquid dispersion medium and applying mechanical means in the
presence of grinding media to reduce the particle size of the drug to the desired effective
average particle size. The particles can be reduced in size in the presence of one or more
surface modifiers. Alternatively, the particles can be contacted with one or more surface
modifiers after attrition. Other compounds, such as a diluent, can be added to the
drug/surface modifier composition during the size reduction process. Dispersions can be
manufactured continuously or in a batch mode.
Another method of forming nanoparticle dispersion is by microprecipitation. This is a
method of preparing stable dispersions of drugs in the presence of one or more surface
modifiers and one or more colloid stability enhancing surface active agents free of any trace
toxic solvents or solubilized heavy metal impurities. Such a method comprises, for example,
(1) dissolving the drug in a suitable solvent with mixing; (2) adding the formulation from step
(1) with mixing to a solution comprising at least one surface modifier to form a clear
solution; and (3) precipitating the formulation from step (2) with mixing using an appropriate
nonsolvent. The method can be followed by removal of any formed salt, if present, by
dialysis or diafiltration and concentration of the dispersion by conventional means. The
resultant nanoparticulate drug dispersion can be utilized in liquid nebulizers or processed to
form a dry powder for use in a DPI or pMDI.
In a non-aqueous, non-pressurized milling system, a non-aqueous liquid having a
vapor pressure of about 1 atm or less at room temperature and in which the drug substance is
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essentially insoluble may be used as a wet milling medium to make a nanoparticulate drug
composition. In such a process, a slurry of drug and surface modifier may be milled in the
non-aqueous medium to generate nanoparticulate drug particles. Examples of suitable nonaqueous media include ethanol, trichloromonofluoromethane, (CFC-11), and
dichlorotetafluoroethane (CFC-114). An advantage of using CFC-11 is that it can be handled
at only marginally cool room temperatures, whereas CFC-114 requires more controlled
conditions to avoid evaporation. Upon completion of milling the liquid medium may be
removed and recovered under vacuum or heating, resulting in a dry nanoparticulate
composition. The dry composition may then be filled into a suitable container and charged
with a final propellant. Exemplary final product propellants, which ideally do not contain
chlorinated hydrocarbons, include HFA-134a (tetrafluoroethane) and HFA-227
(heptafluoropropane). While non-chlorinated propellants may be preferred for environmental
reasons, chlorinated propellants may also be used in this embodiment of the invention.
In a non-aqueous, pressurized milling system, a non-aqueous liquid medium having a
vapor pressure significantly greater than 1 atm at room temperature may be used in the
milling process to make nanoparticulate drug compositions. If the milling medium is a
suitable halogenated hydrocarbon propellant, the resultant dispersion may be filled directly
into a suitable pMDI container. Alternately, the milling medium can be removed and
recovered under vacuum or heating to yield a dry nanoparticulate composition. This
composition can then be filled into an appropriate container and charged with a suitable
propellant for use in a pMDI.
Spray drying is a process used to obtain a powder containing nanoparticulate drug
particles following particle size reduction of the drug in a liquid medium. In general, spraydrying may be used when the liquid medium has a vapor pressure of less than about 1 atm at
room temperature. A spray-dryer is a device which allows for liquid evaporation and drug
powder collection. A liquid sample, either a solution or suspension, is fed into a spray
nozzle. The nozzle generates droplets of the sample within a range of about 20 to about 100
micron in diameter which are then transported by a carrier gas into a drying chamber. The
carrier gas temperature is typically from about 80 to about 200º C. The droplets are subjected
to rapid liquid evaporation, leaving behind dry particles which are collected in a special
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reservoir beneath a cyclone apparatus. Smaller particles in the range down about 1 micron to
about 5 microns are also possible.
If the liquid sample consists of an aqueous dispersion of nanoparticles and surface
modifier, the collected product will consist of spherical aggregates of the nanoparticulate
drug particles. If the liquid sample consists of an aqueous dispersion of nanoparticles in
which an inert diluent material was dissolved (such as lactose or mannitol), the collected
product will consist of diluent (e.g., lactose or mannitol) particles which contain embedded
nanoparticulate drug particles. The final size of the collected product can be controlled and
depends on the concentration of nanoparticulate drug and/or diluent in the liquid sample, as
well as the droplet size produced by the spray-dryer nozzle. Collected products may be used
in conventional DPIs for pulmonary or nasal delivery, dispersed in propellants for use in
pMDIs, or the particles may be reconstituted in water for use in nebulizers.
In some instances it may be desirable to add an inert carrier to the spray-dried
material to improve the metering properties of the final product. This may especially be the
case when the spray dried powder is very small (less than about 5 micron) or when the
intended dose is extremely small, whereby dose metering becomes difficult. In general, such
carrier particles (also known as bulking agents) are too large to be delivered to the lung and
simply impact the mouth and throat and are swallowed. Such carriers typically consist of
sugars such as lactose, mannitol, or trehalose. Other inert materials, including
polysaccharides and cellulosics, may also be useful as carriers.
Spray-dried powders containing nanoparticulate drug particles may used in
conventional DPIs, dispersed in propellants for use in pMDIs, or reconstituted in a liquid
medium for use with nebulizers.
For compounds that are denatured or destabilized by heat, such as compounds having
a low melting point (i.e., about 70 to about 150º C.), or for example, biologics, sublimation is
preferred over evaporation to obtain a dry powder nanoparticulate drug composition. This is
because sublimation avoids the high process temperatures associated with spray-drying. In
addition, sublimation, also known as freeze-drying or lyophilization, can increase the shelf
stability of drug compounds, particularly for biological products. Freeze-dried particles can
also be reconstituted and used in nebulizers. Aggregates of freeze-dried nanoparticulate drug
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particles can be blended with either dry powder intermediates or used alone in DPIs and
pMDIs for either nasal or pulmonary delivery.
Sublimation involves freezing the product and subjecting the sample to strong
vacuum conditions. This allows for the formed ice to be transformed directly from a solid
state to a vapor state. Such a process is highly efficient and, therefore, provides greater yields
than spray-drying. The resultant freeze-dried product contains drug and modifier(s). The
drug is typically present in an aggregated state and can be used for inhalation alone (either
pulmonary or nasal), in conjunction with diluent materials (lactose, mannitol, etc.), in DPIs or
pMDIs, or reconstituted for use in a nebulizer.
Liposomal Compositions
In some embodiments, pirfenidone or pyridone analog compounds disclosed herein
may be formulated into liposome particles, which can then be aerosolized for inhaled
delivery. Lipids which are useful in the present invention can be any of a variety of lipids
including both neutral lipids and charged lipids. Carrier systems having desirable properties
can be prepared using appropriate combinations of lipids, targeting groups and circulation
enhancers. Additionally, the compositions provided herein can be in the form of liposomes
or lipid particles, preferably lipid particles. As used herein, the term "lipid particle" refers to
a lipid bilayer carrier which "coats" a nucleic acid and has little or no aqueous interior. More
particularly, the term is used to describe a self-assembling lipid bilayer carrier in which a
portion of the interior layer comprises cationic lipids which form ionic bonds or ion-pairs
with negative charges on the nucleic acid (e.g., a plasmid phosphodiester backbone). The
interior layer can also comprise neutral or fusogenic lipids and, in some embodiments,
negatively charged lipids. The outer layer of the particle will typically comprise mixtures of
lipids oriented in a tail-to-tail fashion (as in liposomes) with the hydrophobic tails of the
interior layer. The polar head groups present on the lipids of the outer layer will form the
external surface of the particle.
Liposomal bioactive agents can be designed to have a sustained therapeutic effect or
lower toxicity allowing less frequent administration and an enhanced therapeutic index.
Liposomes are composed of bilayers that entrap the desired pharmaceutical. These can be
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configured as multilamellar vesicles of concentric bilayers with the pharmaceutical trapped
within either the lipid of the different layers or the aqueous space between the layers.
By non-limiting example, lipids used in the compositions may be synthetic, semisynthetic or naturally-occurring lipids, including phospholipids, tocopherols, steroids, fatty
acids, glycoproteins such as albumin, negatively-charged lipids and cationic lipids.
Phosholipids include egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg
phosphatidylinositol (EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine (EPE),
and egg phosphatidic acid (EPA); the soya counterparts, soy phosphatidylcholine (SPC);
SPG, SPS, SPI, SPE, and SPA; the hydrogenated egg and soya counterparts (e.g., HEPC,
HSPC), other phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol
positions containing chains of 12 to 26 carbon atoms and different head groups in the 1
position of glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as
the corresponding phosphatidic acids. The chains on these fatty acids can be saturated or
unsaturated, and the phospholipid can be made up of fatty acids of different chain lengths and
different degrees of unsaturation. In particular, the compositions of the formulations can
include dipalmitoylphosphatidylcholine (DPPC), a major constituent of naturally-occurring
lung surfactant as well as dioleoylphosphatidylcholine (DOPC) and
dioleoylphosphatidylglycerol (DOPG). Other examples include
dimyristoylphosphatidycholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG)
dipalmitoylphosphatidcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG)
distearoylphosphatidylcholine (DSPC) and distearoylphosphatidylglycerol (DSPG),
dioleylphosphatidylethanolamine (DOPE) and mixed phospholipids like
palmitoylstearoylphosphatidylcholine (PSPC) and palmitoylstearoylphosphatidylglycerol
(PSPG), and single acylated phospholipids like mono-oleoyl-phosphatidylethanolamine
(MOPE).
In a preferred embodiment, PEG-modified lipids are incorporated into the
compositions described herein as the aggregation-preventing agent. The use of a PEGmodified lipid positions bulky PEG groups on the surface of the liposome or lipid carrier and
prevents binding of DNA to the outside of the carrier (thereby inhibiting cross-linking and
aggregation of the lipid carrier). The use of a PEG-ceramide is often preferred and has the
additional advantages of stabilizing membrane bilayers and lengthening circulation lifetimes.
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Additionally, PEG-ceramides can be prepared with different lipid tail lengths to control the
lifetime of the PEG-ceramide in the lipid bilayer. In this manner, "programmable" release
can be accomplished which results in the control of lipid carrier fusion. For example, PEGceramides having C20 -acyl groups attached to the ceramide moiety will diffuse out of a lipid
bilayer carrier with a half-life of 22 hours. PEG-ceramides having C14 - and C8 -acyl groups
will diffuse out of the same carrier with half-lives of 10 minutes and less than 1 minute,
respectively. As a result, selection of lipid tail length provides a composition in which the
bilayer becomes destabilized (and thus fusogenic) at a known rate. Though less preferred,
other PEG-lipids or lipid-polyoxyethylene conjugates are useful in the present compositions.
Examples of suitable PEG-modified lipids include PEG-modified phosphatidylethanolamine
and phosphatidic acid, PEG-modified diacylglycerols and dialkylglycerols, PEG-modified
dialkylamines and PEG-modified 1,2-diacyloxypropanamines. Particularly preferred are
PEG-ceramide conjugates (e.g., PEG-Cer-C8, PEG-Cer-C14 or PEG-Cer-C20) which are
described in U.S. Pat. No. 5,820,873, incorporated herein by reference.
The compositions described herein can be prepared to provide liposome compositions
which are about 50 nm to about 400 nm in diameter. One with skill in the art will understand
that the size of the compositions can be larger or smaller depending upon the volume which is
encapsulated. Thus, for larger volumes, the size distribution will typically be from about 80
nm to about 300 nm.
Surface Modifiers
Pirfenidone or pyridone analog compounds disclosed herein may be prepared in a
pharmaceutical composition with suitable surface modifiers which may be selected from
known organic and inorganic pharmaceutical excipients. Such excipients include low
molecular weight oligomers, polymers, surfactants and natural products. Preferred surface
modifiers include nonionic and ionic surfactants. Two or more surface modifiers can be used
in combination.
Representative examples of surface modifiers include cetyl pyridinium chloride,
gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia, cholesterol, tragacanth,
stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl
alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g.,
macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives,
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polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens™, such
as e.g., Tween 20™, and Tween 80™, (ICI Specialty Chemicals)); polyethylene glycols (e.g.,
Carbowaxs 3350™, and 1450™., and Carbopol 934™, (Union Carbide)), dodecyl trimethyl
ammonium bromide, polyoxyethylenestearates, colloidal silicon dioxide, phosphates, sodium
dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose (HPC, HPC-SL,
and HPC-L), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine,
polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 4-(1,1,3,3-tetaamethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and
triton), poloxamers (e.g., Pluronics F68™, and F108™., which are block copolymers of
ethylene oxide and propylene oxide); poloxamnines (e.g., Tetronic 908™., also known as
Poloxamine 908™., which is a tetrafunctional block copolymer derived from sequential
addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte
Corporation, Parsippany, N.J.)); a charged phospholipid such as dimyristoyl phophatidyl
glycerol, dioctylsulfosuccinate (DOSS); Tetronic 1508™; (T-1508) (BASF Wyandotte
Corporation), dialkylesters of sodium sulfosuccinic acid (e.g., Aerosol OT™., which is a
dioctyl ester of sodium sulfosuccinic acid (American Cyanamid)); Duponol P™., which is a
sodium lauryl sulfate (DuPont); Tritons X-200™., which is an alkyl aryl polyether sulfonate
(Rohm and Haas); Crodestas F-110™., which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-log™, or
Surfactant 10-G™, (Olin Chemicals, Stamford, Conn.); Crodestas SL-40™, (Croda, Inc.);
and SA9OHCO, which is C18 H37 CH2 (CON(CH3)-CH2 (CHOH)4 (CH2 OH)2 (Eastman
Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D25 maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-Nmethylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-Dglucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-Nmethylglucarmide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; and the
like. Tyloxapol is a particularly preferred surface modifier for the pulmonary or intranasal
delivery of steroids, even more so for nebulization therapies.
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Examples of surfactants for use in the solutions disclosed herein include, but are not
limited to, ammonium laureth sulfate, cetamine oxide, cetrimonium chloride, cetyl alcohol,
cetyl myristate, cetyl palmitate, cocamide DEA, cocamidopropyl betaine,
cocamidopropylamine oxide, cocamide MEA, DEA lauryl sulfate, di-stearyl phthalic acid
amide, dicetyl dimethyl ammonium chloride, dipalmitoylethyl hydroxethylmonium, disodium
laureth sulfosuccinate, di(hydrogenated) tallow phthalic acid, glyceryl dilaurate, glyceryl
distearate, glyceryl oleate, glyceryl stearate, isopropyl myristate nf, isopropyl palmitate nf,
lauramide DEA, lauramide MEA, lauramide oxide, myristamine oxide, octyl isononanoate,
octyl palmitate, octyldodecyl neopentanoate, olealkonium chloride, PEG-2 stearate, PEG-32
glyceryl caprylate/caprate, PEG-32 glyceryl stearate, PEG-4 and PEG-150 stearate &
distearate, PEG-4 to PEG-150 laurate & dilaurate, PEG-4 to PEG-150 oleate & dioleate,
PEG-7 glyceryl cocoate, PEG-8 beeswax, propylene glycol stearate, sodium C14-16 olefin
sulfonate, sodium lauryl sulfoacetate, sodium lauryl sulphate, sodium trideceth sulfate,
stearalkonium chloride, stearamide oxide, TEA-dodecylbenzene sulfonate, TEA lauryl sulfate
Most of these surface modifiers are known pharmaceutical excipients and are
described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the
American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The
Pharmaceutical Press, 1986), specifically incorporated by reference. The surface modifiers
are commercially available and/or can be prepared by techniques known in the art. The
relative amount of drug and surface modifier can vary widely and the optimal amount of the
surface modifier can depend upon, for example, the particular drug and surface modifier
selected, the critical micelle concentration of the surface modifier if it forms micelles, the
hydrophilic-lipophilic-balance (HLB) of the surface modifier, the melting point of the surface
modifier, the water solubility of the surface modifier and/or drug, the surface tension of water
solutions of the surface modifier, etc.
In the present invention, the optimal ratio of drug to surface modifier is ~0.1% to
~99.9% pirfenidone or pyridone analog compound, more preferably about 10% to about 90%.
Microspheres
Microspheres can be used for pulmonary delivery of pirfenidone or pyridone analog
compounds by first adding an appropriate amount of drug compound to be solubilzed in
water. For example, an aqueous pirfenidone or pyridone analog compound solution may be
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dispersed in methylene chloride containing a predetermined amount (0.1-1% w/v) of
poly(DL-lactide-co-glycolide) (PLGA) by probe sonication for 1-3 min on an ice bath.
Separately, a pirfenidone or pyridone analog compound may be solubilized in methylene
chloride containing PLGA (0.1-1% w/v). The resulting water-in-oil primary emulsion or the
polymer/drug solution will be dispersed in an aqueous continuous phase consisting of 1-2%
polyvinyl alcohol (previously cooled to 4ºC) by probe sonication for 3-5 min on an ice bath.
The resulting emulsion will be stirred continuously for 2-4 hours at room temperature to
evaporate methylene chloride. Microparticles thus formed will be separated from the
continuous phase by centrifuging at 8000-10000 rpm for 5-10 min. Sedimented particles will
be washed thrice with distilled water and freeze dried. Freeze-dried pirfenidone or pyridone
analog compound microparticles will be stored at -20ºC.
By non-limiting example, a spray drying approach will be employed to prepare
pirfenidone or pyridone analog compound microspheres. An appropriate amount of
pirfenidone or pyridone analog compound will be solubilized in methylene chloride
containing PLGA (0.1-1%). This solution will be spray dried to obtain the microspheres.
By non-limiting example, pirfenidone or pyridone analog compound microparticles
will be characterized for size distribution (requirement: 90% <5 µm, 95% <10 µm), shape,
drug loading efficiency and drug release using appropriate techniques and methods.
By non-limiting example, this approach may also be used to sequester and improve
the water solubility of solid, AUC shape-enhancing formulations, such as low-solubility
pirfenidone or pyridone analog compounds or salt forms for nanoparticle-based formulations.
A certain amount of pirfenidone or pyridone analog compound can be first dissolved
in the minimal quantity of ethanol 96% necessary to maintain the fluoroquinolnoe in solution
when diluted with water from 96 to 75%. This solution can then be diluted with water to
obtain a 75% ethanol solution and then a certain amount of paracetamol can be added to
obtain the following w/w drug/polymer ratios: 1:2, 1:1, 2:1, 3:1, 4:1, 6:1, 9:1, and 19:1.
These final solutions are spray-dried under the following conditions: feed rate, 15 mL/min;
inlet temperature, 110ºC; outlet temperature, 85ºC; pressure 4 bar and throughput of drying
air, 35m3/hr. Powder is then collected and stored under vacuum in a dessiccator.
Solid Lipid Particles
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Preparation of pirfenidone or pyridone analog compound solid lipid particles may
involve dissolving the drug in a lipid melt (phospholipids such as phophatidyl choline and
phosphatidyl serine) maintained at least at the melting temperature of the lipid, followed by
dispersion of the drug-containing melt in a hot aqueous surfactant solution (typically 1-5%
w/v) maintained at least at the melting temperature of the lipid. The coarse dispersion will be
homogenized for 1-10 min using a Microfluidizer® to obtain a nanoemulsion. Cooling the
nanoemulsion to a temperature between 4-25ºC will re-solidify the lipid, leading to formation
of solid lipid nanoparticles. Optimization of formulation parameters (type of lipid matrix,
surfactant concentration and production parameters) will be performed so as to achieve a
prolonged drug delivery. By non-limiting example, this approach may also be used to
sequester and improve the water solubility of solid, AUC shape-enhancing formulations, such
as low-solubility pirfenidone or pyridone analog compounds or salt forms for nanoparticlebased formulations.
Melt-Extrusion AUC Shape-Enhancing Formulation
Melt-Extrusion AUC shape-enhancing pirfenidone or pyridone analog compound
formulations may be preparation by dissolving the drugs in micelles by adding surfactants or
preparing micro-emulsion, forming inclusion complexes with other molecules such as
cyclodextrins, forming nanoparticles of the drugs, or embedding the amorphous drugs in a
polymer matrix. Embedding the drug homogeneously in a polymer matrix produces a solid
dispersion. Solid dispersions can be prepared in two ways: the solvent method and the hot
melt method. The solvent method uses an organic solvent wherein the drug and appropriate
polymer are dissolved and then (spray) dried. The major drawbacks of this method are the
use of organic solvents and the batch mode production process. The hot melt method uses
heat in order to disperse or dissolve the drug in an appropriate polymer. The melt-extrusion
process is an optimized version of the hot melt method. The advantage of the melt-extrusion
approach is lack of organic solvent and continuous production process. As the melt-extrusion
is a novel pharmaceutical technique, the literature dealing with it is limited. The technical
set-up involves a mixture and extrusion of pirfenidone or pyridone analog compound,
hydroxypropyl-b-cyclodextrin (HP-b-CD), and hydroxypropylmethylcellulose (HPMC), in
order to, by non-limiting example create a AUC shape-enhancing formulation of pirfenidone
or pyridone analog compound. Cyclodextrin is a toroidal-shaped molecule with hydroxyl
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groups on the outer surface and a cavity in the center. Cyclodextrin sequesters the drug by
forming an inclusion complex. The complex formation between cyclodextrins and drugs has
been investigated extensively. It is known that water-soluble polymer interacts with
cyclodextrin and drug in the course of complex formation to form a stabilized complex of
drug and cyclodextrin co-complexed with the polymer. This complex is more stable than the
classic cyclodextrin-drug complex. As one example, HPMC is water soluble; hence using
this polymer with HP-b-CD in the melt is expected to create an aqueous soluble AUC shapeenhancing formulation. By non-limiting example, this approach may also be used to
sequester and improve the water solubility of solid, AUC shape-enhancing formulations, such
as low-solubility pirfenidone or pyridone analog compounds or salt forms for nanoparticlebased formulations.
Co-Precipitates
Co-precipitate pirfenidone or pyridone analog compound formulations may be
prepared by formation of co-precipitates with pharmacologically inert, polymeric materials.
It has been demonstrated that the formation of molecular solid dispersions or co-precipitates
to create an AUC shape-enhancing formulations with various water-soluble polymers can
significantly slow their in vitro dissolution rates and/or in vivo absorption. In preparing
powdered products, grinding is generally used for reducing particle size, since the dissolution
rate is strongly affected by particle size. Moreover, a strong force (such as grinding) may
increase the surface energy and cause distortion of the crystal lattice as well as reducing
particle size. Co-grinding drug with hydroxypropylmethylcellulose, b-cyclodextrin, chitin
and chitosan, crystalline cellulose, and gelatin, may enhance the dissolution properties such
that AUC shape-enhancement is obtained for otherwise readily bioavailable pirfenidone or
pyridone analog compounds. By non-limiting example, this approach may also be used to
sequester and improve the water solubility of solid, AUC shape-enhancing formulations, such
as low-solubility pirfenidone or pyridone analog compounds or salt forms for nanoparticlebased formulations.
Dispersion-Enhancing Peptides
Compositions may include one or more di- or tripeptides containing two or more
leucine residues. By further non-limiting example, U.S. Patent No. 6,835,372 disclosing
dispersion-enhancing peptides, is hereby incorporated by reference in its entirety. This patent
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describes the discovery that di-leucyl-containing dipeptides (e.g., dileucine) and tripeptides
are superior in their ability to increase the dispersibility of powdered composition.
In another embodiment, highly dispersible particles including an amino acid are
administered. Hydrophobic amino acids are preferred. Suitable amino acids include
naturally occurring and non-naturally occurring hydrophobic amino acids. Some naturally
occurring hydrophobic amino acids, including but not limited to, non-naturally occurring
amino acids include, for example, beta-arnino acids. Both D, L and racemic configurations
of hydrophobic amino acids can be employed. Suitable hydrophobic amino acids can also
include amino acid analogs. As used herein, an amino acid analog includes the D or L
configuration of an amino acid having the following formula: --NH--CHR--CO--, wherein R
is an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl
group, an aromatic group or a substituted aromatic group and wherein R does not correspond
to the side chain of a naturally-occurring amino acid. As used herein, aliphatic groups
include straight chained, branched or cyclic C1-C8 hydrocarbons which are completely
saturated, which contain one or two heteroatoms such as nitrogen, oxygen or sulfur and/or
which contain one or more units of desaturation. Aromatic groups include carbocyclic
aromatic groups such as phenyl and naphthyl and heterocyclic aromatic groups such as
imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl,
quinolinyl, isoquinolinyl and acridintyl.
Suitable substituents on an aliphatic, aromatic or benzyl group include --OH, halogen
(--Br,--Cl,--I and --F)--O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or
substituted aryl group),--CN, --NO2, --COOH, --NH2, --NH(aliphatic group, substituted
aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), --N(aliphatic group,
substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group)2, --
COO(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl
group), --CONH2, --CONH(aliphatic, substituted aliphatic group, benzyl, substituted benzyl,
aryl or substituted aryl group)), --SH,--S(aliphatic, substituted aliphatic, benzyl, substituted
benzyl, aromatic or substituted aromatic group) and --NH--C(.dbd.NH)--NH2. A substituted
benzylic or aromatic group can also have an aliphatic or substituted aliphatic group as a
substituent. A substituted aliphatic group can also have a benzyl, substituted benzyl, aryl or
substituted aryl group as a substituent. A substituted aliphatic, substituted aromatic or
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substituted benzyl group can have one or more substituents. Modifying an amino acid
substituent can increase, for example, the lypophilicity or hydrophobicity of natural amino
acids which are hydrophilic.
A number of the suitable amino acids, amino acids analogs and salts thereof can be
obtained commercially. Others can be synthesized by methods known in the art.
Hydrophobicity is generally defined with respect to the partition of an amino acid
between a nonpolar solvent and water. Hydrophobic amino acids are those acids which show
a preference for the nonpolar solvent. Relative hydrophobicity of amino acids can be
expressed on a hydrophobicity scale on which glycine has the value 0.5. On such a scale,
amino acids which have a preference for water have values below 0.5 and those that have a
preference for nonpolar solvents have a value above 0.5. As used herein, the term
hydrophobic amino acid refers to an amino acid that, on the hydrophobicity scale, has a value
greater or equal to 0.5, in other words, has a tendency to partition in the nonpolar acid which
is at least equal to that of glycine.
Examples of amino acids which can be employed include, but are not limited to:
glycine, proline, alanine, cysteine, methionine, valine, leucine, tyosine, isoleucine,
phenylalanine, tryptophan. Preferred hydrophobic amino acids include leucine, isoleucine,
alanine, valine, phenylalanine and glycine. Combinations of hydrophobic amino acids can
also be employed. Furthermore, combinations of hydrophobic and hydrophilic (preferentially
partitioning in water) amino acids, where the overall combination is hydrophobic, can also be
employed.
The amino acid can be present in the particles described herein in an amount of at
least 10 weight %. Preferably, the amino acid can be present in the particles in an amount
ranging from about 20 to about 80 weight %. The salt of a hydrophobic amino acid can be
present in the particles described herein in an amount of at least 10 weight percent.
Preferably, the amino acid salt is present in the particles in an amount ranging from about 20
to about 80 weight %. In preferred embodiments the particles have a tap density of less than
about 0.4 g/cm3
.
Methods of forming and delivering particles which include an amino acid are
described in U.S. Patent No. 6,586,008, entitled Use of Simple Amino Acids to Form Porous
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Particles During Spray Drying, the teachings of which are incorporated herein by reference in
their entirety.
Proteins/Amino Acids
Protein excipients may include albumins such as human serum albumin (HSA),
recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable
amino acids (outside of the dileucyl-peptides described herein), which may also function in a
buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid,
aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine,
aspartame, tyrosine, tryptophan, and the like. Preferred are amino acids and polypeptides that
function as dispersing agents. Amino acids falling into this category include hydrophobic
amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine,
phenylalanine, tyrosine, histidine, and proline. Dispersibility-enhancing peptide excipients
include dimers, trimers, tetramers, and pentamers comprising one or more hydrophobic
amino acid components such as those described above.
Carbohydrates
By non-limiting example, carbohydrate excipients may include monosaccharides such
as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides,
such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as
raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as
mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myoinositol,
isomalt, trehalose and the like.
Polymers
By non-limiting example, compositions may also include polymeric
excipients/additives, e.g., polyvinylpyrrolidones, derivatized celluloses such as
hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls
(a polymeric sugar), hydroxyethylstarch, dextrates (by non-limiting example cyclodextrins
may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin,
randomly methylated beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-betacyclodextrin, maltosyl-alpha-cyclodextrin, glucosylalpha-cyclodextrin, glucosylalpha30 cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and
sulfobutylether-beta-cyclodextrin), polyethylene glycols, and pectin may also be used.
176
Highly dispersible particles administered comprise a bioactive agent and a
biocompatible, and preferably biodegradable polymer, copolymer, or blend. The polymers
may be tailored to optimize different characteristics of the particle including: i) interactions
between the agent to be delivered and the polymer to provide stabilization of the agent and
retention of activity upon delivery; ii) rate of polymer degradation and, thereby, rate of drug
release profiles; iii) surface characteristics and targeting capabilities via chemical
modification; and iv) particle porosity.
Surface eroding polymers such as polyanhydrides may be used to form the particles.
For example, polyanhydrides such as poly[(p-carboxyphenoxy)hexane anhydride] (PCPH)
may be used. Biodegradable polyanhydrides are described in U.S. Pat. No. 4,857,311. Bulk
eroding polymers such as those based on polyesters including poly(hydroxy acids) also can
be used. For example, polyglycolic acid (PGA), polylactic acid (PLA), or copolymers
thereof may be used to form the particles. The polyester may also have a charged or
functionalizable group, such as an amino acid. In a preferred embodiment, particles with
controlled release properties can be formed of poly(D,L-lactic acid) and/or poly(DL-lacticco-glycolic acid) ("PLGA") which incorporate a surfactant such as dipalmitoyl
phosphatidylcholine (DPPC).
Other polymers include polyamides, polycarbonates, polyalkylenes such as
polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene
terephthalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and
polyvinyl esters, polymers of acrylic and methacrylic acids, celluloses and other
polysaccharides, and peptides or proteins, or copolymers or blends thereof. Polymers may be
selected with or modified to have the appropriate stability and degradation rates in vivo for
different controlled drug delivery applications.
Highly dispersible particles can be formed from functionalized polyester graft
copolymers, as described in Hrkach et al., Macromolecules, 28: 4736-4739 (1995); and
Hrkach et al., "Poly(L-Lactic acid-co-amino acid) Graft Copolymers: A Class of Functional
Biodegradable Biomaterials" in Hydrogels and Biodegradable Polymers for Bioapplications,
ACS Symposiurn Series No. 627, Raphael M, Ottenbrite et al., Eds., American Chemical
Society, Chapter 8, pp. 93-101, 1996.
177
In a preferred embodiment, highly dispersible particles including a bioactive agent
and a phospholipid are administered. Examples of suitable phospholipids include, among
others, phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols,
phosphatidylserines, phosphatidylinositols and combinations thereof. Specific examples of
phospholipids include but are not limited to phosphatidylcholines dipalmitoyl
phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl
phosphatidyicholine (DSPC), dipalmitoyl phosphatidyl glycerol (DPPG) or any combination
thereof. Other phospholipids are known to those skilled in the art. In a preferred
embodiment, the phospholipids are endogenous to the lung.
The phospholipid, can be present in the particles in an amount ranging from about 0 to
about 90 weight %. More commonly it can be present in the particles in an amount ranging
from about 10 to about 60 weight %.
In another embodiment described herein, the phospholipids or combinations thereof
are selected to impart controlled release properties to the highly dispersible particles. The
phase transition temperature of a specific phospholipid can be below, about or above the
physiological body temperature of a patient. Preferred phase transition temperatures range
from 30 degrees C to 50 degrees C (e.g., within +/-10 degrees of the normal body
temperature of patient). By selecting phospholipids or combinations of phospholipids
according to their phase transition temperature, the particles can be tailored to have controlled
release properties. For example, by administering particles which include a phospholipid or
combination of phospholipids which have a phase transition temperature higher than the
patient's body temperature, the release of dopamine precursor, agonist or any combination of
precursors and/or agonists can be slowed down. On the other hand, rapid release can be
obtained by including in the particles phospholipids having lower transition temperatures.
Taste Masking, Flavor, Other
As also described above, pirfenidone or pyridone analog compound formulations
disclosed herein and related compositions, may further include one or more taste-masking
agents such as flavoring agents, inorganic salts (e.g., sodium chloride), sweeteners,
antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and
"TWEEN 80"), sorbitan esters, saccharin (e.g., sodium saccharin or other saccharin forms,
which as noted elsewhere herein may be present in certain embodiments at specific
178
concentrations or at specific molar ratios relative to a pyridone analog compound such as
pirfenidone), bicarbonate, cyclodextrins, lipids (e.g., phospholipids such as lecithin and other
phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (e.g.,
cholesterol), and chelating agents (e.g., EDTA, zinc and other such suitable cations). Other
pharmaceutical excipients and/or additives suitable for use in the compositions as described
herein are listed in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams &
Williams, (1995), and in the "Physician's Desk Reference", 52nd ed., Medical Economics,
Montvale, N.J. (1998).
By way of non-limiting example, taste-masking agents in pirfenidone or pyridone
analog compound formulations, may include the use of flavorings, sweeteners, and other
various coating strategies, for instance, sugars such as sucrose, dextrose, and lactose,
carboxylic acids, menthol, amino acids or amino acid derivatives such as arginine, lysine, and
monosodium glutamate, and/or synthetic flavor oils and flavoring aromatics and/or natural
oils, extracts from plants, leaves, flowers, fruits, etc. and combinations thereof. These may
include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil, anise oil,
eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, fruit
essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot,
etc. Additional sweeteners include sucrose, dextrose, aspartame (Nutrasweet®), acesulfameK, sucralose and saccharin (e.g., sodium saccharin or other saccharin forms, which as noted
elsewhere herein may be present in certain embodiments at specific concentrations or at
specific molar ratios relative to a pyridone analog compound such as pirfenidone), organic
acids (by non-limiting example citric acid and aspartic acid). Such flavors may be present at
from about 0.05 to about 4 percent by weight, and may be present at lower or higher amounts
as a factor of one or more of potency of the effect on flavor, solubility of the flavorant, effects
of the flavorant on solubility or other physicochemical or pharmacokinetic properties of other
formulation components, or other factors.
Another approach to improve or mask the unpleasant taste of an inhaled drug may be
to decrease the drug’s solubility, e.g., drugs must dissolve to interact with taste receptors.
Hence, to deliver solid forms of the drug may avoid the taste response and result in the
desired improved taste affect. Non-limiting methods to decrease solubility of a pirfenidone
or pyridone analog compound solubility are described herein, for example, through the use in
179
formulation of particular salt forms of pyridone analog compound, such as complexation with
xinafoic acid, oleic acid, stearic acid and/or pamoic acid. Additional co-precipitating agents
include dihydropyridines and a polymer such as polyvinyl pyrrolidone.
Moreover, taste-masking may be accomplished by creation of lipopilic vesicles.
Additional coating or capping agents include dextrates (by non-limiting example
cyclodextrins may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gammacyclodextrin, randomly methylated beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethylbeta-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosylalpha-cyclodextrin, glucosyl
alpha-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and
sulfobutylether-beta-cyclodextrin), modified celluloses such as ethyl cellulose, methyl
cellulose, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose, polyalkylene glycols,
polyalkylene oxides, sugars and sugar alcohols, waxes, shellacs, acrylics and mixtures
thereof. By non-limiting example, other methods to deliver non-dissolved forms of a
pirfenidone or pyridone analog compound according to certain embodiments or, in other
embodiments, non-dissolved forms of a pirfenidone or pyridone analog compound, are to
administer the drug alone or in a simple, non-solubility affecting formulation, such as a
crystalline micronized, dry powder, spray-dried, and/or nanosuspension formulation.
An alternative according to certain other preferred embodiments is to include tastemodifying agents in the pirfenidone or pyridone analog compound formulation. These
embodments contemplate including in the formulation a taste-masking substance that is
mixed with, coated onto or otherwise combined with the active medicament pirfenidone or
pyridone analog compound or salt thereof. Inclusion of one or more such agents in these
formulations may also serve to improve the taste of additional pharmacologically active
compounds that are included in the formulations in addition to the pirfenidone or pyridone
analog compound, e.g., a mucolytic agent. Non-limiting examples of such taste-modifying
substances include acid phospholipids, lysophospholipid, tocopherol polyethyleneglycol
succinate, and embonic acid (pamoate). Many of these agents can be used alone or in
combination with pirfenidone or pyridone analog compound (or a salt thereof) or, in separate
embodiments, pirfenidone or pyridone analog compound for aerosol administration.
Mucolytic Agents
180
Methods to produce formulations that combine agents to reduce sputum viscosity
during aerosol treatment with a pirfenidone or pyridone analog compound include the
following. These agents can be prepared in fixed combination or be administered in
succession with aerosol pirfenidone or pyridone analog compound therapy.
The most commonly prescribed agent is N-acetylcysteine (NAC), which
depolymerizes mucus in vitro by breaking disulphide bridges between macromolecules. It is
assumed that such reduction of sputum tenacity facilitates its removal from the respiratory
tract. In addition, NAC may act as an oxygen radical scavenger. NAC can be taken either
orally or by inhalation. Differences between these two methods of administration have not
been formally studied. After oral administration, NAC is reduced to cysteine, a precursor of
the antioxidant glutathione, in the liver and intestine. The antioxidant properties could be
useful in preventing decline of lung function in cystic fibrosis (CF), chronic obstructive
pulmonary disease (COPD) or pulmonary fibrotic diseases (e.g., idiopathic pulmonmary
fibrosis). Nebulized NAC is commonly prescribed to patients with CF, in particular in
continental Europe, in order to improve expectoration of sputum by reducing its tenacity.
The ultimate goal of this is to slow down the decline of lung function in CF.
L-lysine-N-acetylcysteinate (ACC) or Nacystelyn (NAL) is a novel mucoactive agent
possessing mucolytic, antioxidant, and anti-inflammatory properties. Chemically, it is a salt
of ACC. This drug appears to present an activity superior to its parent molecule ACC
because of a synergistic mucolytic activity of L-lysine and ACC. Furthermore, its almost
neutral pH (6.2) allows its administration in the lungs with a very low incidence of
bronchospasm, which is not the case for the acidic ACC (pH 2.2). NAL is difficult to
formulate in an inhaled form because the required lung dose is very high (approximately 2
mg) and the micronized drug is sticky and cohesive and it is thus problematic to produce a
redispersable formulation. NAL was first developed as a chlorofluorocarbon (CFC)
containing metered-dose inhaler (MDI) because this form was the easiest and the fastest to
develop to begin the preclinical and the first clinical studies. NAL MDI delivered 2 mg per
puff, from which approximately 10% was able to reach the lungs in healthy volunteers. One
major inconvenience of this formulation was patient compliance because as many as 12 puffs
were necessary to obtain the required dose. Furthermore, the progressive removal of CFC
gases from medicinal products combined with the problems of coordination met in a large
181
proportion of the patient population (12) have led to the development of a new galenical form
of NAL. A dry powder inhaler (DPI) formulation was chosen to resolve the problems of
compliance with MDIs and to combine it with an optimal, reproducible, and comfortable way
to administer the drug to the widest possible patient population, including young children.
The DPI formulation of NAL involved the use of a nonconventional lactose (usually
reserved for direct compression of tablets), namely, a roller-dried (RD) anhydrous β-lactose.
When tested in vitro with a monodose DPI device, this powder formulation produces a fine
particle fraction (FPF) of at least 30% of the nominal dose, namely three times higher than
that with MDIs. This approach may be used in combination with a pirfenidone or pyridone
analog compound for either co-administration or fixed combination therapy.
In addition to mucolytic activity, excessive neutrophil elastase activity within airways
of cystic fibrosis (CF) patients results in progressive lung damage. Disruption of disulfide
bonds on elastase by reducing agents may modify its enzymatic activity. Three naturally
occurring dithiol reducing systems were examined for their effects on elastase activity: 1)
Escherichia coli thioredoxin (Trx) system, 2) recombinant human thioredoxin (rhTrx) system,
and 3) dihydrolipoic acid (DHLA). The Trx systems consisted of Trx, Trx reductase, and
NADPH. As shown by spectrophotometric assay of elastase activity, the two Trx systems
and DHLA inhibited purified human neutrophil elastase as well as the elastolytic activity
present in the soluble phase (sol) of CF sputum. Removal of any of the three Trx system
constituents prevented inhibition. Compared with the monothiols N-acetylcysteine and
reduced glutathione, the dithiols displayed greater elastase inhibition. To streamline Trx as
an investigational tool, a stable reduced form of rhTrx was synthesized and used as a single
component. Reduced rhTrx inhibited purified elastase and CF sputum sol elastase without
NADPH or Trx reductase. Because Trx and DHLA have mucolytic effects, we investigated
changes in elastase activity after mucolytic treatment. Unprocessed CF sputum was directly
treated with reduced rhTrx, the Trx system, DHLA, or DNase. The Trx system and DHLA
did not increase elastase activity, whereas reduced rhTrx treatment increased sol elastase
activity by 60%. By contrast, the elastase activity after DNase treatment increased by 190%.
The ability of Trx and DHLA to limit elastase activity combined with their mucolytic effects
makes these compounds potential therapies for CF.
182
In addition, bundles of F-actin and DNA present in the sputum of cystic fibrosis (CF)
patients but absent from normal airway fluid contribute to the altered viscoelastic properties
of sputum that inhibit clearance of infected airway fluid and exacerbate the pathology of CF.
One approach to alter these adverse properties is to remove these filamentous aggregates
using DNase to enzymatically depolymerize DNA to constituent monomers and gelsolin to
sever F-actin to small fragments. The high densities of negative surface charge on DNA and
F-actin suggest that the bundles of these filaments, which alone exhibit a strong electrostatic
repulsion, may be stabilized by multivalent cations such as histones, antimicrobial peptides,
and other positively charged molecules prevalent in airway fluid. Furthermore, as a matter-a10 fact, it has been observed that bundles of DNA or F-actin formed after addition of histone H1
or lysozyme are efficiently dissolved by soluble multivalent anions such as polymeric
aspartate or glutamate. Addition of poly-aspartate or poly-glutamate also disperses DNA and
actin-containing bundles in CF sputum and lowers the elastic moduli of these samples to
levels comparable to those obtained after treatment with DNase I or gelsolin. Addition of
poly-aspartic acid also increased DNase activity when added to samples containing DNA
bundles formed with histone H1. When added to CF sputum, poly-aspartic acid significantly
reduced the growth of bacteria, suggesting activation of endogenous antibacterial factors.
These findings suggest that soluble multivalent anions have potential alone or in combination
with other mucolytic agents to selectively dissociate the large bundles of charged
biopolymers that form in CF sputum.
Hence, NAC, unfractionated heparin, reduced glutathione, dithiols, Trx, DHLA, other
monothiols, DNAse, dornase alfa, hypertonic formulations (e.g., osmolalities greater than
about 350 mOsmol/kg), multivalent anions such as polymeric aspartate or glutamate,
glycosidases and other examples listed above can be combined with pirfenidone or pyridone
analog compounds and other mucolytic agents for aerosol administration to improve
antifibrotic and/or antiinflammatory activity through better distribution from reduced sputum
viscosity, and improved clinical outcome through improved pulmonary function (from
improved sputum mobility and mucociliary clearance) and decreased lung tissue damage
from the immune inflammatory response.
Characterization of Inhalation Devices
183
The efficiency of a particular inhalation device can be measured by many different
ways, including an analysis of pharmacokinetic properties, measurement of lung deposition
percentage, measurement of respirable delivery dose (RDD), a determination of output rates,
geometric standard deviation values (GSD), and mass median aerodynamic diameter values
(MMAD) among others.
Methods and systems for examining a particular inhalation device are known. One
such system consists of a computer means and a hollow cylinder in a pump means with a
connecting piece to which an inhalation device is to be connected. In the pump means there
is a piston rod, which extends out of the hollow cylinder. A linear drive unit can be activated
in such a manner that one or more breathing pattern will be simulated on the connecting piece
of the pump means. In order to be able to carry out the evaluation of the inhalation device,
the computer is connected in an advantageous configuration with a data transmission means.
With the aid of the data transmission means, the computer can be connected with another
computer with specific data banks, in order to exchange the data of breathing patterns. In this
manner, a breathing pattern library which is as representative as possible can be very rapidly
formed. U.S. Pat. No. 6,106,479 discloses this method for examining an inhalation device in
more detail, and is hereby incorporated by reference in its entirety.
Pharmacokinetic Profile
Pharmacokinetics is concerned with the uptake, distribution, metabolism and
excretion of a drug substance. A pharmacokinetic profile comprises one or more biological
measurements designed to measure the absorption, distribution, metabolism and excretion of
a drug substance. One way of visualizing a pharmacokinetic profile is by means of a blood
plasma concentration curve, which is a graph depicting mean active ingredient blood plasma
concentration on the Y-axis and time (usually in hours) on the X-axis. Some
pharmacokinetic parameters that may be visualized by means of a blood plasma
concentration curve include:
• Cmax: The maximum plasma concentration in a patient.
• AUC: area under the curve
• TOE: time of exposure
• T1/2: period of time it takes for the amount in a patient of drug to decrease by half
• Tmax: The time to reach maximum plasma concentration in a patient
184
Pharmacokinetics (PK) is concerned with the time course of a therapeutic agent, such
as pirfenidone, or a pyridone analog compound concentration in the body.
Pharmacodynamics (PD) is concerned with the relationship between pharmacokinetics and
efficacy in vivo. PK/PD parameters correlate the therapeutic agent, such as exposure with
efficacious activity. Accordingly, to predict the therapeutic efficacy of a therapeutic agent,
such as with diverse mechanisms of action different PK/PD parameters may be used.
Any standard pharmacokinetic protocol can be used to determine blood plasma
concentration profile in humans following administration of a formulation comprising
pirfenidone or a pyridone analog compound described herein, and thereby establish whether
that formulation meets the pharmacokinetic criteria set out herein. For example, but in no
way limiting, a type of a randomized single-dose crossover study can be utilized using a
group of healthy adult human subjects. The number of subjects can be sufficient to provide
adequate control of variation in a statistical analysis, and is typically about 8 or greater,
although in certain embodiments a smaller group can be used. In one embodiment, a subject
receives administration, at time zero, a single dose of a test inhalation mixture comprising
pirfenidone or a pyridone analog compound. Blood samples are collected from each subject
prior to administration and at several intervals after administration. Plasma can be separated
from the blood samples by centrifugation and the separated plasma is analyzed, for example,
by a validated high performance liquid chromatography/tandem weight spectrometry
(LC/APCI-MS/MS) procedure such as, for example, those described in Ramu et al., Journal
of Chromatography B, 751:49–59 (2001). In other embodiments, data from a single subject
may be collected and may be used to construct a pK profile and may be indicative of an
enhanced pharmacokinetic profile. In still other embodiments, appropriate in vitro models
may be used to construct a pK profile and may be demonstrate or indicate an enhanced
pharmacokinetic profile.
In some embodiments, a human pK profile can be may be obtained by the use of
allometric scaling. In one embodiment, rat aerosol lung data and plasma delivery is scaled to
provide an indication of possible humans data. In one embodiment, allometric scaling uses
parameters established in the US FDA Guidance for Industry - Estimating the Maximum Safe
Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.
185
Any aqueous inhalable mixture giving the desired pharmacokinetic profile may be
suitable for administration according to the present methods.
As used herein, the “peak period” of a pharmaceutical’s in vivo concentration is
defined as that time of the pharmaceutical dosing interval when the pharmaceutical
concentration is not less than 50% of its maximum plasma or site-of-disease concentration.
In some embodiments, “peak period” is used to describe an interval of pirfenidone or a
pyridone analog compound dosing.
In some embodiments, when considering treatment of lung diseases, a method or
system described herein provides at least a two-fold enhancement in pharmacokinetic profile
for treatment of the lung disease. In some embodiments, the methods and systems described
herein provide at least a two-fold enhancement in the lung tissue pharmacokinetic profile of
pirfenidone or pyridone analog compound as compared to oral administration.
In some embodiments, a delayed appearance of 5-carboxy-pirfenidone (the primary
pirfenidone liver metabolite) has been observed from the methods and systems described
herein. In some embodiments, rapid elimination of pirfenidone from the lung tissue has been
observed. Comparing the initial rapid elimination of pirfenidone from the lung tissue and
parallel appearance of pirfenidone in the plasma suggest that direct pulmonary administration
may be a good route for systemic administration of pirfenidone. The delayed appearance of
-carboxy-pirfenidone metabolite supports this hypothesis in that this metabolite serves as a
marker for re-circulation of pirfenidone to the lung and other tissues following direct aerosol
administration to the lung. In some embodiments, re-circulated pirfenidone is likely
important to support long-term, elevated pirfenidone levels in the lung and other tissues of
potential efficacy.
In some embodiments, the amount of pirfenidone or pyridone analog compound that
is administered to a human by inhalation may be calculated by measuring the amount of
pirfenidone or pyridone analog compound and associated metabolites that are found in the
urine. In some embodiments, about 80% of administered pirfenidone is excreted in the urine
(with 95% being the primary metabolite, 5-carboxy-pirfenidone). In some embodiments, the
calculation based on compound and metabolites in urine may be done through a 48 urine
collection (following a single administration), whereby the total amount of pirfenidone or
pyridone analog compound delivered to the human is the sum of measured pirfenidone and its
186
metabolites. By non-limiting example, knowing that 80% of pirfenidone is excreted, a 50 mg
sum urinary measurement of pirfenidone and its metabolites would translate to a delivered
dose of about 63 mg (50 mg divided by 80%). If by non-limiting example the inhaled aerosol
fine-particle fraction (FPF) is 75%, one may assume that about 75% of the drug deposited in
the lung (and about 25% was swallowed, and subsequently absorbed from the gut with 80%
excreted in the urine). Integrating these two calculations, of a 63 mg delivered dose (as
measured by urinary excretion), about 47 mg would be the amount of inhaled aerosol
pirfenidone delivered to the lung (the actual RDD; calculated as the product of 63 mg and a
75% FPF). This RDD can then be used in a variety of calculations, including lung tissue
concentration.
In some embodiments, method or systems described herein provide pharmacokinetic
profiles of pirfenidone or puridone anlog compounds as described herein. In some
embodiments, method or systems described herein provide pharmacokinetic profiles of
pirfenidone or pyridone anlog compounds as in Examples 6 and 7.
187
Examples
Example 1: Pirfenidone Formulations
Non-limiting examples of compositions of pirfenidone include those described
in Table 1-1 through Table 1-11.
Table 1-1 Composition no.
Ingredient and Amount
Pirfenidone
Phosphate
Buffer (sodium
salt), pH 6.2
(mM)
Phosphate
Buffer (sodium
salt), pH 7.3
(mM)
Citrate Buffer
(acid/sodium
salt), pH 5.8
(mM)
Sodium
Chloride
(µmols)
Magnesium
Chloride
(µmols)
Water
1 1 mg to
500 mg
(5 µmols
to 3
mmols)
- - 0.01 mM
to 500
mM
- - q.s. to
mL
2 1 mg to
500 mg
(5 µmols
to 3
mmols)
0.01 mM
to 500
mM
- - - - q.s. to
mL
3 1 mg to
500 mg
(5 µmols
to 3
mmols)
- 0.01 mM to
500 mM
- - - q.s. to
mL
4 54 µmols 0.01 to
500
- q.s. to
mL
54 µmols - 0.01 to 500 q.s. to
mL
6 54 µmols - - 0.01 to
500
150 - q.s. to
mL
7 54 µmols 0.01 to
500
- - - 150 q.s. to
mL
8 54 µmols - 0.01 to 500 - - 150 q.s. to
mL
9 54 µmols - - 0.01 to
500
- 150 q.s. to
mL
54 µmols 0.01 to
500
- - 13.5 - q.s. to
mL
11 54 µmols - 0.01 to 500 - 13.5 - q.s. to
mL
188 Composition no.
Ingredient and Amount
Pirfenidone
Phosphate
Buffer (sodium
salt), pH 6.2
(mM)
Phosphate
Buffer (sodium
salt), pH 7.3
(mM)
Citrate Buffer
(acid/sodium
salt), pH 5.8
(mM)
Sodium
Chloride
(µmols)
Magnesium
Chloride
(µmols)
Water
12 54 µmols - - 0.01 to
500
13.5 - q.s. to
mL
13 54 µmols 0.01 to
500
- - - 13.5 q.s. to
mL
14 54 µmols - 0.01 to 500 - - 13.5 q.s. to
mL
54 µmols - - 0.01 to
500
- 13.5 q.s. to
mL
16 54 µmols 0.01 to
500
- q.s. to
mL
17 54 µmols - 0.01 to 500 q.s. to
mL
18 54 µmols - - 0.01 to
500
54 - q.s. to
mL
19 54 µmols 0.01 to
500
- - - 54
µmols
q.s. to
mL
54 µmols - 0.01 to 500 - - 54
µmols
q.s. to
mL
21 54 µmols - - 0.01 to
500
- 54
µmols
q.s. to
mL
22 54 µmols 0.01 to
500
- q.s. to
mL
23 54 µmols - 0.01 to 500 q.s. to
mL
24 54 µmols - - 0.01 to
500
27 - q.s. to
mL
54 µmols 0.01 to
500
- - - 27 q.s. to
mL
26 54 µmols - 0.01 to 500 - - 27 q.s. to
mL
27 54 µmols - - 0.01 to
500
- 27 q.s. to
mL
189
Table 1-2 Composition no.
Ingredient and Amount
Pirfenidone
Citrate Buffer
(acid/sodium salt),
pH 2.0 to 9.0 (mM)
Phosphate Buffer
(monobasic/dibasic
sodium salts), pH
2.0 to 9.0 (mM)
Sodium Chloride
(µmols)
Magnesium
Chloride
Saccharin (sodium
salt) (mM)
Water
28 5 µmols
to 3
mmols
0.01 to
500
- - 1 µmol to 15
mmols
0.01 to
.0
q.s. to
mL
29 5 µmols
to 3
mmols
- 0.01 to 500 - 1 µmol to 15
mmols
0.01 to
.0
q.s. to
mL
5 µmols
to 3
mmols
0.01 to
500
- 1 µmol to
mmols
- 0.01 to
.0
q.s. to
mL
31 5 µmols
to 3
mmols
- 0.01 to 500 1 µmol to
mmols
- 0.01 to
.0
q.s. to
mL
Table 1-3 Composition no.
Ingredient and Amount
Pirfenidone
Citrate Buffer
(acid/sodium salt), pH
.8 (mM)
Phosphate Buffer
(monobasic/dibasic
sodium salts), pH 6.2
(mM)
Phosphate Buffer
(monobasic/dibasic
sodium salts), pH 7.3
(mM)
Saccharin (sodium
salt) (mM)
Water
32 1 mg to 500
mg (5 µmols
to 3 mmols)
0.01 to
500
- - 0.01 to
.0
q.s. to 5 mL
33 1 mg to 500
mg (5 µmols
to 3 mmols)
- 0.01 to 500 - 0.01 to
.0
q.s. to 5 mL
34 1 mg to 500
mg (5 µmols
0.01 to 500 0.01 to
.0
q.s. to 5 mL
190 Composition no.
Ingredient and Amount
Pirfenidone
Citrate Buffer
(acid/sodium salt), pH
.8 (mM)
Phosphate Buffer
(monobasic/dibasic
sodium salts), pH 6.2
(mM)
Phosphate Buffer
(monobasic/dibasic
sodium salts), pH 7.3
(mM)
Saccharin (sodium
salt) (mM)
Water
to 3 mmols)
In some embodiments, pirfenidone exhibited aqueous solubility to ~17 mg/mL across
a pH range of about 4.0 to about 8.0. However, at this (and lower) concentration it was
determined that salt addition was required to improve acute tolerability upon inhalation of a
nebulized solution (otherwise a hypotonic solution). To address tonicity, NaCl or MgCl2
were added. In some embodiments, addition of NaCl improved acute tolerability, but
destabilized the formulation and resulted in precipitation upon ambient storage. In some
embodiments, it was determined that addition of MgCl2 maintained a stable, soluble solution
at this concentration with an osmolality in a tolerable range. By non-limiting example, 81
mM MgCl2 provides a 1:1 mole ratio of magnesium to pirfenidone where pirfenidone is at 15
mg/mL (or 81 mM). This effect was also observed at various pirfenidone concentrations with
1:1 and 1:2 mole ratios of magnesium to pirfenidone, but not at ratios less than or equal to
0.25:1 or greater than or equal to 1:0.33 magnesium to pirfenidone, respectively. This effect
was observed in 5 mM to 50 mM citrate buffer at pH 4.0 and pH 5.8, and 5 mM to 50 mM
phosphate buffer at pH 6.2, pH 7.3 and pH 7.8. Other observations included: 1) Formulations
of both buffer systems exhibited a metallic, bitter flavor and throat irritation; 2) From 0.1 to
0.7 mM sodium saccharin was required to taste mask these formulations; 3) 0.6 mM sodium
saccharin was the best concentration and improved the flavor of 2:1 mol ratio pirfenidone to
magnesium in phosphate buffer more so than the 1:1 mol ratio; 4) The taste of 2:1 mol ratio
pirfenidone to magnesium in citrate buffer without sodium saccharin was equivalent to the
1:1 mol ratio pirfenidone to magnesium in phosphate buffer with 0.6 mM sodium saccharin;
) The taste of 2:1 mol ratio pirfenidone to magnesium in citrate buffer with 0.2 mM sodium
saccharin was equivalent to the 2:1 mol ratio pirfenidone to magnesium in phosphate buffer
191
with 0.6 mM sodium saccharin; 6) The taste of 1:1 mol ratio pirfenidone to magnesium in
citrate buffer with 0.6 mM sodium saccharin was equivalent to 2:1 mol ratio pirfenidone to
magnesium in phosphate buffer 0.6 mM sodium saccharin; and 7) 1:1 mol ratio pirfenidone
to magnesium dissolved in up to 40% the time required to dissolve 2:1 mol ratio pirfenidone
to magnesium in either buffer system at ~pH 6. This effect was not observed at ~pH 8.
Table 1-4 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Phosphate Buffer
(monobasic/dibasic
sodium salts), pH
.5 to 8.5 (mM)
Ethanol (% v/v)
Propylene Glycol
(% v/v)
Glycerol (% v/v)
Polysorbate 80
(% v/v)
Cetylpyridinium
Bromide (or
chloride) (%)
Osmolality
(mOsmo/kg)
Water
1 to
500
0.01 to
500
0.001
to 25
- - - - 50 to
5000
q.s. to
mL
36* 1 to
500
0.01 to
500
- 0.001
to 25
- - - 50 to
5000
q.s. to
mL
37 1 to
500
0.01 to
500
- - 0.001
to 25
- - 50 to
5000
q.s. to
mL
38 1 to
500
0.01 to
500
- - - 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
39 * 1 to
500
0.01 to
500
- - - - 0.0001
to 5.0
50 to
5000
q.s. to
mL
40 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - - 50 to
5000
q.s. to
mL
41 1 to
500
0.01 to
500
0.001
to 25
- 0.001
to 25
- - 50 to
5000
q.s. to
mL
42 1 to
500
0.01 to
500
0.001
to 25
- - 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
43 1 to
500
0.01 to
500
0.001
to 25
- - - 0.0001
to 5.0
50 to
5000
q.s. to
mL
44 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- - 50 to
5000
q.s. to
mL
45 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
46 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
50 to
5000
q.s. to
mL
192 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Phosphate Buffer
(monobasic/dibasic
sodium salts), pH
.5 to 8.5 (mM)
Ethanol (% v/v)
Propylene Glycol
(% v/v)
Glycerol (% v/v)
Polysorbate 80
(% v/v)
Cetylpyridinium
Bromide (or
chloride) (%)
Osmolality
(mOsmo/kg)
Water
47 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
0.0001
to 1.0
- 50 to
5000
q.s. to
mL
48 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
49 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- 0.0001
to 5.0
50 to
5000
q.s. to
mL
50 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
50 to
5000
q.s. to
mL
* Phosphate Buffer (monobasic/dibasic sodium salts), pH 6.2
Table 1-5 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Citrate Buffer (citric
acid/sodium citrate),
pH 3.5 to pH 6.5
(mM)
Ethanol (% v/v)
Propylene Glycol (%
v/v)
Glycerol (% v/v)
Polysorbate 80
(% v/v)
Cetylpyridinium
Bromide (or chloride)
(%)
Osmolality
(mOsmo/kg)
Water
51 1 to
500
0.01 to
500
0.001
to 25
- - - - 50 to
5000
q.s. to
mL
52 1 to
500
0.01 to
500
- 0.001
to 25
- - - 50 to
5000
q.s. to
mL
53 1 to
500
0.01 to
500
- - 0.001
to 25
- - 50 to
5000
q.s. to
mL
54 1 to
500
0.01 to
500
- - - 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
55 1 to
500
0.01 to
500
- - - - 0.0001
to 5.0
50 to
5000
q.s. to
mL
56 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - - 50 to
5000
q.s. to
mL
193 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Citrate Buffer (citric
acid/sodium citrate),
pH 3.5 to pH 6.5
(mM)
Ethanol (% v/v)
Propylene Glycol (%
v/v)
Glycerol (% v/v)
Polysorbate 80
(% v/v)
Cetylpyridinium
Bromide (or chloride)
(%)
Osmolality
(mOsmo/kg)
Water
57 1 to
500
0.01 to
500
0.001
to 25
- 0.001
to 25
- - 50 to
5000
q.s. to
mL
58 1 to
500
0.01 to
500
0.001
to 25
- - 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
59 1 to
500
0.01 to
500
0.001
to 25
- - - 0.0001
to 5.0
50 to
5000
q.s. to
mL
60 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- - 50 to
5000
q.s. to
mL
61 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
62 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
50 to
5000
q.s. to
mL
63 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
0.0001
to 1.0
- 50 to
5000
q.s. to
mL
64 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 50 to
5000
q.s. to
mL
65 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- 0.0001
to 5.0
50 to
5000
q.s. to
mL
66 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
50 to
5000
q.s. to
mL
Table 1-6 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Phosphate Buffer
(monobasic/dibasic sodium
salts), pH 5.5 to 8.5 (mM)
Ethanol (% v/v)
Propylene Glycol (% v/v)
Glycerol (% v/v)
Polysorbate 80 (%)
Cetylpyridinium Bromide
(or chloride) (%)
Chloride ion (sodium,
magnesium or calcium
salts) (%)
Osmolality (mOsmo/kg)
Water
67 1 to 0.01 to 0.001 - - - - 0.01 to 50 to q.s.
194 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Phosphate Buffer
(monobasic/dibasic sodium
salts), pH 5.5 to 8.5 (mM)
Ethanol (% v/v)
Propylene Glycol (% v/v)
Glycerol (% v/v)
Polysorbate 80 (%)
Cetylpyridinium Bromide
(or chloride) (%)
Chloride ion (sodium,
magnesium or calcium
salts) (%)
Osmolality (mOsmo/kg)
Water
500 500 to 25 5 5000 to 5
mL
68* 1 to
500
0.01 to
500
- 0.001
to 25
- - - 0.01 to
50 to
5000
q.s.
to 5
mL
69 1 to
500
0.01 to
500
- - 0.001
to 25
- - 0.01 to
50 to
5000
q.s.
to 5
mL
70 1 to
500
0.01 to
500
- - - 0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
71 * 1 to
500
0.01 to
500
- - - - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
72 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - - 0.01 to
50 to
5000
q.s.
to 5
mL
73 1 to
500
0.01 to
500
0.001
to 25
- 0.001
to 25
- - 0.01 to
50 to
5000
q.s.
to 5
mL
74 1 to
500
0.01 to
500
0.001
to 25
- - 0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
75 1 to
500
0.01 to
500
0.001
to 25
- - - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
76 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- - 0.01 to
50 to
5000
q.s.
to 5
mL
77 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
78 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
79 1 to 0.01 to 0.001 0.001 0.001 0.0001 - 0.01 to 50 to q.s.
195 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Phosphate Buffer
(monobasic/dibasic sodium
salts), pH 5.5 to 8.5 (mM)
Ethanol (% v/v)
Propylene Glycol (% v/v)
Glycerol (% v/v)
Polysorbate 80 (%)
Cetylpyridinium Bromide
(or chloride) (%)
Chloride ion (sodium,
magnesium or calcium
salts) (%)
Osmolality (mOsmo/kg)
Water
500 500 to 25 to 25 to 25 to 1.0 5 5000 to 5
mL
80 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
81 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
82 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
* Phosphate Buffer (monobasic/dibasic sodium salts), pH 6.2
196
Table 1-7 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Citrate Buffer (citric
acid/sodium citrate), pH 3.5 to
pH 6.5 (mM)
Ethanol (% v/v)
Propylene Glycol (% v/v)
Glycerol (% v/v)
Polysorbate 80 (%)
Cetylpyridinium Bromide (or
chloride) (%)
Chloride ion (sodium,
magnesium or calcium salts)
(%)
Osmolality (mOsmo/kg)
Water
83 1 to
500
0.01 to
500
0.001
to 25
- - - - 0.01 to
50 to
5000
q.s.
to 5
mL
84 1 to
500
0.01 to
500
- 0.001
to 25
- - - 0.01 to
50 to
5000
q.s.
to 5
mL
85 1 to
500
0.01 to
500
- - 0.001
to 25
- - 0.01 to
50 to
5000
q.s.
to 5
mL
86 1 to
500
0.01 to
500
- - - 0.0001
to 1.0
- 0.01%
to 5%
50 to
5000
q.s.
to 5
mL
87 1 to
500
0.01 to
500
- - - - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
88 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - - 0.01 to
50 to
5000
q.s.
to 5
mL
89 1 to
500
0.01 to
500
0.001
to 25
- 0.001
to 25
- - 0.01 to
50 to
5000
q.s.
to 5
mL
90 1 to
500
0.01 to
500
0.001
to 25
- - 0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
91 1 to
500
0.01 to
500
0.001
to 25
- - - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
92 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- - 0.01 to
50 to
5000
q.s.
to 5
mL
93 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
197 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Citrate Buffer (citric
acid/sodium citrate), pH 3.5 to
pH 6.5 (mM)
Ethanol (% v/v)
Propylene Glycol (% v/v)
Glycerol (% v/v)
Polysorbate 80 (%)
Cetylpyridinium Bromide (or
chloride) (%)
Chloride ion (sodium,
magnesium or calcium salts)
(%)
Osmolality (mOsmo/kg)
Water
94 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
95 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
96 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- 0.0001
to 1.0
- 0.01 to
50 to
5000
q.s.
to 5
mL
97 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
0.001
to 25
- 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
98 1 to
500
0.01 to
500
0.001
to 25
0.001
to 25
- - 0.0001
to 5.0
0.01 to
50 to
5000
q.s.
to 5
mL
198
Table 1-8 Composition no.
Ingredient and Amount
Pirfenidone
(mg)
Citrate Buffer
(citric
acid/sodium
citrate), pH
4.0 to pH 5.0
(mM)
Ethanol
(% v/v/)
Propylene
Glycol (%
v/v)
Osmolality
(mOsmo/kg)
Water
99 5 mg (27
µmols)
0.5% 1.0% 200 to 400 q.s. to 5 mL
100 5 mg (27
µmols)
1.0% 2.0% 400 to 600 q.s. to 5 mL
101 10 mg (54
µmols)
1.0% 2.0% 400 to 600 q.s. to 5 mL
102 15 (81
µmols)
1.0% 2.0% 400 to 600 q.s. to 5 mL
103 25 mg
(135
µmols)
1.0% 2.0% 400 to 600 q.s. to 5 mL
104 37.5 mg
(202
µmols)
1.0% 2.0% 400 to 600 q.s. to 5 mL
105 75 mg
(405
µmols)
1.0% 2.0% 400 to 600 q.s. to 5 mL
106 100 mg
(541
µmols)
2.0% 4.0% 900 to 1100 q.s. to 5 mL
107 115 mg
(621
µmols)
4.0% 8.0% 1800 to 2100 q.s. to 5 mL
108 150 mg
(810
µmols)
6.0% 12.0% 1800 to 2100 q.s. to 5 mL
109 190 mg
(1027
µmols)
8.0% 16.0% 3500 to 3900 q.s. to 5 mL
110 220 mg
(1189
µmols)
8.0% 16.0% 3600 to 4000 q.s. to 5 mL
199
Table 1-9 Composition no.
Ingredient and Amount
Pirfenidone
(mg)
Phosphate
Buffer
(monobasic/di
basic sodium
salts), pH 6.0
to pH 7.0
( M) Ethanol
(% v/v)
Propylene
Glycol (% v/v)
Osmolality
(mOsmo/kg)
Water
111 5 mg (27
µmols)
0.5% 1.0% 200 to 400 q.s. to 5
mL
112 5 mg (27
µmols)
1.0% 2.0% 200 to 600 q.s. to 5
mL
113 10 mg (54
µmols)
1.0% 2.0% 400 to 600 q.s. to 5
mL
114 15 (81
µmols)
1.0% 2.0% 400 to 600 q.s. to 5
mL
115 25 mg (135
µmols)
1.0% 2.0% 400 to 600 q.s. to 5
mL
116 37.5 mg
(202
µmols)
1.0% 2.0% 400 to 600 q.s. to 5
mL
117 75 mg (405
µmols)
1.0% 2.0% 400 to 600 q.s. to 5
mL
118 100 mg
(541
µmols)
2.0% 4.0% 900 to 1100 q.s. to 5
mL
119 115 mg
(621
µmols)
4.0% 8.0% 1800 to
2100
q.s. to 5
mL
120 150 mg
(810
µmols)
6.0% 12.0% 1800 to
2100
q.s. to 5
mL
121 190 mg
(1027
µmols)
8.0% 16.0% 3500 to
3900
q.s. to 5
mL
122 220 mg
(1189
µmols)
8.0% 16.0% 3600 to
4000
q.s. to 5
mL
200
Table 1-10 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Citrate Buffer
(citric
acid/sodium
citrate), pH 4.0
to pH 5.0 (mM)
Ethanol
(% v/v)
Propylene
Glycol (% v/v)
Chloride ion
(sodium,
magnesium or
calcium salts)
Osmolality
(mOsmo/kg)
Water
123 5 mg (27
µmols)
0.5% 1.0% 0.1% to
0.9%
200 to 500 q.s. to
mL
124 5 mg (27
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to 700 q.s. to
mL
125 10 mg (54
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to 700 q.s. to
mL
126 15 (81
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to 700 q.s. to
mL
127 25 mg (135
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to 700 q.s. to
mL
128 37.5 mg
(202
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to 700 q.s. to
mL
129 75 mg (405
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to 700 q.s. to
mL
130 100 mg
(541
µmols)
2.0% 4.0% 0.1% to
0.9%
900 to
1200
q.s. to
mL
131 115 mg
(621
µmols)
4.0% 8.0% 0.1% to
0.9%
1800 to
2200
q.s. to
mL
132 150 mg
(810
µmols)
6.0% 12.0% 0.1% to
0.9%
1800 to
2200
q.s. to
mL
133 190 mg
(1027
µmols)
8.0% 16.0% 0.1% to
0.9%
3500 to
4000
q.s. to
mL
134 220 mg
(1189
µmols)
8.0% 16.0% 0.1% to
0.9%
3600 to
4100
q.s. to
mL
201
Table 1-11 Composition no.
Ingredient and Amount
Pirfenidone (mg)
Phosphate Buffer
(monobasic/dibasi
c sodium salts),
pH 6.0 to pH 7.0
(mM)
Ethanol
Propylene Glycol
Chloride ion
(sodium,
magnesium or
calcium salts)
Osmolality
(mOsmo/kg)
Water
135 5 mg (27
µmols)
0.5% 1.0% 0.1% to
0.9%
200 to
500
q.s. to
mL
136 5 mg (27
µmols)
1.0% 2.0% 0.1% to
0.9%
200 to
700
q.s. to
mL
137 10 mg (54
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to
700
q.s. to
mL
138 15 (81
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to
700
q.s. to
mL
139 25 mg (135
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to
700
q.s. to
mL
140 37.5 mg
(202
µmols)
1.0% 2.0% 0.1% to
0.9%
400 to
700
q.s. to
mL
141 75 mg (405
µmols)
1.0% 2.0% - 400 to
700
q.s. to
mL
142 100 mg
(541
µmols)
2.0% 4.0% 0.1% to
0.9%
900 to
1200
q.s. to
mL
143 115 mg
(621
µmols)
4.0% 8.0% 0.1% to
0.9%
1800 to
2200
q.s. to
mL
144 150 mg
(810
µmols)
6.0% 12.0
%
0.1% to
0.9%
1800 to
2200
q.s. to
mL
145 190 mg
(1027
µmols)
8.0% 16.0
%
0.1% to
0.9%
3500 to
4000
q.s. to
mL
146 220 mg
(1189
µmols)
8.0% 16.0
%
0.1% to
0.9%
3600 to
4100
q.s. to
mL
202
Example 2: Buffer and pH Effects Development Study
Pirfenidone solubility in citrate and phosphate buffers were investigated (Table 2).
Pirfenidone (250 mg) was reconstituted with 5 mL of buffer in water or water alone and
mixed thoroughly with sonication and vortexing. The sample was agitated at ambient
temperature overnight. The sample was visually inspected, appearance recorded, centrifuged
to sediment any un-dissolved material, and the supernatant withdrawn via syringe through a
0.22 µm PVDF filter. The filtered sample was tested with respect to: appearance, pH (USP
<791>), osmolality (USP <785>), and Pirfenidone concentration and Pirfenidone % purity by
RP-HPLC. The remaining filtered sample was split into three equal volumes in glass vials
and placed at 25o
C/60RH, 40o 10 C/75RH and refrigeration. Samples were wrapped in
aluminum foil to reduce light exposure. After the first night of incubation, samples were
briefly visually inspected for any signs of discoloration or precipitate formation.
Table 2. Buffer/pH Effects Study Results
Buffer Buffer(mM) pH
Pirfenidone Saturation
Solubility (mg/mL)
Citrate 5 4 18.4
Citrate 50 4 18.1
Citrate 5 6 18.4
Citrate 50 6 16.4
Phosphate 5 6 18.3
Phosphate 50 6 17.2
Phosphate 5 7.5 19.0
Phosphate 50 7.5 16.3
Water 0 7.9 18.4
Table 2 shows the observed solubility of pirfenidone under the conditions described.
Example 3: Co-Solvent and Surfactant Effects
Pirfenidone solubility in the presence of added co-solvent (ethanol, propylene glycol,
or glycerin) and surfactant (polysorbate 80 or cetylpyridinium bromide) were investigated.
The buffer type, strength, and pH of the aqueous vehicle are selected based on results from
the Buffer/pH Effects study results (Example 2). Pirfenidone (375 mg) is reconstituted with
5 mL of each sovent system shown in Table 3.
Table 3. Co-Solvent/Surfactant Effects Study Results
203
Added Co-Solvent and/or
Surfactant, %
%
Water
%
Citrate
Buffer
(10
mM)
%
Phosphate
Buffer
(5 mM) pH
Pirfenidone
Saturation
Solubility
(mg/mL)
EtO
H PG
Gl
y PS80
CP
B
0 0 0 0.04 0 100.0 0 0 6.5 19.9
0 0 0 0 0.1 99.9 0 0 6.2 20.0
0 0 0 0.04 0 100.0 0 0 4.8 8.3
0 0 0 0 0.1 99.9 0 0 4.6 19.3
0 0 0 0.04 0 0 100.0 0 4.5 19.1
0 0 0 0 0.1 0 99.9 0 4.5 19.3
4 0 0 0 0 96.0 0 0 6.9 24.3
0 8 0 0 0 92.0 0 0 6.8 24.6
0 0 4 0 0 96.0 0 0 6.7 20.1
4 0 0 0 0 96.0 0 0 5.0 22.8
0 8 0 0 0 92.0 0 0 5.0 24.3
0 0 4 0 0 96.0 0 0 4.8 20.1
4 0 0 0 0 0 96.0 0 4.5 22.3
0 8 0 0 0 0 92.0 0 4.4 23.2
0 0 4 0 0 0 96.0 0 4.4 19.8
4 0 0 0.04 0 96.0 0 0 6.7 24.5
0 8 0 0.04 0 92.0 0 0 6.6 23.2
0 0 4 0.04 0 96.0 0 0 6.5 20.2
4 0 0 0.04 0 96.0 0 0 4.7 22.5
0 8 0 0.04 0 92.0 0 0 4.6 23.4
0 0 4 0.04 0 96.0 0 0 4.9 20.0
4 0 0 0.04 0 0 96.0 0 4.5 21.9
0 8 0 0.04 0 0 92.0 0 4.5 23.2
0 0 4 0.04 0 0 96.0 0 4.4 17.6
4 0 0 0 0.1 95.9 0 0 6.1 23.9
0 8 0 0 0.1 91.9 0 0 6.2 23.4
0 0 4 0 0.1 95.9 0 0 ND ND
4 0 0 0 0.1 95.9 0 0 4.9 20.2
0 8 0 0 0.1 91.9 0 0 5.0 22.3
0 0 4 0 0.1 95.9 0 0 ND ND
4 0 0 0 0.1 0 95.9 0 4.5 20.4
0 8 0 0 0.1 0 91.9 0 4.5 21.0
0 0 4 0 0.1 0 95.9 0 ND ND
4 8 0 0 0 88.0 0 0 6.2 30.0
4 8 0 0.04 0 88.0 0 0 5.8 28.9
4 8 0 0 0 0 0 88.0 6.6 27.2
4 8 0 0.04 0 0 0 88.0 6.6 29.4
6 12 0 0 0 0 0 82.0 7.0 34.7
8 16 0 0 0 0 0 76.0 7.0 43.7
8 0 0 0 0 0 0 92 6.6 26.7
8 4 0 0 0 0 0 88 6.8 30.4
8 8 0 0 0 0 0 84 6.8 35.0
204
Added Co-Solvent and/or
Surfactant, %
%
Water
%
Citrate
Buffer
(10
mM)
%
Phosphate
Buffer
(5 mM) pH
Pirfenidone
Saturation
Solubility
(mg/mL)
EtO
H PG
Gl
y PS80
CP
B
8 12 0 0 0 0 0 80 6.7 37.7
8 16 0 0 0 0 0 76 6.8 45.4
6 16 0 0 0 0 0 78 6.9 40.9
4 16 0 0 0 0 0 80 6.9 36.8
2 16 0 0 0 0 0 82 6.8 31.0
0 16 0 0 0 0 0 84 6.8 29.3
* Buffer type, buffer strength, and pH chosen on the basis of Buffer/pH study results
(Example 2). EtOH: ethanol, PG: propylene glycol, Gly: glycerol, PS80: polysorbate 80
(Tween 80), CPB: Cetylpyridinium chloride. % in Table 3 refers to volume/volume.
Each sample was agitated at ambient temperature overnight. The samples were
visually inspected and appearance recorded. Samples were centrifuged to sediment any undissolved material and the supernatant withdrawn via syringe through a 0.22 µm PVDF filter.
The filtered sample was tested with respect to: appearance, pH (USP <791>), osmolality
(USP <785>), and Pirfenidone concentration and Pirfenidone % purity by RP-HPLC. The
remaining filtered sample was split into three equal volumes in glass vials and placed at
25o
C/60RH, 40o 10 C/75RH and refrigeration. Samples are wrapped in aluminum foil to reduce
light exposure. After the first night of incubation, samples are briefly visually inspected for
any signs of discoloration or precipitate formation.
Both ethanol (EtOH) and propylene glycol (PG) increase the saturation solubility of
pirfenidone. Ethanol and propylene glycol together have an additive effect in increasing the
saturation solubility of pirfenidone.
Selected formulations were subjected to osmolality determination and nebulization for
taste testing and throat irritation and or cough response. Table 4 shows these results.
205
Table 4. Compositions and Additional Analysis
Added CoSolvent
and/or
Surfactant
(%)a
Sodium
Saccharin (mM)
%Phosphate
Buffer (5 mM) pH
Pirfenidone
(mg/mL)
Osmolality
(mOsmo/Kg)
Taste
Throat
Irritation?
EtOH PG
Cough Response?
4 8 0 88 6.6 27.2 ~1830*
4.5 micron aerosol
particle: Mild taste,
unremarkable flavor
No No
6 12 0 82 7.0 34.7 ~2750*
4.5 micron aerosol
particle: Mild taste,
slight sweet flavor,
slight bitter after-taste
No No
8 16 0 76 7.0 43.7 3672
4.5 micron aerosol
particle: Mild taste,
moderate sweet flavor,
moderate bitter aftertaste
3.5 micron aerosol
particle: Mild taste,
similar sweet flavor and
bitter after-taste as 6%
EtOH + 12% PG
No No
8 16 0.3 76 7.0 43.7 3672
3.5 micron aerosol
particle: Mild taste,
similar sweet flavor and
slightly bitter after-taste
similar to 6% EtOH +
12% PG
No No
8 16 0 76 4.5 0 3672
3.5 micron aerosol
particle: Mild taste,
slightly sweeter than 6%
EtOH + 12% PG, with
similar bitter after-taste
No No
* Calculated. a - % volume/volume
Results from Table 4 show that co-solvent-containing formulations contain a
relatively high osmolality. Unexpectedly, these high osmolar solutions do not exhibit poor
inhalation tolerability. Solutions containing up to 8% (v/v) ethanol plus 16% (v/v) propylene
glycol are well-tolerated, have a slight sweet flavor with minimal bitter after-taste, minimal
206
throat irritation and minimal stimulation of cough response. Formulations lacking co-solvents
are limited to about 15 mg/mL. These same formulations exhibited a bitter, slightly metallic
taste. Unexpectedly, co-solvent-enabling high concentration pirfenidone formulations (by
non-limiting example up to 44 mg/mL) do not exhibit these poor taste characteristics.
Saturated pirfenidone formulations appeared stable out to 2-5 days under the tested
conditions. However, in all cases pirfenidone eventually re-crystallized. This recrystallization was not inhibited by pre-filtration of the sample. From this observation,
pirfenidone concentrations less then saturation were explored. 85% saturation pirfenidone
concentrations were exposed to several temperatures. These results are shown in Table 5.
Table 5. Compositions and Additional Analysis
Added CoSolvent
(%)
%Phosphate
Buffer
(5 mM)
pH
Pirfenidone
(mg/mL)
Recrystallization upon storagea
EtOH PG 25oC 15oC 4oC -20oC
4 8 88 6.6 27.2b
Yes NDd
ND ND
4 8 88 6.6 23.0e
No No No Yesf
6 12 82 7.0 34.7 Yes ND ND ND
6 12 82 7.0 29.5 No No No Yesf
8 16 76 7.0 43.7 Yes ND ND ND
8 16 76 7.0 37.0 No No No Yesf
a. Observation after overnight storage at designated temperature
b. Pirfenidone saturation solubility at given formulation
c. Calculated
d. Not determined
e. Pirfenidone concentration at 85% saturation solubility
f. Crystals re-dissolved at 25o
C without agitation
% refers to % v/v
Results from Table 5 show that these 85% pirfenidone saturation formulations do not
re-crystallize down to 4o 20 C (at least following overnight incubation). These results suggest
that these formulations will survive periodic exposures down to 4o
C, and even upon freezing
will re-dissolve without agitation.
Additional studies examined pirfenidone stability in 5 mM sodium phosphate buffer,
pH 6.5, as a function of optimized co-solvent strength for stability assessment. The target
concentrations represent roughly 85% of the saturated concentration possible at each
specified co-solvent concentration. Two additional formulations examined pirfenidone
207
stability at 1 mg/mL in specific formulations. Pirfenidone (amounts are outlined in Table 6)
was reconstituted with 100 mL vehicle as described and mixed thoroughly by agitation. The
sample was agitated until completely dissolved. Once dissolved, samples were filtered via
syringe through a 0.22 µm PVDF filter.
Samples were refrigerated to reduce evaporative loss of volatile co-solvents (ethanol)
during filtration and dispensing. An approximate 5.0-mL aliquot of each formulation was
transferred to class A glass 6 ml containers with suitable closures (20 mm stopper). At least 8
containers are being maintained in the upright orientation at 25o
C/60RH, and another 8
containers maintained at 40 o
C/75RH. One container for each formulation was used for the
initial evaluation, t=0, with testing for: appearance, pH, osmolality, HPLC = RP-HPLC for
pirfenidone assay (reported as % label claim) and individual impurities (reported as %
pirfenidone and RRT). Stability time point testing will evaluate for appearance, and HPLC =
RP-HPLC for pirfenidone assay (reported as % label claim) and individual impurities
(reported as % pirfenidone and RRT).
Table 6. Representative Pirfenidone Formulations for Stability Assessment
Target
mM Phosphate
Buffer, pH 6.5, plus
Target
Pirfenidone
(mg/mL)
Add
Pirfenidone
(mg)
Add
Buffer
(mL)
Add
Ethanol
(mL)
Add
PG
(mL)
8% (v/v) EtOH, 16% (v/v) PG 38 3800 20 8.0 16.0
8% (v/v) EtOH, 16% (v/v) PG 1 100 20 8.0 16.0
6% (v/v) EtOH, 12% (v/v) PG 30 300 20 6.0 12.0
4% (v/v) EtOH, 8% (v/v) PG 23 230 20 4.0 8.0
1% (v/v) EtOH, 2% (v/v) PG 15 150 20 1.0 2.0
1% (v/v) EtOH, 2% (v/v) PG 1 100 20 1.0 2.0
For each variant Formulation, samples are tested according to the schedule shown in
Table 7.
Table 7. Stability Schedule
Tests* Performed at Time Point (mo) =
Condition 0 0.5** 1 3 6 9 12 contingency total
ºC/60 %RH 1 1 1 1 1 1 1 2 9
40 ºC/75 %RH 1 1 1 1 1 1 2 8
* all samples will be tested for appearance by visual observation, pH, HPLC = RP-HPLC for
pirfenidone assay (reported as % label claim), and individual impurities (reported as %
pirfenidone and RRT). At t=0, testing will also include osmolality.
** Appearance only
208
Table 8. Time-Zero Stability Assessment
Target
mM Phosphate
Buffer, pH 6.5,
plus
Target
Pirfenidone
(mg/mL)
Measured
Pirfenidone
(mg/mL) pH mOsmol/kg
App.
8% (v/v) EtOH,
16% (v/v) PG 38 38.9 7.04 3750 *
8% (v/v) EtOH,
16% (v/v) PG 1 1.0 6.98 3590 *
6% (v/v) EtOH,
12% (v/v) PG 30 30.3 6.90 2863 *
4% (v/v) EtOH, 8%
(v/v) PG 23 24.1 6.78 1928 *
1% (v/v) EtOH, 2%
(v/v) PG 15 16.1 6.65 512 *
1% (v/v) EtOH, 2%
(v/v) PG 1 1.0 6.69 452 *
* All solutions are clear and colorless without visible signs of crystallization.
Selected formulations were prepared for pharmacokinetic analysis following aerosol
delivery to rat lung. In these studies, lung, heart, kidney and plasma tissue samples were
analyzed for pirfenidone and metabolite content (Tables 16-19). Formulations prepared for
this study are outlined in Table 9. Briefly, this study prepared pirfenidone in 5 mM sodium
phosphate buffer, pH 6.5, as a function of optimized co-solvent strength. The target
concentration in each formulation is 12.5 mg/mL. Pirfenidone (amounts as described in
Table 9) were reconstituted with 30 mL vehicle as described and mixed thoroughly by
agitation. The sample was agitated until completely dissolved. Once pirfenidone had
dissolved completely, formulations were filtered via syringe through a 0.22 µm PVDF filter.
Filtered samples were analyzed by HPLC.
The samples were then refrigerated to reduce evaporative loss of volatile co-solvents
(ethanol) during filtration and dispensing. Formulations were transferred to class A glass
containers (approximately 10 mL) with suitable closures (20 mm stopper).
209
Table 9. Formulations for Co-Solvent Effects Pharmacokinetic and Tissue
Distribution Study
Dosing
Group
Target
mM
Phosphate
Buffer, pH
6.5, plus
Vol.
(mL)
* Target
Pirfenidone
(mg/mL)
Add
Pirfenidone
(mg)
Add
Buffer*
* (mL)
Add
EtO
H
(mL)
Add
PG
(mL)
Add
NaCl
(g)
1 8% (v/v)
EtOH, 16%
(v/v) PG 30 12.5 375 6 2.4 4.8 0
2 6% (v/v)
EtOH, 12%
(v/v) PG 30 12.5 375 6 1.8 3.6 0
3 4% (v/v)
EtOH, 8%
(v/v) PG 30 12.5 375 6 1.2 2.4 0
4 2% (v/v)
EtOH, 4%
(v/v) PG 30 12.5 375 6 0.6 1.2 0
1% (v/v)
EtOH, 2%
(v/v) PG 30 12.5 375 6 0.3 0.6 0
6
0.4% NaCl 30 12.5 375 6 0 0 0.12
* Pirfenidone was reconstituted with 30 mL of the indicated Vehicle by QS’ing the
remaining volume with water.
** 25mM NaPO4, pH 6.5 (5X solution)
Example 4: Nebulization Device Perfomance
Selected formulations were prepared for nebulization device aerosol characterization.
Briefly, this study prepared pirfenidone in 5 mM sodium phosphate buffer, pH 6.5, as a
function of optimized co-solvent strength. These formulations are outlined in Table 10.
Pirfenidone (amounts as listed in Table 10) were reconstituted as described and mixed
thoroughly by agitation. Each sample was agitated until completely dissolved. Once
dissolved completely, formulations were filtered via syringe through a 0.45 µm PVDF filter.
Filtered samples were analyzed by HPLC.
Each sample was refrigerated to reduce evaporative loss of volatile co-solvents
(ethanol) during filtration and dispensing. As described in Table 10, each formulation was
transferred to class A glass containers with suitable closures.
210
Table 10. Formulations for Nebulization Device Aerosol Performance Studies
Test
Article
Target
mM
Phosphate
Buffer, pH
6.5, plus
Vol.
(mL) Target
Pirfenidone
(mg/mL)
Add
Pirfenidon
e
(mg)
Add
Buffe
r*
(mL)
Add
Ethanol
(mL)
Add
PG
(mL
)
Add
NaCl
(g)
1 8% (v/v)
EtOH,
16% (v/v)
PG 200 38** 7600 40 16 32 0
2 8% (v/v)
EtOH,
16% (v/v)
PG 200 0 0 40 16 32 0
3 1% (v/v)
EtOH, 2%
(v/v) PG 200 0 0 40 2 4 0
4 0.2% (v/v)
EtOH,
0.4% (v/v)
PG NA 0.475 Diluted Test Articles 1 and 3
0.4% NaCl 200 0 0 40 0 0 0.8
* 25mM NaPO4, pH 6.5 (5X solution)
** Active formulations were diluted with water and vehicle by the device characterization
facility as necessary to characterize lower pirfenidone concentrations.
Philips I-neb® AAD System
For aerosol analysis, three units of each I-neb breath-actuated nebulizer were studied
in triplicate for each device/formulation combination. Using Malvern Mastersizer aerosol
particle sizer, the particle size and distribution was characterized. Parameters reported were
mass median diameter (MMD), span, fine particle fraction (FPF= % ≤ 5 microns), output rate
(mg formulation per second), nebulized volume, delivered volume (volume of dose in range
of FPF), respirable delivered dose (mg pirfenidone delivered volume). Aerosol output was
measured using a 5 second inhalation, 2 second exhalation breathing pattern with a 1.25 L
tidal volume. The results are shown in Table 11.
211
Table 11. Nebulization of Pirfenidone Formulations using the Philips I-neb Device
Parameter Test
Article 1
Test
Article 2
Test
Article 3
Test
Article 4
Test
Article 5
MMD (micron) 3.31 3.64 4.95 5.52 4.95
Span (micron) 1.13 1.36 1.21 1.14 1.20
FPF (% < 5
microns)
84.41 74.70 51.40 42.01 51.11
Output rate
(mg/sec)
0.96 1.31 3.52 6.92 4.60
Nebulized vol
(mg)
776.63 810.42 846.42 853.30 814.51
Delivered vol
(mg)
653.44 605.83 436.19 345.55 417.12
RDD (mg)* 24.83 NA NA 0.16 NA
* Exemplary (RDD = FPF X Nebulized Volume x loaded dose)
PARI eFlow® – 35 head
For aerosol analysis, three units of each eFlow nebulizer containing a 35-head were
studied in duplicate for each device/formulation combination. Using an Insitec Spraytec
Laser Particle sizer, the particle size and distribution was characterized. Parameters reported
were volumetric mean diameter (VMD), geometric standard deviation (GSD), time to
nebulize dose (duration), remaining dose following nebulization (dead volume), and fine
particle fraction (FPF= % ≤ 5 microns). 4 mL of each formulation was tested. The results
are shown in Table 12.
Table 12. Nebulization of Pirfenidone Formulations using the PARI eFlow Device
Parameter Test
Article 1
Test
Article 2
Test Article
3
Test
Article 4
Test
Article 5
Loaded Dose (mg) 152 0 0 1.9 0
VMD (micron) 2.60 2.84 3.60 3.88 3.81
GSD (micron) 1.86 1.85 1.74 1.68 1.68
FPF (% < 5
microns)
85.47 81.81 71.26 67.70 68.78
Duration (min) 9.87 8.85 6.26 5.99 5.86
Dead volume (mL) 0.15 0.16 0.19 0.18 0.16
Output rate
(mL/min)
0.40 0.44 0.61 0.64 0.67
Nebulized vol (mL) 3.85 3.84 3.81 3.82 3.84
RDD (mg)* 87.04 NA NA 0.86 NA
RDD (mg)/minute 8.82 NA NA 0.14 NA
* Exemplary (RDD = FPF X Inhaled Mass X Loaded Dose). For the exemplary calculation,
assume a 67% delivered dose (i.e. inhaled mass). (Representative of a 1:1
inhalation:exhalation breathing pattern using the eFlow device with 35 head.)
212
Aerogen Aeroneb® Solo
For aerosol analysis, between two and four units of each Aeroneb® Solo nebulizer
with Aeroneb® Pro-X controller were studied with each formulation. Using a Malvern
Spraytech aerosol particle sizer, the particle size and distribution were characterized.
Parameters reported were volumetric mean diameter (VMD), geometric standard deviation
(GSD), time to nebulize dose (duration), remaining dose following nebulization (dead
volume), and fine particle fraction (FPF= % ≤ 5 microns). 1 mL of each formulation was
tested. The results are shown in Table 13.
Table 13. Nebulization of Pirfenidone Formulations using the Aeroneb Solo Device
Parameter Test
Article 1
Test
Article 2
Test
Article 3
Test
Article 5
Loaded Dose (mg) 38 0 0 0
VMD (micron) 9.73 5.49 4.31 4.76
GSD (micron) 3.21 3.43 2.25 2.23
FPF (% < 5
microns)
38.97 48.13 59.09 53.77
Duration (min) 5.88 5.56 4.17 2.17
Output rate
(mL/min)
0.17 0.18 0.24 0.46
RDD (mg)* 9.9 NA NA NA
RDD (mg)*/minute 1.68 NA NA NA
* Exemplary (RDD = FPF X Inhaled Mass X Loaded Dose). For the exemplary calculation,
assume a 67% inhaled mass.
Example 5. Process temperature Development study
This study examined the above-ambient temperature stability of pirfenidone in
aqueous solution to best understand stability at this temperature and saturation solubility.
This information may be utilized with manufacturing process embodiments described herein
wherein high temperature pirfenidone aqueous dissolution, in the presence of or followed by
co-solvent and/or surfactant and/or cation addition, and subsequent cooling to ambient
temperature provide higher pirfenidone saturation solubility then ambient temperature
dissolution alone. In this process, added co-solvent and/or surfactant and/or cation may
stabilize the high-temperature-dissolved pirfenidone during the cooling process and provide a
stable, high-concentration, ambient-temperature formulation for long-term storage.
Alternatively, the added co-solvent and/or surfactant and/or cation may provide access to
greater soluble pirfenidone for which to maintain in solution then ambient temperature
213
dissolution alone. Alternatively, high-temperature dissolution may be integrated into
manufacturing process embodiments to reduce dissolution time and/or reduce the effects of
lot-to-lot crystal structure, amorphic content and polymorph variability on dissolution time
and degree of dissolution.
Formulations were prepared as described in Table 11. Briefly, this study prepared
250 mg pirfenidone in 5 mM sodium phosphate buffer, pH 6.5, in the presence of ethanol,
propylene glycol and/or polysorbate 80. The final volume of each formulation was 5 mL.
Pirfenidone (amounts as listed in Table 11) were reconstituted as described and mixed
thoroughly by agitation. Each sample was mixed thoroughly and agitated overnight at 60o
C.
Rapid cooling and step-wise cooling from 60o
C to 25o 10 C was performed. HPLC analysis was
performed on samples taken after overnight incubation and after cooling to 25o
C. Prior to
HPLC analysis, formulations were filtered via syringe through a 0.45 µm PVDF filter.
Results for this evaluation are shown in Table 14.
214
Table 14. Formulations for Process Temperature Study
Added Co-Solvent
and/or Surfactant
(% v/v)
%Phosphate
Buffer (5 mM)
pH
Pirfenidone
(mg/mL)
Observations
EtO
H PG PS80
> 60oCa
>Recrystalb
4 8 0 88 6.7 50.3
4 27.6
Fully dissolved after overnight at
60o
C. Stable at 25o
C for >4 hours
before re-crystallization
4 8 0.04 88 6.7 51.8 26.8
Fully dissolved after overnight at
60o
C. Stable at 25o
C for >4 hours
before re-crystallization
4 0 0.04 96 6.6 50.7 22.4
Fully dissolved after overnight at
60o
C. Stable at 25o
C for >4 hours
before re-crystallization
0 8 0.04 92 6.7 52.8 22.3
Fully dissolved after overnight at
60o
C. Stable at 25o
C for >4 hours
before re-crystallization
0 8 0 92 6.6 54.6 18.6
Fully dissolved after overnight at
60o
C. Stable at 25o
C for >4 hours
before re-crystallization
a. Pirfenidone assay content after stepwise cooling to 25o
C
b. Pirfenidone assay content after stepwise cooling to 25o
C and then later recrystallization
c. Calculated
d. Not determined
e. Pirfenidone concentration at 85% saturation solubility
f. Crystals re-dissolved at 25o
C without agitation
The results in Table 14 show that heating pirfenidone to 60o
C enables full dissolution
up to or potentially greater than 50 mg/mL. Rapid cooling to 25o 10 C of this dissolved material
led to rapid recrystallization (data not shown). Slow cooling to 25o
C (step-wise from 60o
C to
40o
C to 30o
C then 25o
C, with temperature equilibration occurring at each step prior to further
reducing the temperature) enabled pirfenidone to stay in solution at about 50 mg/mL for
several hours before each solution ultimately re-crystallized. Filtering each formulation prior
to re-crystallization (either at 30o
C or after equilibrium at 25o 15 C) did not noticeably extend or
prevent re-crystallization. Pirfenidone dissolution time is reduced by heating and appears to
be stable at this temperature during the dissolution process. Thus, heating pirfenidone
formulations can be beneficial in a manufacturing process embodiments to overcome the
slower dissolution observed at ambient temperature.
215
Example 6: Pharmacokinetics and Lung-Tissue Distribution
Sprague-Dawley rats (300-350 grams) were administered pirfenidone by either the
oral (gavage) or aerosol (intratracheal Penn Century nebulizing catheter) routes. For oral
administration, 50 mg pirfenidone was dissolved in 3.33 mL distilled water containing 0.5%
CMC to a final concentration of 15 mg/mL. Solutions were vortexed until all crystals
dissolved. Rats were administered 70 mg/kg pirfenidone (~ 1.4 mL). Plasma samples were
taken at pre-dose, 0.08, 0.16, 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, and 6 hours post dosing. For lung
tissue samples, eight additional rats were also dosed 70 mg/kg by the oral route. Lungs were
taken at pre-dose 0.08, 0.5, 2, and 4 hours post dosing. Materials were extracted and
pirfenidone quantitated as µg/mL plasma and µg/gram lung tissue. For aerosol
administration, 60 mg pirfenidone was dissolved in 10 mM phosphate buffer, pH 6.2
containing 81 mM MgCl2 (1:1 pirfenidone to magnesium). Rats were administered 5 mg/kg
pirfenidone (~100 µL) by nebulizing catheter. Plasma samples were taken at pre-dose, 0.08,
0.16, 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, and 6 hours post dosing. For lung tissue samples, eight
additional rats were also dosed 70 mg/kg by the oral route. Lungs were taken at pre-dose
0.08, 0.5, 2, and 4 hours post dosing. Materials were extracted and pirfenidone quantitated as
µg/mL plasma and µg/gram lung tissue. Results from these studies are shown in Table 15.
216
Table 15. Pirfenidone pharmacokinetics and tissue distribution following oral and
aerosol administration to rats.
Aerosol Measureda Oral
Rat dose (mg/kg) 1 5 70 Lung
Cmaxb
101 508 3.6
T1/2c
<1, 45 <1, 45 45
AUCd
5.2 25.4 4.3
TOEe
5 84 89
Plasma
Cmaxf
1.1 7.0 8.1
T1/2 30 30 30
AUC0-6hrsg
0.9 4.5 13.5
a. Bolus aerosol intratracheal delivery
b. Cmax: Lung tissue (µg/g) immediate post-dose calculated from the direct-lung
delivered dose. All other time points measured. Plasma measured (µg/mL)
c. T1/2: Minutes (aerosol = α, β; oral = α only observed)
d. AUC: Lung tissue (mg⋅hr/kg for time >1 µg/g)
e. TOE: Time of exposure as minutes over 1 µg/g lung tissue)
f. Cmax: Plasma (µg/mL)
g. AUC0-6hrs: Plasma (mg⋅hr/L)
Example 7: Pharmacokinetics and Tissue Distribution of Co-solvent Formulations
To assess the pharmacokinetics and tissue distribution of co-solvent formulations
(described in Table 9), Sprague-Dawley rats (350-400 grams) in triplicate were administered
pirfenidone by bolus aerosol (intratracheal Penn Century nebulizing catheter). Rats were
dosed about 4 mg/kg pirfenidone (~150 µL) by nebulizing catheter. Plasma samples, and
entire lungs, hearts and kidneys were taken at pre-dose, 0.033, 0.067, 0.1, 0.167, 0.333,
0.667, 1.0, 1.5, 2, and 2.5 hours post dosing. Materials were extracted and pirfenidone
quantitated as µg/mL plasma and µg/gram lung, heart or kidney tissue. Results from these
studies are shown in Table 16 thru 19. No adverse events were noted in these studies.
Table 16. Pirfenidone Pharmacokinetics and Lung Tissue Distribution - CoSolvent-Based Formulation Study (Dosing group formulations listed in Table 9)
217
Analyte
Time
(hr)
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
PIRFENIDONE
0A 107.58
0.0333 3.57 3.93 5.56 3.16 5.24 2.25
0.0667 2.66 2.16 2.29 1.94 2.68 2.06
0.1 1.93 1.49 1.84 1.87 1.51 1.71
0.167 1.38 1.43 1.54 1.31 1.45 1.31
0.333 1.07 0.95 0.95 1.00 1.27 0.96
0.667 0.52 0.60 0.61 0.62 0.48 0.57
1 0.38 0.31 0.26 0.34 0.36 0.31
1.5 0.15 0.18 0.11 0.17 0.12 0.09
2 0.07 0.09 0.08 0.05 0.07 0.08
2.5 0.02 0.03 0.03 0.03 0.02 0.05
-CARBOXY-N-phenyl1H-pyridone
0 MIN 0.00
0.0333
H
0.03
NOT TESTED
0.03
NOT TESTED
0.07 0.04
0.0667
H
0.03 0.10 0.10 0.11
0.100
H
0.12 0.14 0.09 0.09
0.167
H
0.13 0.22 0.14 0.16
0.333
H
0.25 0.27 0.36 0.24
0.667
H
0.24 0.20 0.24 0.23
1 H 0.18 0.17 0.19 0.20
1.50 H 0.12 0.13 0.11 0.11
2 H 0.05 0.08 0.05 0.06
2.50 H 0.03 0.03 0.02 0.04
a. Average of 18 immediate post-dose measurements
218
Table 17. Pirfenidone Plasma Pharmacokinetics - Co-Solvent-Based Formulation
Study (Dosing group formulations listed in Table 9)
Analyte
Time
(hr)
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
Mean
µg/mL
Mean
µg/mL
Mean
µg/mL
Mean
µg/mL
Mean
µg/mL
Mean
µg/mL
PIRFENIDONE
0 0.03 0.01 0.06 0.01 0.02 0.06
0.0333 6.80 6.20 7.47 7.23 7.72 6.84
0.0667 6.09 6.04 6.52 7.43 7.05 7.31
0.1 5.72 5.12 5.39 3.98 5.55 5.75
0.167 5.56 5.60 5.51 4.75 4.59 5.31
0.333 3.94 4.53 4.53 3.98 3.84 4.26
0.667 2.74 3.02 2.54 2.41 2.24 2.87
1 1.93 1.65 1.39 1.45 1.68 1.49
1.5 0.67 0.80 0.54 0.85 0.59 0.43
2 0.29 0.37 0.36 0.22 0.29 0.33
2.5 0.09 0.12 0.11 0.11 0.08 0.13
Table 18. Pirfenidone Pharmacokinetics and Heart Tissue Distribution - CoSolvent-Based Formulation Study (Dosing group formulations listed in Table 9)
Analyte
Time
(hr)
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
PIRFENIDONE
0 0.00 0.05
NOT TESTED
0.02
0.0667 1.97 1.48 1.58
0.167 1.23 1.02 1.24
0.333 0.96 0.78 0.86
0.667 0.45 0.55 0.55
1 0.35 0.27 0.31
1.5 0.15 0.17 0.09
2.5 0.02 0.03 0.03
219
Table 19. Pirfenidone Pharmacokinetics and Kidney Tissue Distribution - CoSolvent-Based Formulation Study (Dosing group formulations listed in Table 9)
Analyte
Time
(hr)
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
Mean
µg/gram
PIRFENIDONE
0 0.00 0.13
NOT TESTED
0.08
0.0667 2.65 2.87 3.42
0.167 1.70 2.21 1.74
0.333 1.30 2.02 1.23
0.667 0.74 0.84 0.88
1 0.51 0.46 0.43
1.5 0.26 0.24 0.15
2.5 0.05 0.05 0.05
Results from the co-solvent effects tissue distribution studies show that the presence
of up to 8% ethanol with 16% propylene glycol to change the tissue or plasma
pharmacokinetic profile compared to a 0.4% sodium chloride formulation. Further, these
results show a delayed appearance of 5-Carboxy-pirfenidone (the primary pirfenidone liver
metabolite). Comparing the initial rapid elimination of pirfenidone from the lung tissue and
parallel appearance of pirfenidone in the plasma suggest that direct pulmonary administration
may be a good route for systemic administration of pirfenidone. The delayed appearance of
5-Carboxy-pirfenidone metabolite supports this hypothesis in that this metabolite serves as a
marker for re-circulation of pirfenidone to the lung and other tissues following direct aerosol
administration to the lung. Further, as suggested in Tables 15 and 16 and supported by the
modeled data in Figure 1 and Table 20, re-circulated pirfenidone is likely important to
support long-term, elevated pirfenidone levels in the lung and other tissues of potential
efficacy.
To understand pirfenidone human lung tissue distribution and associated
pharmacokinetics following a 10-12 minute aerosol administration from a nebulizer,
measured rat pharmacokinetic and lung tissue distribution data following bolus nebulizing
catheter administration was scaled. Briefly, using allometric scaling, rat aerosol lung data
and plasma delivery was scaled to humans. Rat data was taken from Table 16 and 17.
Allometric scaling used parameters established in the US FDA Guidance for Industry -
220
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in
Adult Healthy Volunteers. July, 2005, and Caldwell et al., European Journal of Drug
Metabolism and Pharmacokinetics, 2004, Vol. 29, No.2, pp. 133-143. For comparative
purposes, human plasma pharmacokinetic data resulting from oral administration was taken
directly Rubino et al., 2009. For oral data, fed-state human data was used. To model plasma
pirfenidone pharmacokinetics where plasma pirfenidone was delivered from aerosol
administration, pharmacokinetics data from fasting-state humans was used (Rubino et al.,
2009). Inhaled aerosol-derived plasma pirfenidone levels were calculated based upon an
assumed 100% bioavailability of inhaled, respirable-deposited pirfenidone to a 5,000 mL
total blood volume. The contribution of plasma-derived pirfenidone (whether from oral or
aerosol inhalation dosing) to lung tissue distribution and pharmacokinetics assumed at any
given time 50% of plasma pirfenidone was delivered to the lung tissue. By example, a plasma
level of 10 µg/mL contributed 5 µg/gram pirfenidone to the lung tissue. Results of this
analysis are shown in Figure 1 and Table 20.
Aerosol deliver parameters based on Table 10 formulation characterization in highefficiency, mesh-based nebulizers (Tables 11-13). Respirable delivered dose (RDD)
calculated by the product of fine particle fraction (FPF, %<5 microns) and inhaled mass. An
about 110 mg RDD was calculated from a 5 mL device-loaded dose of a 40 mg/mL
pirfenidone formulation (200 mg loaded dose). The FPF and inhaled mass were 85% and
67%, respectively. Inhaled mass was calculated based upon breathing pattern. A 1:1
inhalation:exhalation breathing pattern (e.g. a 2 second inhalation followed by a 2 second
exhalation) using the eFlow device and 35-head is predicted to produce an inhaled mass of
about 67%. From this, a 2:1 breathing pattern (e.g., a 4 second inhalation followed by a 2
second exhalation) may produce an inhaled mass between about 74% and about 80%. Using
the inhaled mass of 74% and the FPF of 85%, a 200 mg device-loaded dose may produce an
RDD of about 125 mg. Similarly, the inhaled mass of 80% may produce an RDD of about
136 mg from a 200 mg device-loaded dose. Continuing, a 3:1 breathing pattern (e.g., a 6
second inhalation followed by a 2 second exhalation) may produce an inhaled mass between
about 80% and about 87%. Using the inhaled mass of 87% and the FPF of 85%, a 200 mg
device-loaded dose may produce an RDD of about 148 mg. In some embodiments, the RDD
may be further increased or decreased by additional means: by non-limiting example,
221
changing the device-loaded volume and/or changing the formulation pirfenidone
concentration. In some embodiments, increasing the formulation concentration to 50 mg/mL
and using the 5 mL device-loaded volume will provide a 250 mg device-loaded dose. Using
the FPF of 85% and inhaled mass of about 67%, a 250 mg device-loaded dose may produce
an RDD of about 142 mg, a 74% inhaled mass may produce an RDD of about 157 mg, a 80%
inhaled mass may produce an RDD of about 170 mg, and a 87% inhaled mass may produce
an RDD of about 185 mg. Additional dose escalations are possible with increased co-solvent
addition to the pirfenidone formulation. Similarly, dose de-escalations are possible with
reduced device-loaded dose (reduced volume and/or reduced pirfenidone formulation
concentration) and/or less-efficient breathing pattern. While allometric scaling is an
established means to predict pharmacokinetic parameters and dose scaling between animals
and humans, precedent exists that supports human-inhaled therapies remaining in the lung
significantly longer than the duration predicted by allometric scaling. This possibility may
also result in longer lung pirfenidone residence time and may also translate to reduced plasma
exposure.
Table 20. Modeled human pirfenidone pharmacokinetics and tissue distribution.
Parameter
Aerosol (RDDa) Oral (801 mg)
110 mg 154 mg 185 mg Fed-State Fasted-State
LT P LT P LT P LT P LT P
Cmaxb
57.5 17.7 71.2 24.8 85.8 30.0 3.9 7.9 7.1 14.2
AUCc
43.4 68.9 61.0 96.8 75.1 118.3 22.1 58.9 33.9 67.7
TOEd
8.7 − 9.9 − 10.4 − 10.4 − 10.0 −
T1/2 alpha (min) 5 − 5 − 5 − − − − −
T1/2 beta (hr)e
2.5 2.5 2.5 2.5 2.5 2.5 2.4 2.4 2.5 2.5
T1/2 Absorption
(hr)f − 0.1 − 0.1 − 0.1 − 1.8 − 0.4
222
LT = lung tissue; P = plasma.
a. RDD: respirable delivered dose = fine particle fraction (FPF; %particles <5 microns) X
inhaled mass
b. Cmax: Lung tissue = microgram/gram; plasma = microgram/mL
c. AUC: Expressed as AUC over 0-18 hours, Lung tissue in mg⋅hr/kg and plasma expressed
in mg⋅hr/L.
d. TOE: Time of exposure measured as minutes over 1 microgram/gram lung tissue
e. T1/2 beta: Lung tissue pirfenidone levels and associated beta phase lung tissue T1/2 derived
solely from plasma-pirfenidone and hence, plasma pirfenidone T1/2. Aerosol = Rubino et al.,
2009 fasted-state; Oral = Rubino et al., 2009
f. T1/2 absorption: Aerosol = modeled from allometrically-scaled bolus aerosol rat data; Oral =
Rubino et al., 2009.
The various embodiments described above can be combined to provide further
embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent
applications, foreign patents, foreign patent applications and non-patent publications referred
to in this specification are incorporated herein by reference, in their entirety. Aspects of the
embodiments can be modified, if necessary to employ concepts of the various patents,
applications and publications to provide yet further embodiments. These and other changes
can be made to the embodiments in light of the above-detailed description. In general, in the
following claims, the terms used should not be construed to limit the claims to the specific
embodiments disclosed in the specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents to which such claims are
entitled. Accordingly, the claims are not limited by the disclosure.
Claims (24)
1. An aqueous solution for nebulized inhalation administration comprising: water; pirfenidone at a concentration from about 5.0 to about 19.0 mg/mL; a sodium or magnesium salt, or a combination thereof, in an amount sufficient to provide a permeant ion concentration of between about 25 and 200 mM, wherein the permeant ions are chloride ions, bromide ions, or a combination thereof, a taste masking agent at a concentration of between 0.1 and 2.0 mM, wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg.
2. The aqueous solution of claim 1, wherein the pH of the solution is between approximately 5.0 and approximately 6.0.
3. The aqueous solution of claim 1 or claim 2, wherein: the solution further comprises one or more additional ingredients selected from surfactants, buffers and salts.
4. The aqueous solution of claim 3, wherein: the surfactant is polysorbate 80 or cetylpyridinium bromide; the buffer is a citrate buffer or phosphate buffer; and the salt is sodium chloride or magnesium chloride.
5. The solution of claim 1, optionally including the taste masking agent, wherein the aqueous solution further comprises: one or more co-solvents, wherein the total amount of the one or more co-solvents is about 1% to about 40% v/v, where the one or more co-solvents are selected from about 1% to about 25% v/v of ethanol, about 1% to about 25% v/v of propylene glycol, and about 1% to about 25% v/v of glycerol.
6. The solution of claim 1, wherein the aqueous solution comprises: one or more co-solvents, wherein the total amount of the one or more co-solvents if about 1 to about 30% v/v, where the one or more co-solvents are selected from about 1% to about 10% v/v of ethanol, and about 1% to about 20% v/v of propylene glycol; and optionally a phosphate buffer that maintains the pH of the solution from about pH 6.0 to about pH 8.0; 224 wherein the osmolality of the aqueous solution is from about 400 mOsmol/kg to about 6000 mOsmol/kg.
7. A unit dosage adapted for use in a liquid nebulizer comprising from about 0.5 mL to about 6 mL of an aqueous solution of pirfenidone, a sodium or magnesium salt, or a combination thereof, in an amount sufficient to provide a permeant ion concentration of between about 25 and 200 mM, wherein the permeant ions are chloride ions, bromide ions, or a combination thereof, and a taste masking agent at a concentration of between 0.1 and 2.0 mM, wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg.
8. The unit dosage of claim 7, wherein: the aqueous solution further comprises one or more additional ingredients selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, salts, and buffers.
9. The unit dosage of claim 7, wherein the aqueous solution further comprises: one or more co-solvents selected from ethanol, propylene glycol, and glycerol; and one or both of a citrate buffer or a phosphate buffer.
10. The unit dosage of claim 7, wherein the total amount of the one or more co-solvents is about 1 to about 30% v/v, and where the one or more co-solvents are selected from about 1% to about 10% v/v of ethanol, and about 1% to about 20% v/v of propylene glycol.
11. A kit comprising: a unit dosage of any one of claims 7-10 in a container that is adapted for use in a liquid nebulizer.
12. An aqueous aerosol comprising a plurality of aqueous droplets of pirfenidone, wherein the plurality of aqueous droplets have a volumetric mean diameter (VMD), mass median aerodynamic diameter (MMAD), and/or mass median diameter (MMD) of less than about 5.0 μm.
13. The aqueous aerosol of claim 12, wherein the plurality of aqueous droplets was produced from a liquid nebulizer and an aqueous solution of pirfenidone.
14. The aqueous aerosol of claim 13, wherein the aerosol provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm and provides: 225 a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 1 μm to about 5 μm; b) a volumetric mean diameter (VMD) of about 1 μm to about 5 μm; and/or c) a mass median diameter (MMD) of about 1 μm to about 5 μm.
15. The aqueous aerosol of claim 12, wherein at least 30% of the aqueous droplets in the aerosol have a diameter less than about 5 μm.
16. The aqueous aerosol of claim 12 produced by a nebulizing an aqueous solution of any one of claim 1-6 with a liquid nebulizer.
17. An inhalation system for administration of pirfenidone compound to the respiratory tract of a mammal, the system comprising: (a) about 0.5 mL to about 6 mL of an aqueous solution of pirfenidone at a concentration from about 5.0 to about 19.0 mg/mL; and a sodium or magnesium salt, or a combination thereof, in an amount sufficient to provide a permeant ion concentration of between about 25 and 200 mM, wherein the permeant ions are chloride ions, bromide ions, or a combination thereof, one or more co-solvents, and a taste masking agent at a concentration of between 0.1 and 2.0 mM, wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg; and (b) a liquid nebulizer having a vibrating mesh membrane and a reservoir in fluid communication therewith containing the aqueous solution of pirfenidone.
18. The inhalation system of claim 17, wherein the aqueous solution of pirfenidone is an aqueous solution of any one of claims 1-6.
19. The inhalation system of claim 17 or claim 18, wherein the liquid nebulizer: (i) achieves lung deposition of at least 7% of the pirfenidone administered to the mammal; (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm; (iii) provides: a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 1 μm to about 5 μm; b) a volumetric mean diameter (VMD) of about 1 μm to about 5 μm; and/or c) a mass median diameter (MMD) of about 1 μm to about 5 μm; 226 (iv) provides a fine particle fraction (FPF= % ≤ 5 microns) of droplets emitted from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least 0.1 mL/min; and/or (vi) provides at least about 25% of the aqueous solution to the mammal.
20. An aqueous solution as defined in claim 1 substantially as herein described with reference to any example thereof.
21. A unit dosage as defined in claim 7 substantially as herein described with reference to any example thereof.
22. A kit as defined in claim 11 substantially as herein described with reference to any example thereof.
23. An aqueous aerosol as defined in claim 12 substantially as herein described with reference to any example thereof.
24. An inhalation system as defined in claim 17 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
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US201161438203P | 2011-01-31 | 2011-01-31 | |
US61/438,203 | 2011-01-31 | ||
US201161508542P | 2011-07-15 | 2011-07-15 | |
US61/508,542 | 2011-07-15 | ||
US201161559670P | 2011-11-14 | 2011-11-14 | |
US61/559,670 | 2011-11-14 | ||
US201261584119P | 2012-01-06 | 2012-01-06 | |
US61/584,119 | 2012-01-06 | ||
NZ612962A NZ612962B2 (en) | 2011-01-31 | 2012-01-31 | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
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NZ719737B2 true NZ719737B2 (en) | 2018-03-23 |
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