NZ730805B2 - Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator - Google Patents
Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator Download PDFInfo
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- NZ730805B2 NZ730805B2 NZ730805A NZ73080515A NZ730805B2 NZ 730805 B2 NZ730805 B2 NZ 730805B2 NZ 730805 A NZ730805 A NZ 730805A NZ 73080515 A NZ73080515 A NZ 73080515A NZ 730805 B2 NZ730805 B2 NZ 730805B2
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- PASYJVRFGUDDEW-WMUGRWSXSA-J tetrasodium;[[(2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C(NC(=O)C=C2)=O)O)[C@@H](O)C1 PASYJVRFGUDDEW-WMUGRWSXSA-J 0.000 description 1
- 230000036575 thermal burns Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- 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
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/18—Acetic acid esters of trihydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
- C07C69/30—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with trihydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
- C07C69/58—Esters of straight chain acids with eighteen carbon atoms in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Abstract
The present disclosure relates to co-crystals comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and a co-former comprising one triglyceride and methods for their preparation. The present disclosure further relates to pharmaceutical compositions comprising the co-crystal forms, as well as methods of treatment therewith and kits. itions comprising the co-crystal forms, as well as methods of treatment therewith and kits.
Description
CO-CRYSTALS OF MODULATORS OF CYSTIC FIBROSIS
TRANSMEMBRANE CONDUCTANCE REGULATOR
This application claims priority to U.S. provisional application No.
62/060,828, filed on October 7, 2014, which is herein incorporated by reference in its
entirety.
TECHNICAL FIELD
The present disclosure generally relates to co-crystals of N-[2,4-bis(1,1-
dimethylethyl)hydroxyphenyl]-1,4-dihydrooxoquinolinecarboxamide
(Compound 1), and pharmaceutical compositions thereof. Methods therewith are
described herein.
BACKGROUND
Cystic fibrosis (CF) is a recessive genetic disease that affects approximately
,000 children and adults in the United States and approximately 30,000 children
and adults in Europe. Despite progress in the treatment of CF, there is no cure.
CF is caused by mutations in the cystic fibrosis transmembrane conductance
regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for
aiding in the regulation of salt and water absorption and secretion in various
tissues. Small molecule drugs known as potentiators that increase the probability of
CFTR channel opening represent one potential therapeutic strategy to treat
CF. Potentiators of this type are disclosed in , which is herein
incorporated by reference in its entirety. Another potential therapeutic strategy
involves small molecule drugs known as CF correctors that increase the number and
function of CFTR channels. Correctors of this type are disclosed in WO
2005/075435, which is herein incorporated by reference in its entirety.
Specifically, CFTR is a cAMP/ATP-mediated anion channel that is
expressed in a variety of cell types, including absorptive and secretory epithelial cells,
where it regulates anion flux across the membrane, as well as the activity of other ion
channels and proteins. In epithelial cells, normal functioning of CFTR is critical for
the maintenance of electrolyte transport throughout the body, including respiratory
and digestive tissue. CFTR is composed of approximately 1480 amino acids that
encode a protein made up of a tandem repeat of transmembrane domains, each
containing six transmembrane helices and a nucleotide binding domain. The two
transmembrane domains are linked by a large, polar, regulatory (R)-domain with
multiple phosphorylation sites that regulate channel activity and cellular trafficking.
The gene encoding CFTR has been identified and sequenced (See Gregory,
R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362),
(Riordan, J. R. et al. (1989) Science 245:1066-1073). A defect in this gene causes
mutations in CFTR resulting in cystic fibrosis ("CF"), the most common fatal genetic
disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in
the United States. Within the general United States population, up to 10 million
people carry a single copy of the defective gene without apparent ill effects. In
contrast, individuals with two copies of the CF associated gene suffer from the
debilitating and fatal effects of CF, including chronic lung disease.
In patients with CF, mutations in CFTR endogenously expressed in
respiratory epithelia leads to reduced apical anion secretion causing an imbalance in
ion and fluid transport. The resulting decrease in anion transport contributes to
enhanced mucus accumulation in the lung and the accompanying microbial infections
that ultimately cause death in CF patients. In addition to respiratory disease, CF
patients typically suffer from gastrointestinal problems and pancreatic insufficiency
that, if left untreated, result in death. In addition, the majority of males with cystic
fibrosis are infertile, and fertility is decreased among females with cystic fibrosis. In
contrast to the severe effects of two copies of the CF associated gene, individuals with
a single copy of the CF associated gene exhibit increased resistance to cholera and to
dehydration resulting from diarrhea – perhaps explaining the relatively high frequency
of the CF gene within the population.
Sequence analysis of the CFTR gene of CF chromosomes has revealed a
variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369;
Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science
245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451).
To date, greater than 1000 disease causing mutations in the CF gene have been
identified (http://www.genet.sickkids.on.ca/cftr/app). The most prevalent mutation is
a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is
commonly referred to as ΔF508-CFTR. This mutation occurs in approximately 70%
of cystic fibrosis cases and is associated with a severe disease.
The deletion of residue 508 in ΔF508-CFTR prevents the nascent protein
from folding correctly. This results in the inability of the mutant protein to exit the
ER, and traffic to the plasma membrane. As a result, the number of channels present
in the membrane is far less than observed in cells expressing wild-type CFTR. In
addition to impaired trafficking, the mutation results in defective channel gating.
Together, the reduced number of channels in the membrane and the defective gating
lead to reduced anion transport across epithelia leading to defective ion and fluid
transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown,
however, that the reduced numbers of ΔF508-CFTR in the membrane are functional,
albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-
528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-
50). In addition to ΔF508-CFTR, other disease causing mutations in CFTR that result
in defective trafficking, synthesis, and/or channel gating could be up- or down-
regulated to alter anion secretion and modify disease progression and/or severity.
Although CFTR transports a variety of molecules in addition to anions, it is
clear that this role (the transport of anions) represents one element in an important
mechanism of transporting ions and water across the epithelium. The other elements
+ + - + + +
include the epithelial Na channel (ENaC), Na /2Cl /K co-transporter, Na -K -
ATPase pump and the basolateral membrane K channels that are responsible for the
uptake of chloride into the cell.
These elements work together to achieve directional transport across the
epithelium via their selective expression and localization within the cell. Chloride
absorption takes place by the coordinated activity of ENaC and CFTR present on the
+ + -
apical membrane and the Na -K -ATPase pump and Cl ion channels expressed on the
basolateral surface of the cell. Secondary active transport of chloride from the
luminal side leads to the accumulation of intracellular chloride, which can then
passively leave the cell via Cl channels, resulting in a vectorial transport.
+ - + + +
Arrangement of Na /2Cl /K co-transporter, Na -K -ATPase pump and the basolateral
membrane K channels on the basolateral surface and CFTR on the luminal side
coordinate the secretion of chloride via CFTR on the luminal side. Because water is
probably never actively transported itself, its flow across epithelia depends on tiny
transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.
As discussed above, it is believed that the deletion of residue 508 in ΔF508-
CFTR prevents the nascent protein from folding correctly, resulting in the inability of
this mutant protein to exit the ER and traffic to the plasma membrane. As a result,
insufficient amounts of the mature protein are present at the plasma membrane and
chloride transport within epithelial tissues is significantly reduced. In fact, this
cellular phenomenon of defective ER processing of ABC transporters by the ER
machinery has been shown to be the underlying basis not only for CF disease but for a
wide range of other isolated and inherited diseases.
N-[2,4-bis(1,1-dimethylethyl)hydroxyphenyl]-1,4-dihydro
oxoquinolinecarboxamide (Compound 1) is a potent and selective CFTR
potentiator of wild-type and mutant (including, but not limited to, e.g., ΔF508 CFTR,
R117H CFTR, G551D CFTR, G178R CFTR, S549N CFTR, S549R CFTR, G551S
CFTR, G970R CFTR, G1244E CFTR, S1251N CFTR, S1255P CFTR, and G1349D
CFTR) forms of human CFTR. N-[2,4-bis(1,1-dimethylethyl)hydroxyphenyl]-1,4-
dihydrooxoquinolinecarboxamide is useful for treatment of patients age 6 years
and older with cystic fibrosis and one of the following mutations in the CFTR gene:
G551D CFTR, G1244E CFTR, G1349D CFTR, G178R CFTR, G551S CFTR,
S1251N CFTR, S1255P CFTR, S549N CFTR, S549R CFTR, or R117H CFTR
Accordingly, stable bioavailable forms of Compound 1 that can be
manufactured easily, including co-crystals comprising N-[2,4-bis(1,1-dimethylethyl)-
-hydroxyphenyl]-1,4-dihydrooxoquinolinecarboxamide, and pharmaceutical
compositions thereof, may be useful for developing products and/or methods for
treating patients suffering from CF thereof. It is an object of the present invention to
go some way to satisfying this desideratum, and/or to at least provide the public with
a useful choice.
[0013a] Accordingly, in a first aspect, the present invention provides a
pharmaceutical composition comprising a co-crystal of Compound 1 and only one
triglyceride, wherein the triglyceride is chosen from the following structural formula:
wherein R1, R2, and R3 are independently C1-29 aliphatic,
and wherein Compound 1 is represented by the following structural formula:
and wherein the pharmaceutical composition is a solid formulated for oral
administration.
[0013b] In a further aspect, the present invention provides a pharmaceutical
composition comprising a therapeutically effective amount of Compound 1 and a
pharmaceutically acceptable carrier or excipient, wherein Compound 1 is represented
by the following structural formula:
, and
further wherein at least 30% of Compound 1 is present as a co-crystal comprising
Compound 1 and a triglyceride, wherein the triglyceride is chosen from the following
structural formula:
wherein R1, R2, and R3 are independently C1-29 aliphatic, and wherein the
pharmaceutical composition is a solid formulated for oral administration.
[0013c] In another aspect, the present invention provides use of a co-crystal of
Compound 1 and only one triglyceride, wherein the triglyceride is chosen from the
following structural formula:
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
and wherein Compound 1 is represented by the following structural formula:
in the manufacture of a medicament for treating or lessening the severity of a disease
in a patient, wherein said disease is selected from cystic fibrosis, hereditary
emphysema, COPD, or dry-eye disease, and wherein the medicament is a solid
formulated for oral administration.
[0013d] In another aspect, the present invention provides a method of preparing a co-
crystal comprising Compound 1 and a triglyceride,
wherein Compound 1 is represented by the following structural formula:
and wherein the triglyceride is chosen from the following structural formula:
wherein R , R , and R are independently C aliphatic;
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the triglyceride; and
(b) heating the mixture.
[0013e] In the description in this specification reference may be made to subject
matter which is not within the scope of the appended claims. That subject matter
should be readily identifiable by a person skilled in the art and may assist in putting
into practice the invention as defined in the appended claims.
In one aspect, the disclosure provides a co-crystal comprising Compound 1
and a co-former, wherein Compound 1 is represented by the following formula:
and the co-former is chosen from the following structural formula:
wherein R , R , and R are independently C aliphatic.
1 2 3 1-29
In some embodiments, the co-crystal is isolated.
In some embodiments, in the co-crystal, the stoichiometry of Compound 1 to
the co-former ranges from 2 to 1 to 6 to 1.
In some embodiments, the stoichiometry of Compound 1 to the co-former in
the co-crystal is 6 to 1.
In some embodiments, the stoichiometry of Compound 1 to the co-former in
the co-crystal is about 6 to about 1.
In some embodiments, the stoichiometry of Compound 1 to the co-former in
the co-crystal is 3 to 1.
In some embodiments, the stoichiometry of Compound 1 to the co-former in
the co-crystal is about 3 to about 1.
In some embodiments, Compound 1 may form hexameric supermolecules
(hexamers) in the co-crystal, wherein each of the hexamers contains six molecules of
Compound 1 bound by hydrogen bonds as shown in Figure 1.
In some embodiments, the co-crystals are capable of yielding a concentration
of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated intestinal
fluid in fed state (FeSSIF).
In some embodiments, the co-crystals are capable of yielding a
concentration of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated
intestinal fluid in fed state (FeSSIF) and the concentration is maintained for at least 10
hours.
In some embodiments, the co-crystals are characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, and 10.9.
In yet some embodiments, the co-crystals are characterized as having a C
ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the following
positions: 178.6, 155.0, and 119.4.
In yet some other embodiments, the co-crystals are characterized as having a
C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the
following positions: 178.6, 155.0, 130.5, and 119.4.
Another aspect of the present disclosure provides for pharmaceutical
compositions comprising a therapeutic effective amount of Compound 1 and a
pharmaceutically acceptable carrier or excipient, wherein at least 30% of Compound 1
is present in the form of co-crystals disclosed herein.
In some embodiments, the pharmaceutical composition further comprises an
additional therapeutic agent.
For example, in one embodiment, the additional therapeutic agent is selected
from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an
anti-inflammatory agent, a CFTR modulator other than Compound 1, or a nutritional
agent, or combinations thereof. In another embodiment, the additional therapeutic
agent is a CFTR modulator other than Compound 1.
Further as an example, in one embodiment, the CFTR modulator is (3-(6-(1-
(2,2-difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido)methylpyridin-
2-yl)benzoic acid or (R)(2,2-difluorobenzo[d][1,3]dioxolyl)-N-(1-(2,3-
dihydroxypropyl)fluoro(1-hydroxymethylpropanyl)-1H-indol
yl)cyclopropanecarboxamide.
In another aspect, the present disclosure provides for a method treating or
lessening the severity of a disease in a patient, wherein said disease is selected from
cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, the method
comprising the step of administering to the patient an effective amount of any of the
co-crystals presented herein. For example, in one embodiment, the disease is cystic
fibrosis.
In some embodiments, the method further comprises co-administering one or
more additional therapeutic agents to the subject. For example, in one embodiment,
the additional therapeutic agent is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxolyl)
cyclopropanecarboxamido)methylpyridinyl)benzoic acid or (R)(2,2-
difluorobenzo[d][1,3]dioxolyl)-N-(1-(2,3-dihydroxypropyl)fluoro(1-
hydroxymethylpropanyl)-1H-indolyl)cyclopropanecarboxamide. In another
embodiment, the additional therapeutic agent is administered concurrently with, prior
to, or subsequent to the co-crystal.
Another aspect of the present disclosure provides for a method of preparing a
co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is
represented by the following structural formula:
the co-former is chosen from the following structural formula:
R O O R
, R , and R are independently C aliphatic
wherein R1 2 3 1-29
comprising the step of:
combining Compound 1 and the co-former to form the co-crystal.
One aspect of the present disclosure provides for a method of preparing a co-
crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented
by the following structural formula:
the co-former is chosen from the following structural formula:
R O O R
wherein R1, R2, and R3 are independently C1-29 aliphatic.
Another aspect of the present disclosure provides for a method of preparing
co-crystals comprising Compound 1 and a co-former, wherein Compound 1 is
represented by the following structural formula:
the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic.
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former; and
(b) heating the mixture to 80ºC.
Further another aspect of the present disclosure provides for a method of
preparing co-crystals comprising Compound 1 and a co-former, wherein Compound 1
is represented by the following structural formula:
the co-former is chosen from the following structural formula:
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former; and
(b) heating the mixture to a temperature that is about 5 to 10 °C higher than
the melting point of the co-former.
One aspect of the present disclosure provides for a method of preparing co-
crystals comprising Compound 1 and a co-former, wherein Compound 1 is
represented by the following structural formula:
the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic;
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former;
(b) heating the mixture;
(c) cooling down the mixture; and
(d) repeating step (b) and (c).
Another aspect of the present disclosure provides for a method of preparing a
co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is
represented by the following structural formula:
the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former;
(b) heating the mixture to 80ºC;
(c) cooling the mixture down to 40ºC; and
(d) repeating step (b) and (c).
In some embodiments, the mixture comprising Compound 1 and the co-
former is heated for 12 hours. In other embodiments, the mixture comprising
Compound 1 and the co-former is heated for at least 12 hours. In some embodiments,
the mixture comprising Compound 1 and the co-former is heated for 24 hours. In
other embodiments, the mixture comprising Compound 1 and the co-former is heated
for at least 24 hours.
In some embodiments, co-crystals disclosed herein, such as Compound
1:triglyceride co-crystals, may exhibit several advantages. For example, Compound
1:triglyceride co-crystals may show a better maintenance of the supersaturation than
both the neat amorphous and solid amorphous dispersed form of Compound 1
(Compound 1 SDD) over longer time periods. Further as an example, in-vivo the
Compound 1:triglyceride co-crystals may be metabolized in the small intestine by
lipid esterase (lipases), which would effectively remove the triglycerides and further
boost the Compound 1 concentration according to Le-Chatelier’s principle.
In some embodiments, co-crystals disclosed herein, such as Compound
1:triglyceride co-crystals, may have the following advantages over the solid
amorphous dispersed form (Compound 1 SDD) of Compound 1: (1) the co-crystals
may be formulated, stored, and used under conditions where they are
thermodynamically stable; (2) a controlled crystallization may be developed that can
reduces potential impurity levels (impurities include, but are not limited to, solvent);
(3) a manufacturing process may be developed that is more efficient and cost effective
(for example, less solvent can be used in manufacturing and a lower cost process than
spray drying can be developed); and (4) a stabilizing polymer may not be required for
formulating co-crystals.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows structural features of the Compound 1:triglyceride co-crystal
in some embodiments. Figure 1 (left) shows a hexamer (six molecules of Compound
1) which are present in a Compound 1:triglyceride co-crystal. Figure 1 (right) shows
a hexamer made of two trimers (A and B) each formed by three molecules of
Compound 1 (trimer A: A1, A2, and A3; and trimer B: B1, B2, and B3).
Figure 2 shows examples of hydrogen bonding in a Compound 1:triglyceride
co-crystal in some embodiments. Figure 2 (left) shows a trimer A of compound 1 and
the hydrogen bonds that may be present between the molecules of Compound 1 (A1,
A2, and A3) within a trimer [R3,3(18) >b>b>b]. Figure 2 (right) depicts hydrogen
bonds that may be present within a molecule of compound 1 [S1,1(6)a], and hydrogen
bonds that may be present in between two molecules of compound 1 from two trimers
(A and B) [R2,2(20) >c>c]. Trimers A and B form a hexamer.
Figure 3 is an examplary X-Ray Powder Diffraction (XRPD) pattern of
Compound 1:glyceryltrioctanoate.
Figure 4 is an examplary C solid state nuclear magnetic resonance
spectroscopy ( C ssNMR) spectrum of Compound 1:glyceryltrioctanoate.
Figure 5 is an examplary thermal gravimetric analysis (TGA) trace
Compound 1:glyceryltrioctanoate.
Figure 6 is an examplary Differential Scanning Calorimetry (DSC)
thermogram of Compound 1:glyceryltrioctanoate.
Figure 7 is an examplary H Nuclear Magnetic Resonance ( H NMR)
spectrum of Compound 1:glyceryltrioctanoate in DMSO-d .
Figure 8 is an examplary XRPD pattern of Compound 1:glyceryltrioleate.
Figure 9 is an examplary C ssNMR spectrum of Compound
1:glyceryltrioleate.
Figure 10 is an examplary TGA trace Compound 1:glyceryltrioleate.
Figure 11 is an examplary DSC thermogram of Compound
1:glyceryltrioleate.
Figure 12 is an examplary H NMR spectrum of Compound
1:glyceryltrioleate in acetone-d .
Figure 13 is an examplary XRPD pattern of Compound
1:glyceryltrilinoleate.
Figure 14 is an examplary C ssNMR spectrum of Compound
1:glyceryltrilinoleate.
Figure 15 is an examplary TGA trace Compound 1:glyceryltrilinoleate.
Figure 16 is an examplary DSC thermogram of Compound
1:glyceryltrilinoleate.
Figure 17 is an examplary H NMR spectrum of Compound
1:glyceryltrilinoleate in acetone-d .
Figure 18 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltriacetate.
Figure 19 is an examplary C ssNMR spectrum of Compound 1:triacetin.
Figure 20 is an examplary DSC thermogram of Compound
1:glyceryltiacetin.
Figure 21 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltributyrate.
Figure 22 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltristearate.
Figure 23 is an examplary C ssNMR spectrum of Compound
1:glyceryltristearate.
Figure 24 is an examplary DSC thermogram of Compound
1:glyceryltristearate.
Figure 25 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltripalmitate.
Figure 26 is an examplary C ssNMR spectrum of Compound
1:glyceryltripalmitate.
Figure 27 is an examplary DSC thermogram of Compound
1:glyceryltripalmitate.
Figure 28 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltridodecanoate.
Figure 29 is an examplary C ssNMR spectrum of Compound
1:glyceryltridodecanoate.
Figure 30 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltrimyristate.
Figure 31 is an examplary C ssNMR spectrum of Compound
1:glyceryltrimyristate.
Figure 32 is an examplary DSC thermogram of Compound
1:glyceryltrimyristate.
Figure 33 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltrihexanoate.
Figure 34 is an examplary XRPD diffraction pattern of cocrystals of
Compound 1 with glyceryltridecanoate.
Figure 35 is an examplary C ssNMR spectrum of Compound 1:
glyceryltridecanoate.
Figure 36 is a comparison of examplary dissolution profiles in FeSSIF of
Compound 1:glyceryltrioctanoate (filled circles) Compound 1:glyceryltrioleate (filled
squares), and Compound 1:glyceryltrilinoleate (filled triangles) with amorphous
Compound 1 (filled diamonds), Compound 1 spray dried dispersion (SDD) (filled
upside-down triangles).
Figure 37 is an examplary XRPD diffraction patterns of cocrystals of
Compound 1 with different pure triglycerides and cocrystals isolated from mixture of
infant formula and Compound.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Definitions
As used herein, the following definitions shall apply unless otherwise
indicated.
[0079a] The term “comprising” as used in this specification and claims means
“consisting at least in part of”. When interpreting statements in this specification and
claims which include the term “comprising”, other features besides the features
prefaced by this term in each statement can also be present. Related terms such as
“comprise”, and “comprises” are to be interpreted in a similar manner.
As used herein, “a”, “an”, and “at least one” each means “one or more than
one.”
The term “ABC-transporter” as used herein means an ABC-transporter
protein or a fragment thereof comprising a binding domain, wherein said protein or
fragment thereof is present in vivo or in vitro. The term “binding domain” as used
herein means a domain on the ABC-transporter that can bind to a modulator. See,
e.g., Hwang, T. C. et al., J. Gen. Physiol. (1998): 111(3), 477-90.
As used herein, “CFTR” stands for cystic fibrosis transmembrane
conductance regulator.
As used herein, “mutations” can refer to mutations in the CFTR gene or the
CFTR protein. A “CFTR mutation” refers to a mutation in the CFTR gene, and a
“CFTR mutation” refers to a mutation in the CFTR protein. A genetic defect or
mutation, or a change in the nucleotides in a gene in general results in a mutation in
the CFTR protein translated from that gene. Genetic defects or mutations include, but
are not limited to, ΔF508 CFTR, R117H CFTR, G551D CFTR, G178R CFTR, S549N
CFTR, S549R CFTR, G551S CFTR, G970R CFTR, G1244E CFTR, S1251N CFTR,
S1255P CFTR, and G1349D CFTR or ΔF508 CFTR, R117H CFTR, G551D CFTR,
G178R CFTR, S549N CFTR, S549R CFTR, G551S CFTR, G970R CFTR, G1244E
CFTR, S1251N CFTR, S1255P CFTR, and G1349D CFTR (see, e.g.,
http://www.genet.sickkids.on.ca/app for CFTR mutations).
As used herein, a “ ΔF508 mutation” or “F508del mutation” is a specific
mutation within the CFTR protein. The mutation is a deletion of the three nucleotides
that comprise the codon for amino acid phenylalanine at position 508, resulting in
CFTR protein that lacks this phenylalanine residue. The mutated CFTR protein is
commonly referred to as “F508del.”
The term “CFTR gating mutation” as used herein means a CFTR mutation
that results in the production of a CFTR protein for which the predominant defect is a
low channel open probability compared to normal CFTR (Van Goor, F., Hadida S.
and Grootenhuis P., “Pharmacological Rescue of Mutant CFTR function for the
Treatment of Cystic Fibrosis”, Top. Med. Chem. 3: 91-120 (2008)). Gating mutations
include, but are not limited to, G551D, G178R, S549N, S549R, G551S, G970R,
G1244E, S1251N, S1255P, and G1349D.
As used herein, a patient who is “homozygous” for a particular mutation, e.g.
F508del, has the same mutation on each allele.
As used herein, a patient who is “heterozygous” for a particular mutation,
e.g. F508del, has this mutation on one allele and a different mutation on the other
allele.
As used herein, the term “modulator” refers to a compound that increases the
activity of a compound such as a protein. For example, a CFTR modulator is a
compound that increases the activity of CFTR. The increase in activity resulting from
a CFTR modulator may be through a corrector mechanism, a potentiator mechanism,
or through a dual corrector and potentiator mechanism.
As used herein, the term “CFTR corrector” refers to a compound that
increases the amount of functional CFTR protein to the cell surface, resulting in
enhanced ion transport.
As used herein, the term “CFTR potentiator” refers to a compound that
increases the channel activity of CFTR protein located at the cell surface, resulting in
enhanced ion transport.
The term “crystalline” refers to solid materials comprising atoms, molecules,
and/or ions arranged in ordered geometric patterns or lattices. Crystalline solids show
definite melting points and have rigid long range order.
The term “co-crystal” as used herein means a crystalline entity containing at
least two molecules in either stoichiometric or nonstoichiometric ratio. The co-crystal
may optionally further contain ions.
The co-crystals typically comprise an active pharmaceutical ingredient (API)
and a co-former. The co-former typically may be hydrogen-bonded directly to the API
or may be hydrogen-bonded to an additional molecule that is bound to the API. Other
modes of molecular recognition may also be present including, pi-stacking, guest-host
complexation and van der Waals interactions.
As used herein, the term “co-former”, or alternatively “co-crystal former,”
refers to a molecule such as a triglyceride in a co-crystal other than an API. The co-
former may or may not undergo any changes after forming co-crystal with an API.
“Compound 1:triglyceride” refers to co-crystals comprising Compound 1 and
a triglyceride. For example, “Compound 1:glyceryltrioctanoate” is used herein to refer
to co-crystals comprising Compound 1 and glyceryltrioctanoate. “Compound
1:glyceryltrioleate” is used herein to refer to co-crystals comprising Compound 1 and
glyceryltrioleate. “Compound 1:glyceryltrilinoleate” is used herein to refer to co-
crystals comprising Compound 1 and glyceryltrilinoleate.
As used herein, the term “active pharmaceutical ingredient” or “API” refers
to a biologically active compound.
The term “pure” as used herein means chemically pure or free from
impurities detectable by routine chemical analysis, for example by HPLC.
“Substantially pure” as used herein means at least 70%, 75%, 80%, 85%,
90%, 95%, 97%, 98%, or 99% purity of the target material within a mixture.
As used herein, the term “isolated,” as in an isolated co-crystal, refers to a
co-crystal that is separated away from other materials, such as other crystalline
materials that may be distinguished from the target co-crystal through routine analysis
such as XRPD. In some embodiments, the co-crystals may be isolated or separated
from other materials by filtration or centrifugation. In some embodiments, an isolated
co-crystal may be at least 50% pure. In some embodiments, the isolated co-crystal
may contain impurities such as, as non-limiting examples, residual co-former, solvent,
or other materials presented in the medium in which the co-crystal was produced,
which may be difficult to be removed from the co-crystal. In other embodiments, an
isolated co-crystal may be substantially pure.
As used herein, the term “aliphatic” encompasses substituted or
unsubstituted alkyl, alkenyl, and alkynyl groups. An “alkyl” group refers to a
saturated aliphatic hydrocarbon group containing 1-29 carbon atoms. An alkyl group
can be straight or branched. As used herein, an “alkenyl” group refers to an aliphatic
carbon group that contains 2-29 carbon atoms and a double bond. Like an alkyl
group, an alkenyl group can be straight or branched. As used herein, an “alkynyl”
group refers to an aliphatic carbon group that contains 2-29 carbon atoms and has a
triple bond. An alkynyl group can be straight or branched.
As used herein, the term “inducing,” as in inducing CFTR activity, refers to
increasing CFTR activity, whether by the corrector, potentiator, or other mechanism.
The term “modulating” as used herein means increasing or decreasing, e.g.,
activity, by a measurable amount.
The term “reduced CFTR” or “reduced CFTR function” as used herein
means less than normal CFTR or less than normal CFTR function.
A “patient,” “subject” or “individual” are used interchangeably and refer to
either a human or non-human animal. The term includes mammals such as humans.
The terms “effective dose” or “effective amount” are used interchangeably
herein and refer to that amount that produces the desired effect for which it is
administered (e.g., improvement in CF or a symptom of CF or lessening the severity
of CF or a symptom of CF). The exact amount will depend on the purpose of the
treatment, and will be ascertainable by one skilled in the art using known techniques
(see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical
Compounding).
As used herein, the terms “treatment,” “treating,” and the like generally
mean the improvement of CF or its symptoms or lessening the severity of CF or its
symptoms in a subject. “Treatment,” as used herein, includes, but is not limited to,
the following: increased growth of the subject, increased weight gain, reduction of
mucus in the lungs, improved pancreatic and/or liver function, reduced incidences of
chest infections, and/or reduced instances of coughing or shortness of breath.
Improvements in or lessening the severity of any of these conditions can be readily
assessed according to standard methods and techniques known in the art.
As used herein, the term “in combination with” when referring to two or
more compounds or agents means that the order of administration includes the
compounds or agents being administered prior to, concurrent with, or subsequent to
each other to the patient.
Co-crystals
The present disclosure provides co-crystals comprising N-[2,4-bis(1,1-
dimethylethyl)hydroxyphenyl]-1,4-dihydrooxoquinolinecarboxamide
(Compound 1) having the structural formula:
Compound 1
Compound 1 is described in International PCT publication WO2006002421
and has the molecular formula of C24H28N2O3.
In one aspect, the present disclosure provides a co-crystal comprising
Compound 1 and a co-former, wherein the co-former is chosen from the following
structural formula:
, wherein R1, R2, and R3 are
independently C aliphatic.
1-29
In some embodiments, the co-crystal is isolated.
In some embodiments, R1, R2, and R3 are independently C7-29 aliphatic.
In some embodiments, the co-former has an average molecular weight
ranging from 470 to 1400 Da.
In some embodiments, the co-former is chosen from glyceryltrioleate,
glyceryltristearate, glyceryltrihexanoate, glyceryltridecanoate, glyceryltrioctanoate,
glyceryltrimyristate, glyceryltripalmitate, glyceryltributyrate, glyceryltrilinoleate,
glyceryltridodecanoate, glyceryltripalmitoleate, glyceryltrierucate,
glyceryltripropionate, palmitodiolein, triarachidonin, glyceryl trilinolenate, trierucin,
glycerol triarachidate, glyceryl tri(cisdocosenoate), glyceryl tripetroselinate,
glyceryl tribehenate, glyceryl trielaidate, glyceryltriacetate (triacetin),
glyceryltributyrate .
In some embodiments, the co-former is chosen from:
, and
In some embodiments, the co-former is chosen from: glyceryltrioleate,
glyceryltristearate, glyceryltrihexanoate, glyceryltridecanoate, glyceroltrioctanoate,
glyceryltrimyristate, glyceryltripalmitate, glyceryltrilinoleate, glyceryltridodecanoate,,
glyceryltripalmitoleate, glyceroltrierucate, palmitodiolein, triarachidonin, glyceryl
trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cisdocosenoate),
glyceryl tripetroselinate, glyceryl tribehenate, and glyceryl trielaidate.
In some embodiments, the co-former is chosen from glyceryltrioctanoate,
glyceryltrioleate, glyceryltrilinoleate, glyceryltrihexanoate, glyeryltristearate,
glyceryltridecanoate, glycerltripalmitate, glyceryltrimyristate, glyceryltripalmitate,
glyceryltristearate, and glyceryltridodecanoate.
In some embodiments, the co-former is chosen from glyceryltriacetate and
glyceryltributyrate.
In some embodiments, only one co-former is present in the co-crystal. As
non-limiting examples, the co-crystal of Compound 1 comprises only
glyceryltrioctanoate, only glyceryltrioleate, only glyceryltrilinoleate, only
glyceryltrihexanoate, only glyeryltristearate, only glyceryltridecanoate, only
glycerltripalmitate, only glyceryltridodecanoate, only glyceryltriacetate, or only
glyceryltributyrate.
In some embodiments, more than one, such as two, three, four, five, or six
triglycerides are present in the co-crystal. As non-limiting examples, the co-crystal of
Compound 1 comprises two triglycerides, such as (i) glyceryltrioctanoate and
glyceryltrioleate; (ii) glyceryltrioleate and glyceryltrilinoleate; or (iii)
glyceryltrioctanoate and glyceryltrilinoleate.
In some embodiments, in the co-crystal, the stoichiometry of Compound 1 to
the co-former ranges from 2 to 1 to 6 to 1. In one embodiments, in the co-crystal, the
stoichiometry of Compound 1 to the co-former ranges from 3 to 1 to 6 to 1. In one
embodiments, in the co-crystal, the stoichiometry of Compound 1 to the co-former
ranges from 4 to 1 to 6 to 1. In one embodiments, in the co-crystal, the stoichiometry
of Compound 1 to the co-former ranges from 5 to 1 to 6 to 1.
In one embodiment, in the co-crystal, the stoichiometry of Compound 1 to
the co-former is about 6 to about 1. In one embodiment, in the co-crystal, the
stoichiometry of Compound 1 to the co-former is 6 to 1.
As non-limiting examples, the co-crystal of Compound 1 comprises a co-
former chosen from glyceryltrioleate, glyceryltrilinoleate, glyceryltristearate, and
glyceryltripalmitate, and the stoichiometry of Compound 1 to the co-former in the co-
crystal is about 6 to about 1. Further as non-limiting examples, in one embodiment,
the co-crystal comprises Compound 1 and glyceryltrioleate, wherein the stoichiometry
of Compound 1 to glyceryltrioleate is about 6 to about 1. In another embodiment, the
co-crystal comprises Compound 1 and glyceryltrilinoleate, wherein the stoichiometry
of Compound 1 to glyceryltrilinoleate is about 6 to about 1. In another embodiment,
the co-crystal comprises Compound 1 and glyceryltristearate, wherein the
stoichiometry of Compound 1 to glyceryltristearate is about 6 to about 1. In another
embodiment, the co-crystal comprises Compound 1 and glyceryltripalmitate, wherein
the stoichiometry of Compound 1 to glyceryltripalmitate is about 6 to about 1. In any
of the above embodiments, the ratio or stoichiometry of Compound 1 to the co-former
in Compound 1:triglyceride is 6 to 1.
In some embodiments, the stoichiometry of Compound 1 to the co-former in
the co-crystal is about 3 to about 1. In one embodiment, the stoichiometry of
Compound 1 to the co-former in the co-crystal is 3 to 1.
As non-limiting examples, the co-crystal of Compound 1 comprises a co-
former chosen from glyceryltrioctanoate, glyceryltridodecanoate, and
glyceryltridecanoate and the stoichiometry of Compound 1 to the triglyceride in the
co-crystal is about 3 to about 1.
Further as non-limiting examples, in one embodiment, the present disclosure
provides for a co-crystal comprising Compound 1 and glyceryltrioctanoate, wherein
the stoichiometry of Compound 1 to glyceryltrioctanoate is about 3 to about 1. In
another embodiment, the present disclosure provides a co-crystal comprising
Compound 1 and glyceryltridodecanoate, wherein the stoichiometry of Compound 1
to glyceryltridodecanoate is about 3 to about 1. In another embodiment, the present
disclosure provides a co-crystal comprising Compound 1 and glyceryltridecanoate,
wherein the stoichiometry of Compound 1 to glyceryltridecanote is about 3 to about 1.
In any of the above embodiments, the ratio or stoichiometry of Compound 1 to
triglyceride co-former in Compound 1:triglyceride is 3 to 1.
In some embodiments, R , R , and R are independently C aliphatic and
1 2 3 7-29
Compound 1 may be present in the form of a hexamer in the co-crystal.
In some embodiments, Compound 1 may be present in the form of a hexamer
in the co-crystal, wherein each of the hexamers contains six molecules of Compound
1 bonded by hydrogen bonding as shown in Figure 1.
In some embodiments, Compound 1 may be present in the form of a hexamer
in the co-crystal, wherein each of the hexamers contains six molecules of Compound
1 bonded by hydrogen bonding as shown in Figure 1, and further wherein R , R , and
R3 are independently C7-29 aliphatic.
As a non-limiting example, as shown in Figure 2 (left), in one embodiment,
three molecules of Compound 1 (A1, A2, A3) may bound by three hydrogen bonds to
form a Compound trimer, and two Compound 1 trimers may further bound by
additional, such as six, hydrogen bonds to form a Compound 1 hexamer, wherein each
of Compound 1 molecules in a given trimer is bound to the corresponding Compound
1 molecule in the second trimer by two hydrogen bonds as shown in Figure 2 (right).
In one embodiment, intramolecular hydrogen bonds are present in the hexamer of
Compound 1 as shown in Figure 2 (right).
In one embodiment, molecules of Compound 1 may be bound by the one or
more of the following hydrogen bonds to form a hexamer:
S1,1(6) a;
R2,2(20) >c>c;
R3,3(18) >b>b>b;
R4,4(28) >b>c>b>c;
R4,4(30) >b>c>b<c;
R4,4(32) >b<c>b<c;
R5,5(36) >b>b<c<b<c;
R5,5(36) >b>b<c<b>c;
R5,5(36) >b>b>c<b<c;
R5,5(36) >b>b>c<b>c;
R6,6(40) >b>b>c>b>b>c;
R6,6(42) >b>b>c>b>b<c;
R6,6(44) >b>b<c>b>b<c.
A description of graph set notation may be found in Bernstein, J., Davis, R.
E., Shimoni, L. & Chang, N.-L, “Patterns in Hydrogen Bonding: Functionality and
Graph Set Analysis in Crystals,” Angew. Chem. Int. Ed. Engl. 34, 1555–1573 (1995);
W. D. S. Motherwell, G. P. Shields, and F. H. Allen, “Automated assignment of
graph-set descriptors for crystallographically symmetric molecules,” Acta. Cryst. B56,
466-473 (2000), and M. C. Etter, “Encoding and decoding hydrogen-bond patterns of
organic compounds,” Acc. Chem. Res., 23, 120-126 (1990).
In yet another embodiment, a Compound 1 hexamer in a Compound
1:triglyceride co-crystal is stabilized by the presence of the triglyceride co-former.
In some embodiments, the co-crystals are capable of yielding a concentration
of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated intestinal
fluid in fed state (FeSSIF).
In some embodiments, the co-crystals are capable of yielding a
concentration of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated
intestinal fluid in fed state (FeSSIF) and the concentration is maintained for at least 10
hours.
In some embodiments, the co-crystals are characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, and 10.9.
In some embodiments, the co-crystals are characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, and 18.0.
In some embodiments, the co-crystals are characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.0, and 23.8.
In yet some embodiments, the co-crystals are characterized as having a 13C
ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the following
positions: 178.6, 155.0, and 119.4.
In also yet some embodiments, the co-crystals are characterized as having a
13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the
following positions: 178.6, 155.0, 130.5, and 119.4.
The present disclosure also provides a co-crystal comprising Compound 1
and a co-crystal former selected from the group consisting of glyceryltrioctanoate,
glyceryltrioleate, and glyceryltrilinoleate, wherein Compound 1 is represented by the
following structural formula:
In some embodiments, the co-crystal described in the paragraph immediately
above dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a
concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is
maintained for at least 10 hours.
In one embodiment, the co-crystal former is glyceryltrioctanoate.
In one embodiment, the stoichiometry of Compound 1 to
glyceryltrioctanoate is 3 to 1.
In one embodiment, the co-crystal is characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, and 10.9.
In one embodiment, the co-crystal is characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.0, 6.9, 9.1, 10.9, 16.9, 18.0, and 23.8.
In one embodiment, the co-crystal is characterized as having a 13C ssNMR
spectrum with characteristic peaks expressed in ppm ± 0.1 at the following positions:
178.6, 155.0, and 119.4.
In one embodiment, the co-crystal is characterized as having an endothermic
peak in differential scanning calorimetry (DSC) at 186.7 ± 0.5ºC.
In some embodiments, the co-crystal former is glyceryltrioleate.
In one embodiment, the stoichiometry of Compound 1 to glyceryltrioleate is
6 to 1.
In one embodiment, the co-crystal is characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, and 10.9.
In one embodiment, the co-crystal is characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.1 and 23.8.
In one embodiment, the co-crystal is characterized as having a 13C ssNMR
spectrum with characteristic peaks expressed in ppm ± 0.1 at the following positions:
178.6, 155.0, 130.5, and 119.4.
In one embodiment, the co-crystal is characterized as having an endothermic
peak in differential scanning calorimetry (DSC) at 197.5 ± 0.5ºC.
In some embodiments, the co-crystal former is glyceryltrilinoleate.
In one embodiment, the stoichiometry of Compound 1 to glyceryltrilinoleate
is 6 to 1.
In one embodiment, the co-crystal is characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.9, and 10.9.
In one embodiment, the co-crystal is characterized as having an X-ray
powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees
at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9, 17.0, 18.1, and 23.8.
In one embodiment, the co-crystal is characterized as having a 13C ssNMR
spectrum with characteristic peaks expressed in ppm ± 0.1 at the following positions:
178.5, 155.0, 130.6, and 119.3.
In one embodiment, the co-crystal is characterized as having an endothermic
peak in differential scanning calorimetry (DSC) at 182.3 ± 0.5ºC.
In alternative embodiments, deuterium (2H) may be incorporated into
Compound 1 to manipulate the oxidative metabolism of the compound by way of the
primary kinetic isotope effect. The primary kinetic isotope effect is a change of the
rate for a chemical reaction that results from exchange of isotopic nuclei, which in
turn is caused by the change in ground state energies necessary for covalent bond
formation after this isotopic exchange. Exchange of a heavier isotope usually results
in a lowering of the ground state energy for a chemical bond and thus causes a
reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the
vicinity of a saddle-point region along the coordinate of a multi-product reaction, the
product distribution ratios can be altered substantially. For explanation: if deuterium
is bonded to a carbon atom at a non-exchangeable position, rate differences of kM/kD
= 2-7 are typical. If this rate difference is successfully applied to Compound 1, the
profile of this compound in vivo can be drastically modified and result in improved
pharmacokinetic properties. For a further discussion, see S. L. Harbeson and R. D.
Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011,
46, 403-417, incorporated by reference herein in its entirety.
When discovering and developing therapeutic agents, a person skilled in the
art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro
properties. It is reasonable to assume that many compounds with poor
pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver
microsomal assays currently available provide valuable information on the course of
oxidative metabolism of this type, which in turn permits the rational design of
deuterated compounds of Compound 1 with improved stability through resistance to
such oxidative metabolism. Significant improvements in the pharmacokinetic profiles
of Compound 1 are thereby obtained and can be expressed quantitatively in terms of
increases in the in vivo half-life (t1/2), concentration at maximum therapeutic effect
(Cmax), area under the dose response curve (AUC), and bioavailability; and in terms
of reduced clearance, dose and materials costs.
For example, in one alternative embodiment, at least one hydrogen atoms in
Compound 1 are replaced by deuterium atoms to provide a deuterated compound. In
one alternative embodiment, one or both of the t-butyl groups in Compound 1 is
replaced by d9-t-butyl. In another alternative embodiment, the t-butyl group adjacent
to the OH group in Compound 1 is replaced d9-t-butyl (Compound 2). Co-crystals of
Compound 2 may be formed using the methods described herein. A person skilled in
the art would understand that the XRPD pattern of a co-crystal of Compound 2 and a
triglyceride, or a co-crystal of any other of the deuterated compounds in these
alternative embodiments and a triglyceride, would have the same characteristic peaks
as a Compound 1:triglyceride co-crystal. Half-life determinations enable favorable
and accurate determination of the extent to which resistance to oxidative metabolism
has improved.
In some alternative embodiments, deuterium-hydrogen exchange in
Compound 1 can also be used to achieve a favorable modification of the metabolite
spectrum of the starting compound in order to diminish or eliminate undesired toxic
metabolites. For example, if a toxic metabolite arises through oxidative carbon-
hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated
compound will greatly diminish or eliminate production of the unwanted metabolite,
even if the particular oxidation is not a rate-determining step. Further information on
the state of the art with respect to deuterium-hydrogen exchange may be found, for
example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org.
Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al,
Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-
688, 1993.
Compound 1:glyceryltrioctanoate
The co-crystal comprising Compound 1 and glyceryltrioctanoate is
hereinafter referred to as “Compound 1:glyceryltrioctanoate”.
The characterization of Compound 1:glyceryltrioctanoate is detailed later in
the Example section. Figure 3 is an examplary X-Ray Powder Diffraction (XRPD)
pattern of Compound 1:glyceryltrioctanoate. Figure 4 is an examplary 13C solid state
nuclear magnetic resonance spectroscopy (13C ssNMR) spectrum of Compound
1:glyceryltrioctanoate. Figure 5 is an examplary thermal gravimetric analysis (TGA)
trace Compound 1:glyceryltrioctanoate. Figure 6 is an examplary Differential
Scanning Calorimetry (DSC) thermogram of Compound 1:glyceryltrioctanoate.
Figure 7 is an examplary 1H Nuclear Magnetic Resonance (1H NMR) spectrum of
Compound 1:glyceryltrioctanoate in DMSO-d6.
In one embodiment, Compound 1:glyceryltrioctanoate is characterized as
having an X-ray powder diffraction (XRPD) pattern with one or more characteristic
peaks expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.1,
.9, 12.0, 12.5, 13.2, 13.7, 15.0, 16.2, 16.9, 18.0, 19.3, 20.2, 21.7, 22.5, 23.8, 25.8,
27.0, 27.6, 28.3, 30.0, 31.0, and 32.6.
In one embodiment, Compound 1:glyceryltrioctanoate is characterized as
having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-
theta ± 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
In another embodiment, Compound 1:glyceryltrioctanoate is characterized as
having a X-ray powder diffraction pattern with characteristic peaks expressed in 2-
theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.1, 10.9, 16.9, 18.0, and
23.8.
In yet another embodiment, Compound 1:glyceryltrioctanoate is
characterized as having an X-ray powder diffraction pattern with characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.1, 10.9,
12.0, 12.5, 13.2, 13.7, 15.0, 16.2, 16.9, 18.0, 19.3, 20.2, 21.7, 22.5, 23.8, 25.8, 27.0,
27.6, 28.3, 30.0, 31.0, and 32.6.
In another embodiment, Compound 1:glyceryltrioctanoate is characterized as
having an X-ray powder diffraction pattern substantially the same as shown in Figure
3. The X-ray powder diffraction patterns are obtained at room temperature using Cu
K alpha radiation.
In one embodiment, Compound 1:glyceryltrioctanoate is characterized as
having a 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with one
or more characteristic peaks expressed in ppm ± 0.1 selected from: 178.6, 172.9,
171.6, 169.9, 165.1, 155.0, 143.2, 139.4, 137.3, 134.6, 133.0, 126.0, 119.4, 117.7,
112.1, 67.3, 64.0, 62.0, 59.6, 54.2, 35.8, 34.8, 31.7, 30.5, 23.5, and 14.6.
In one embodiment, Compound 1:glyceryltrioctanoate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.6, 155.0, and 119.4.
In another embodiment, Compound 1:glyceryltrioctanoate is characterized
by having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions 178.6, 155.0, 134.6, 126.0, 119.4, and 35.8.
In yet another embodiment, Compound 1:glyceryltrioctanoate is
characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in
ppm ± 0.1 at the following positions: 178.6, 172.9, 171.6, 169.9, 165.1, 155.0, 143.2,
139.4, 137.3, 134.6, 133.0, 126.0, 119.4, 117.7, 112.1, 67.3, 64.0, 62.0, 59.6, 54.2,
.8, 34.8, 31.7, 30.5, 23.5, and 14.6.
In one embodiment, Compound 1:glyceryltrioctanoate is characterized as
having an endothermic peak in differential scanning calorimetry (DSC) at 186.7ºC. In
another embodiments, Compound 1:glyceryltrioctanoate is characterized as having an
endothermic peak in differential scanning calorimetry (DSC) at 186.7 ± 0.2 ºC. In
another embodiments, Compound 1:glyceryltrioctanoate is characterized as having an
endothermic peak in differential scanning calorimetry (DSC) at 186.7 ± 0.5 ºC.
In some embodiments, the ratio or stoichiometry of Compound 1 to
glyceryltrioctanoate in Compound 1:glyceryltrioctanoate is 3:1. In some
embodiments, the ratio or stoichiometry of Compound 1 to glyceryltrioctanoate in
Compound 1:glyceryltrioctanoate is about 3 to about 1.
Compound 1:glyceryltrioleate
The co-crystal comprising Compound 1 and glyceryltrioleate is hereinafter
referred to as “Compound 1:glyceryltrioleate”.
The characterization of Compound 1:glyceryltrioleate is detailed later in the
Example section. Figure 8 is an examplary XRPD pattern of Compound
1:glyceryltrioleate. Figure 9 is an examplary 13C ssNMR spectrum of Compound
1:glyceryltrioleate. Figure 10 is an examplary TGA trace Compound
1:glyceryltrioleate. Figure 11 is an examplary DSC thermogram of Compound
1:glyceryltrioleate. Figure 12 is an examplary 1H NMR spectrum of Compound
1:glyceryltrioleate in acetone-d6.
In one embodiment, Compound 1:glyceryltrioleate is characterized as having
an X-ray powder diffraction pattern with one or more characteristic peaks expressed
in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 9.8, 10.4, 10.9, 12.0,
12.7, 13.3, 13.8, 15.1, 16.3, 16.9, 18.1, 18.5, 19.4, 19.9, 20.2, 21.2, 21.8, 22.6, 23.8,
26.0, 27.0, 27.8, 28.5, 30.0, 30.7, and 32.7.
In one specific embodiment, Compound 1:glyceryltrioleate is characterized
as having an X-ray powder diffraction pattern with characteristic peaks expressed in
2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
In another embodiment, Compound 1:glyceryltrioleate is characterized as
having a X-ray powder diffraction pattern with characteristic peaks expressed in 2-
theta ± 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.1 and 23.8.
In yet another embodiment, Compound 1:glyceryltrioleate is characterized as
having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-
theta ± 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 9.8, 10.9, 12.0, 12.7, 13.3,
13.8, 15.1, 16.3, 16.9, 18.1, 18.5, 19.4, 19.9, 20.2, 21.2, 21.8, 22.6, 23.8, 26.0, 27.0,
27.8, 28.5, 30.0, 30.7, and 32.7. In one embodiment, Compound 1:glyceryltrioleate is
characterized as having an X-ray powder diffraction pattern with characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 9.8, 10.4,
.9, 12.0, 12.7, 13.3, 13.8, 15.1, 16.3, 16.9, 18.1, 18.5, 19.4, 19.9, 20.2, 21.2, 21.8,
22.6, 23.8, 26.0, 27.0, 27.8, 28.5, 30.0, 30.7, and 32.7.
In another embodiment, Compound 1:glyceryltrioleate is characterized as
having an XRPD powder diffraction pattern substantially the same as shown in Figure
8. The X-ray powder diffraction patterns are obtained at room temperature using Cu
K alpha radiation.
In one embodiment, Compound 1:glyceryltrioleate is characterized as
having a 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with
one or more characteristic peaks expressed in ppm ± 0.1 selected from: 178.6, 172.9,
171.6, 169.9, 165.0, 155.0, 142.9, 139.3, 137.4, 134.5, 133.0, 130.5, 127.3, 126.0,
119.4, 117.7, 112.1, 67.2, 63.9, 59.6, 35.8, 34.8, 31.7, 30.5, 28.2, 24.6, 23.6, and 14.7.
In one embodiment, Compound 1:glyceryltrioleate is characterized as having
a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the
following positions: 178.6, 155.0, 130.5, and 119.4.
In another embodiment, Compound 1:glyceryltrioleate is characterized by
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.6, 155.0, 134.5, 130.5, 126.0, 119.4, and 35.8.
In yet another embodiment, Compound 1:glyceryltrioleate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.6, 172.9, 171.6, 169.9, 165.0, 155.0, 142.9, 139.3, 137.4,
134.5, 133.0, 130.5, 127.3, 126.0, 119.4, 117.7, 112.1, 67.2, 63.9, 59.6, 35.8, 34.8,
31.7, 30.5, 28.2, 24.6, 23.6, and 14.7.
In one embodiment, Compound 1:glyceryltrioleate is characterized as having
an endothermic peak in differential scanning calorimetry (DSC) at 197.5ºC. In another
embodiment, Compound 1:glyceryltrioleate is characterized as having an endothermic
peak in differential scanning calorimetry (DSC) at 197.5 ± 0.2 ºC. . In another
embodiment, Compound 1:glyceryltrioleate is characterized as having an endothermic
peak in differential scanning calorimetry (DSC) at 197.5 ± 0.5 ºC.
In some embodiments, the ratio or stoichiometry of Compound 1 to
glyceryltrioleate in Compound 1: glyceryltrioleate is 6:1. In some embodiments, the
ratio or stoichiometry of Compound 1 to glyceryltrioleate in Compound 1:
glyceryltrioleate is about 6 to about 1.
Compound 1:glyceryltrilinoleate
The co-crystal comprising Compound 1 and glyceryltrilinoleate is hereinafter
referred to as “Compound 1:glyceryltrilinoleate”.
The characterization of Compound 1:glyceryltrilinoleate is detailed later in
the Example section. Figure 13 is an examplary XRPD pattern of Compound
1:glyceryltrilinoleate. Figure 14 is an examplary 13C ssNMR spectrum of Compound
1:glyceryltrilinoleate. Figure 15 is an examplary TGA trace Compound
1:glyceryltrilinoleate. Figure 16 is an examplary DSC thermogram of Compound
1:glyceryltrilinoleate. Figure 17 is an examplary 1H NMR spectrum of Compound
1:glyceryltrilinoleate in acetone-d6.
In one embodiment, Compound 1:glyceryltrilinoleate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9,
12.0, 12.5, 13.8, 15.1, 16.3, 17.0, 18.1, 19.4, 20.2, 21.8, 22.6, 23.8, 25.9, 27.1, 27.8,
28.4, and 32.7.
In one specific embodiment, Compound 1:glyceryltrilinoleate is
characterized as having an X-ray powder diffraction pattern with characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
In another embodiment, Compound 1:glyceryltrilinoleate is characterized as
having a X-ray powder diffraction pattern with characteristic peaks expressed in 2-
theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9, 17.0, 18.1, and
23.8.
In yet another embodiment, Compound 1:glyceryltrilinoleate is characterized
as having an X-ray powder diffraction pattern with characteristic peaks expressed in
2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9, 12.0, 12.5,
13.8, 15.1, 16.3, 17.0, 18.1, 19.4, 20.2, 21.8, 22.6, 23.8, 25.9, 27.1, 27.8, 28.4, and
32.7.
In another embodiment, Compound 1:glyceryltrilinoleate is characterized as
having an XRPD powder diffraction pattern substantially the same as shown in Figure
13. The X-ray powder diffraction patterns are obtained at room temperature using Cu
K alpha radiation.
In one embodiment, Compound 1:glyceryltrilinoleate is characterized as
having a 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with one
or more characteristic peaks expressed in ppm ± 0.1 selected from: 178.6, 172.8,
171.5, 169.8, 165.1, 155.0, 142.9, 139.3, 137.4, 134.4, 133.1, 130.6, 126.0, 119.4,
117.6, 112.0, 86.5, 67.2, 63.9, 59.7, 35.8, 34.8, 31.7, 30.6, 28.2, and 14.8.
In one embodiment, Compound 1:glyceryltrilinoleate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.6, 155.0, 130.6, and 119.4.
In another embodiment, Compound 1:glyceryltrioleate is characterized by
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions 178.6, 155.0, 134.4, 130.6, 126.0, 119.4, and 35.8.
In yet another embodiment, Compound 1:glyceryltrilinoleate is characterized
as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.6, 172.8, 171.5, 169.8, 165.1, 155.0, 142.9, 139.3, 137.4,
134.4, 133.1, 130.6, 126.0, 119.4, 117.6, 112.0, 86.5, 67.2, 63.9, 59.7, 35.8, 34.8,
31.7, 30.6, 28.2, and 14.8.
In one embodiment, Compound 1:glyceryltrilinoleate is characterized as
having an endothermic peak in differential scanning calorimetry (DSC) at 182.3ºC.
In another embodiment, Compound 1:glyceryltrilinoleate is characterized as having
an endothermic peak in differential scanning calorimetry (DSC) at 182.3 ± 0.2 ºC. In
another embodiment, Compound 1:glyceryltrilinoleate is characterized as having an
endothermic peak in differential scanning calorimetry (DSC) at 182.3 ± 0.5 ºC.
In some embodiments, the ratio or stoichiometry of Compound 1 to
glyceryltrilinoleate in Compound 1: glyceryltrilinoleate is 6:1. In some embodiments,
the ratio or stoichiometry of Compound 1 to glyceryltrilinoleate in Compound 1:
glyceryltrilinoleate is about 6 to about 1.
Compound 1: triacetin
The co-crystal comprising Compound 1 and glyceryltriaceatate (triacetin) is
hereinafter referred to as “Compound 1:glyceryltriaceate” or “Compound 1:triacetin”.
The characterization of Compound 1:triacetin is detailed later in the Example
section. Figure 18 is an examplary XRPD pattern of Compound 1:triacetin. Figure 19
is a 13C ssNMR spectrum of Compound 1:triacetin. Figure 20 is a DSC thermogram
of Compound 1:triacetin.
In one embodiment, Compound 1:triacetin is characterized as having an X-
ray powder diffraction pattern with one or more characteristic peaks expressed in 2-
theta ± 0.2 degrees at the following positions: 4.9, 9.5, 9.8, and 14.7.
In one embodiment, Compound 1:triacetin is characterized as having an X-
ray powder diffraction pattern with one or more characteristic peaks expressed in 2-
theta ± 0.2 degrees at the following positions: 4.9, 9.5, 9.8, 14.7, 16.5, 18.2, and 23.1.
In another embodiment, Compound 1:triacetin is characterized as having an
XRPD powder diffraction pattern substantially the same as shown in Figure 18. The
X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha
radiation.
In one embodiment, Compound 1:triacetin is characterized as having a 13C
ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the following
positions: 178.2, 155.1, 154.8, 119.7, and 119.2.
In one embodiment, Compound 1:triacetin is characterized as having a 13C
ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the following
positions: 178.2, 155.1, 154.8, 134.1, 125.9, 125.6, 119.7, 119.2, and 35.3.
In one embodiment, Compound 1:triacetin is characterized as having a 13C
ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the following
positions: 178.2, 165.4, 164.3, 155.1, 154.8, 154.1, 149.4, 146.8, 145.6, 140.0, 134.1,
133.2, 132.3, 127.0, 125.9, 125.6, 124.3, 120.6, 119.7, 119.2, 118.3, 117.6, 111.9,
111.1, 110.4, 35.3, 35.0, 31.8, 29.8, 21.9, 20.4, and 18.9.
In one embodiment, Compound 1:triacetin is characterized as having an
endothermic peak in differential scanning calorimetry (DSC) at 123.9°C (peak) that
corresponds to the melting of the Compound 1:glyceryltritriacetin co-crystal. This
event is followed by another endotherm at 141.9°C and yet another endotherm at
193.8 °C.
Compound 1:glyceryltributyrate
The co-crystal comprising Compound 1 and glyceryltributyrate is hereinafter
referred to as “Compound 1: glyceryltributyrate”.
The characterization of Compound 1: glyceryltributyrate is detailed later in
the Example section. Figure 21 is an examplary XRPD pattern of Compound 1:
glyceryltributyrate.
In one embodiment, Compound 1:glyceryltributyrate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 6.8, 9.5, and 22.6.
In one embodiment, Compound 1:glyceryltributyrate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 4.8, 4.9, 6.8, 9.5, 9.6,
14.3, 18.0, 19.0, 19.8, 21.4, 22.6, and 23.8.
In another embodiment, Compound 1:glyceryltributyrate is characterized as
having an XRPD powder diffraction pattern substantially the same as shown in Figure
21. The X-ray powder diffraction patterns are obtained at room temperature using Cu
K alpha radiation.
Compound 1:glyceryltristearate
The co-crystal comprising Compound 1 and glyceryltristearate is hereinafter
referred to as “Compound 1: glyceryltristearate”.
The characterization of Compound 1:glyceryltristearate is detailed later in
the Example section. Figure 22 is an examplary XRPD pattern of Compound 1:
glyceryltristearate. Figure 23 is a 13C ssNMR spectrum of Compound
1:glyceryltristearate. Figure 24 is a DSC thermogram of Compound
1:glyceryltristearate.
In one embodiment, Compound 1:glyceryltristearate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.6, 6.9, and 11.0.
In one embodiment, Compound 1:glyceryltristearate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.6, 6.2, 6.9, 9.3, 11.0,
17.0, and 18.2.
In one embodiment, Compound 1:glyceryltristearate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.6, 5.4, 6.2, 6.9, 9.3,
11.0, 12.1, 12.6, 13.4, 13.9, 15.4, 16.4, 17.0, 18.2, 18.5, 19.4, 20.0, 20.4, 21.8, 23.8,
26.0, 27.0, 28.4, 29.1, 29.9, 31.2, and 32.8.
In another embodiment, Compound 1:glyceryltristearate is characterized as
having an XRPD powder diffraction pattern substantially the same as shown in Figure
22. The X-ray powder diffraction patterns are obtained at room temperature using Cu
K alpha radiation.
In one embodiment, Compound 1:glyceryltristearate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.5, 155.0, and 119.5.
In one embodiment, Compound 1:glyceryltristearate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.5, 155.0, 134.4, 126.1, 119.5, and 35.7.
In one embodiment, Compound 1:glyceryltristearate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.5, 172.9, 171.6, 169.9, 165.0, 155.0, 143.6, 139.4, 137.2,
135.1, 134.4, 133.0, 127.3, 126.1, 119.5, 117.6, 112.0, 67.3, 64.1, 59.6, 35.7, 34.7,
31.7, 30.6, 23.6, and 14.8.
In one embodiment, Compound 1:glyceryltristearate is characterized as
having an endothermic peak in differential scanning calorimetry (DSC) at 55.1°C that
corresponds to the eutectic melt of Compound 1:glyceryltrilstearate co-crystal and
glyceryltristearate. This event is followed by another endotherm at 71.3 °C,
corresponding to the melt of neat glyceryltristearate. Overlapping endotherm at
201.3°C and exotherm at 208.1°C correspond to the cocrystal melt and crystallization
of neat Compound 1, respectively. Another endotherm at 284.7°C corresponds to the
melt of a neat form of Compound 1.
Compound 1:glyceryltripalmitate
The co-crystal comprising Compound 1 and glyceryltripalmitate is
hereinafter referred to as “Compound 1: glyceryltripalmitate”.
The characterization of Compound 1: glyceryltripalmitate is detailed later in
the Example section. Figure 25 is an examplary XRPD pattern of Compound 1:
glyceryltripalmitate. Figure 26 is a 13C ssNMR spectrum of Compound
1:glyceryltripalmitate. Figure 27 is a DSC thermogram of Compound
1:glyceryltripalmitate.
In another embodiment, Compound 1:glyceryltripalmitate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, and 11.0.
In one embodiment, Compound 1:glyceryltripalmitate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.3, 17.0,
18.2, and 23.7.
In one embodiment, Compound 1:glyceryltripalmitate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.3, 11.0,
13.8, 15.1, 16.3, 17.0, 18.2, 19.4, 19.9, 20.3, 21.8, and 23.7.
In another embodiment, Compound 1:glyceryltripalmitate is characterized as
having an XRPD powder diffraction pattern substantially the same as shown in Figure
. The X-ray powder diffraction patterns are obtained at room temperature using Cu
K alpha radiation.
In one embodiment, Compound 1:glyceryltripalmitate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.4, 155.0, 144.0, and 119.6.
In one embodiment, Compound 1:glyceryltripalmitate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.4, 155.0, 134.5, 126.0, 119.6, and 35.7.
In one embodiment, Compound 1:glyceryltripalmitate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.4, 173.0, 169.9, 165.0, 155.0, 144.0, 139.5, 137.2, 134.5,
133.0, 127.2, 126.0, 119.6, 117.5, 112.0, 67.2, 64.0, 59.7, 35.7, 34.6, 31.7, 30.6, 23.7,
and 14.8.
In one embodiment, Compound 1:glyceryltripalmitate is characterized as
having an endothermic peak in differential scanning calorimetry (DSC) at 47.7°C
(peak) that corresponds to the eutectic melt of ivacaftor:glyceryltripalmitate co-crystal
and glyceryltripalmitate. This event is followed by another endotherm at 63.0 °C
(peak), corresponding to the melt of neat glyceryltripalmitate. Overlapping
endotherm at 174.9°C (peak) and exotherm at 186.7°C (peak) correspond to the
cocrystal melt and crystallization of neat ivacaftor, respectively. Another endotherm
at 266.2°C (peak) corresponds to the melt of a neat form of ivacaftor.
Compound 1: glyceryltridodecanoate
The co-crystal comprising Compound 1 and glyceryltridodecanoate is
hereinafter referred to as “Compound 1: glyceryltridodecanoate”.
The characterization of Compound 1:glyceryltridodecanoate is detailed later
in the Example section. Figure 28 is an examplary XRPD pattern of Compound
1:glyceryltridodecanoate. Figure 29 is a 13C ssNMR spectrum of Compound
1:glyceryltridodecanoate.
In one embodiment, Compound 1:glyceryltridodecanoate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 4.4, 6.1, 6.9, 8.6,
9.3, 11.0, 12.1, 12.6, 13.2, 13.8, 15.0, 16.3, 17.0, 18.1, 19.5, 20.3, 21.9, 23.3, 23.9,
24.8, and 30.2.
In another embodiment, Compound 1:glyceryltridodecanoate is characterized
as having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, and 11.0.
In another embodiment, Compound 1:glyceryltridodecanoate is characterized
as having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.1, 6.9, 9.3, 11.0,
17.0, 18.1, and 23.3.
In another embodiment, Compound 1:glyceryltridodecanoate is characterized
as having an XRPD powder diffraction pattern substantially the same as shown in
Figure 28. The X-ray powder diffraction patterns are obtained at room temperature
using Cu K alpha radiation.
In one embodiment, Compound 1:glyceryltridodecanoate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.4, 155.0, and 119.6.
In one embodiment, Compound 1:glyceryltridodecanoate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.4, 155.0, 134.6, 126.1, 119.6, and 35.6.
In one embodiment, Compound 1:glyceryltridodecanoate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.4, 173.1, 171.5, 169.8, 165.0, 155.0, 143.0, 139.4, 137.2,
134.6, 133.0, 127.3, 126.1, 119.6, 117.6, 112.1, 67.1, 63.9, 59.7, 35.6, 31.7, 30.6, and
23.6.
Compound 1: glyceryltrimyristate
The co-crystal comprising Compound 1 and glyceryltrimyristate is
hereinafter referred to as “Compound 1: glyceryltrimyristate”.
The characterization of Compound 1:glyceryltrimyristate is detailed later in
the Example section. Figure 30 is an examplary XRPD pattern of Compound
1:glyceryltrimyristate. Figure 31 is a 13C ssNMR spectrum of Compound
1:glyceryltrimyristate. Figure 32 is a DSC thermogram of Compound
1:glyceryltrimyristate.
In one embodiment, Compound 1:glyceryltrimyristate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.8, and 10.9.
In one embodiment, Compound 1:glyceryltrimyristate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.8, 9.2, 10.9,
16.9, and 18.0.
In one embodiment, Compound 1:glyceryltrimyristate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.0, 6.8, 7.4, 8.3,
9.2, 9.9, 10.9, 12.0, 12.5, 13.2, 13.7, 14.9, 16.2, 16.9, 17.6, 18.0, 18.5, 19.4, 20.0,
21.2, 22.1, 23.2, 24.1, 25.1, 26.4, 27.2, 27.7, 28.3, 29.2, 29.7, 31.0, and 32.7.
In another embodiment, Compound 1:glyceryltrimyristate is characterized as
having an XRPD powder diffraction pattern substantially the same as shown in Figure
. The X-ray powder diffraction patterns are obtained at room temperature using Cu
K alpha radiation.
In one embodiment, Compound 1:glyceryltrimyristate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.1, 155.0, and 119.9,
In one embodiment, Compound 1:glyceryltrimyristate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.1, 155.0, 134.6, 126.0, 119.9, and 35.6.
In one embodiment, Compound 1:glyceryltrimyristate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.1, 171.4, 169.8, 165.0, 155.0, 142.9, 139.5, 137.2, 134.6,
133.1, 127.3, 126.0, 119.9, 117.4, 112.0, 67.0, 63.7, 61.4, and 35.6.
In one embodiment, Compound 1:glyceryltrimyristate is characterized as
having an endothermic peak in differential scanning calorimetry (DSC) at 59.2 °C
that corresponds to the melt of glyceryltrimyristate. This event is followed by a broad
exotherm at 134.4 °C that is overlapping with an endotherm. This event is followed
by an exotherm at 171.3 °C corresponding to the crystallization of neat Compound 1.
Another endotherm at 280.1 °C corresponds to the melt of a neat form of Compound
Compound 1: glyceryltrihexanoate
The co-crystal comprising Compound 1 and glyceryltrihexanoate is
hereinafter referred to as “Compound 1:glyceryltrihexanoate”.
The characterization of Compound 1:glyceryltrihexanoate is detailed later in
the Example section. Figure 33 is an examplary XRPD pattern of Compound 1:
glyceryltrihexanoate.
In one embodiment, Compound 1:glyceryltrihexanoate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 6.5, 9.2, and 21.4.
In one embodiment, Compound 1:glyceryltrihexanoate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 4.7, 6.5, 9.2, 14.5, 17.4,
18.7, 19.9, 21.4, and 24.4.
In one embodiment, Compound 1: glyceryltrihexanoate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 4.7, 6.5, 9.2, 9.9, 11.8,
12.5, 14.5, 15.1, 15.6, 17.4, 18.7, 19.9, 21.4, 23.0, 24.4, 25.2, 26.5, 28.3, 29.1, 30.5,
and 35.6.
In another embodiment, Compound 1:glyceryltrihexanoate is characterized
as having an XRPD powder diffraction pattern substantially the same as shown in
Figure 33. The X-ray powder diffraction patterns are obtained at room temperature
using Cu K alpha radiation.
Compound 1:glyceryltridecanoate
The co-crystal comprising Compound 1 and glyceryltridecanoate is
hereinafter referred to as “Compound 1:glyceryltridecanoate”.
The characterization of Compound 1:glyceryltridecanoate is detailed later in
the Example section. Figure 34 is an examplary XRPD pattern of Compound
1:glyceryltridecanoate. Figure 35 is a 13C ssNMR spectrum of Compound
1:glyceryltridecanoate.
In one embodiment, Compound 1:glyceryltridecanoate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
In one embodiment, Compound 1:glyceryltridecanoate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.1, 6.9, 9.2, 10.9,
16.9, 18.1, and 23.9.
In one embodiment, Compound 1:glyceryltridecanoate is characterized as
having an X-ray powder diffraction pattern with one or more characteristic peaks
expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.1, 6.9, 9.2, 10.9,
11.8, 12.1, 12.6, 13.2, 13.8, 14.9, 16.3, 16.9, 18.1, 18.5, 19.4, 19.8, 20.3, 21.7, 23.4,
23.9, 25.2, 25.8, 27.2, and 28.4.
In another embodiment, Compound 1:glyceryltridecanoate is characterized
as having an XRPD powder diffraction pattern substantially the same as shown in
Figure 34. The X-ray powder diffraction patterns are obtained at room temperature
using Cu K alpha radiation.
In one embodiment, Compound 1:glyceryltridecanoate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.5, 155.0, and 119.5.
In one embodiment, Compound 1:glyceryltridecanoate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.5, 155.0, 134.9, 126.1, and 35.7.
In one embodiment, Compound 1:glyceryltridecanoate is characterized as
having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at
the following positions: 178.5, 171.6, 169.9, 165.0, 155.0, 143.3, 139.5, 137.2, 134.9,
133.0, 127.3, 126.1, 119.5, 117.6, 112.1, 67.2, 64.0, 59.8, 35.7, 34.7, 31.7, 30.5, and
.8, 23.5.
Dissolution Comparison
A comparison of the dissolution profiles in FeSSIF of the Compound
1:glyceryltrioctanoate, Compound 1:glyceryltrioleate, and Compound
1:glyceryltrilinoleate with amorphous Compound 1 and Compound 1 SDD
(amorphous Compound 1 dispersed in HPMCAS (hydroxypropyl methylcellulose
acetate succinate or hypromellose acetate succinate) (i.e., spray dried dispersion
(SDD)) is shown in Figure 36. Compound 1 has a solubility-limited oral
bioavailability, and maintenance of high solution concentration in FeSSIF is required
for any solid form of Compound 1 to be viable for oral dosage form development.
The Compound 1:triglyceride co-crystals have similar performance in terms of
dissolution rate and maintenance of the high solution concentrations in FeSSIF to
each other. The Compound 1:triglyceride co-crystals also show a better maintenance
of the supersaturation than both the neat amorphous and solid amorphous dispersed
form of Compound 1 (Compound 1 SDD) over longer time periods. Furthermore, in-
vivo the Compound 1:triglyceride co-crystals should be metabolized in the small
intestine by lipid esterase (lipases), which would effectively remove the triglycerides
and further boost the Compound 1 concentration according to Le-Chatelier’s
principle.
In addition, the crystalline Compound 1:triglyceride co-crystals may have the
following advantages over the solid amorphous dispersed form (Compound 1 SDD)
of Compound 1: (1) the co-crystals can be formulated, stored and used under
conditions where they are thermodynamically stable; (2) a controlled crystallization
can be developed that can reduces potential impurity levels (impurities include, but
are not limited to, solvent); (3) a manufacturing process can be developed that is more
efficient and cost effective (for example, less solvent can be used in manufacturing
and a lower cost process than spray drying can be developed); and (4) a stabilizing
polymer is not required for co-crystals.
In one embodiment, the co-crystal dissolves in simulated intestinal fluid in
fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL.
In another embodiment, the co-crystal dissolves in simulated intestinal fluid in fed
state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL and
the concentration is maintained for at least 10 hours. In another embodiment, the co-
crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) at a temperature of
37°C to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the
concentration is maintained for at least 10 hours. In some embodiments, the co-crystal
dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of
Compound 1 of greater than 0.4 mg/mL within 2 hours. In another embodiment, the
co-crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a
concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is
maintained for at least 10 hours without need for a stabilizing polymer. In some
embodiments, the stabilizing polymer is HPMCAS.
Processes for Making Co-crystal Forms
In one aspect, the present disclosure is directed to a method of preparing a
co-crystal comprising Compound 1 and a co-former, wherein the co-crystal is chosen
from the following structural formula:
wherein R , R , and R are independently C aliphatic, wherein Compound 1 is
1 2 3 1-29
represented by the following structural formula:
comprising the step of:
stirring or mixing Compound 1 and the co-former to form the co-crystal.
In some embodiments, R , R , and R are independently C aliphatic
1 2 3 7-29
In some embodiments, the co-former has an average molecular weight
between 470 and 1400 Da.
In some embodiments, the co-former is chosen from glyceryl trioleate,
glyceryl tristearate, glycerol tridecanoate, glycerol trihexanoate, glyceryl
tritridecanoate, glycerol trioctanoate, glyceryl trimyristate, glyceryl tripalmitate,
glyceryl tributyrate, glyceryl trilinoleate, glyceryl tridodecanoate, glyceryl decanoate,
glyceryl tripalmitoleate, glycerol trierucate, glyceryl tripropionate, palmitodiolein,
triarachidonin, glyceryl trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cis-
13-docosenoate), glyceryl tripetroselinate, glyceryl tribehenate, glyceryl trielaidate,
and triacetin.
In some embodiments, the co-former is chosen from
O O O O
, and
In one embodiment, Compound 1 is neat amorphous. In another
embodiment, the co-former is neat. In one embodiment, Compound 1 and the co-
former are stirred for at least 0.5 hours. In another embodiment, Compound 1 and co-
former are stirred for 18 hours. In yet another embodiment, Compound 1 and the co-
former are stirred for at least 18 hours. In one embodiment, Compound 1 and the co-
former are stirred for more than 0.5 hours (including, but not limited to, 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11
hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours). In
another embodiment, Compound 1 and the co-former are stirred at 40 °C. In another
embodiment, Compound 1 and the co-former are stirred at about 40 °C. In yet other
embodiments, Compound 1 and the co-former are stirred at 35-45 °C (for example, at
°C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C or 45 °C). In
one embodiment, Compound 1 and the co-former are stirred for at least 18 hours at
40ºC. In one embodiment, Compound 1 and the co-former are stirred for at least 0.5
hours at 40ºC. In one embodiment, Compound 1 and the co-former are stirred for at
least 18 hours at 40ºC.
As non-limiting examples, in one embodiment, Compound 1 and
glyceryltrioctanoate are stirred for at least 0.5 hours; in yet one embodiment,
Compound 1 and glyceryltrioctanoate are stirred for 0.5 hours; in yet another
embodiment, Compound 1 and glyceryltrioctanoate are stirred for at least 0.5 hours at
40ºC; in also yet another embodiment, Compound 1 and glyceryltrioctanoate are
stirred for 0.5 hours at 40ºC.
In one embodiment, the present disclosure provides a method of preparing a
co-crystal comprising Compound 1 and a co-former,
wherein Compound 1 is represented by the following structural formula:
wherein the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the triglyceride to form
the co-crystal; and
(b) collecting the co-crystals by filtration.
In another embodiment, the method optionally, further comprises, the steps
(c) collecting mother liquor;
(d) stirring Compound 1 with the collected mother liquor for at least 18
hours; and
(e) collecting the co-crystals.
One aspect of the present disclosure provides for a method of preparing a co-
crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented
by the following structural formula:
and wherein the co-former is chosen from the
following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic;
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former; and
(b) heating the mixture.
In one embodiment, Compound 1 and the co-former are heated to about
80ºC. In one embodiment, Compound 1 and the co-former are heated to 80ºC. In
another embodiment, Compound 1 and the co-former are heated to about 80ºC for 12
hours. In yet another embodiment, Compound 1 and the co-former are heated to 80ºC
for 12 hours. In another embodiment, Compound 1 and the co-former are heated to
about 80ºC for 24 hours. In yet another embodiment, Compound 1 and the co-former
are heated to 80ºC for 24 hours.
One aspect of the present disclosure provides for a method of preparing a co-
crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented
by the following structural formula:
the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
comprising the steps of:
(c) preparing a mixture comprising Compound 1 and the co-former; and
(d) heating the mixture to 80ºC.
In yet another embodiment, Compound 1 and the co-former are heated to
80ºC for 12 hours. In yet another embodiment, Compound 1 and the co-former are
heated to 80ºC for 24 hours.
Further another aspect of the present disclosure provides for a method of
preparing co-crystals comprising Compound 1 and a co-former, wherein Compound 1
is represented by the following structural formula:
the co-former is chosen from the following structural formula:
wherein R , R , and R are independently C aliphatic.
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former; and
(b) heating the mixture to a temperature that is about 5 to 10 °C higher than
the melting point of the co-former.
One aspect of the present disclosure provides for a method of preparing a co-
crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented
by the following structural formula:
wherein the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former;
(b) heating the mixture;
(c) cooling the mixture down; and
(d) repeating step (b) and (c).
In one embodiment, Compound 1 and the co-former are heated to about
80ºC. In another embodiment, Compound 1 and the co-former are heated to about
80ºC and cooled down to about 40ºC. In one embodiment, Compound 1 and the co-
former are heated to 80ºC. In another embodiment, Compound 1 and the co-former
are heated to 80ºC and cooled down to 40ºC. In another embodiment, Compound 1
and the co-former are heated to 80ºC for 12 hours. In another embodiment,
Compound 1 and the co-former are heated to 80ºC for 24 hours. In yet another
embodiment, Compound 1 and the co-former are heated to 80ºC for 12 hours and
cooled down to about 40ºC. In another embodiment, Compound 1 and the co-former
are heated to 80ºC for 12 hours. In yet another embodiment, Compound 1 and the co-
former are heated to 80ºC for 24 hours and cooled down to about 40ºC. In any of the
above embodiments, the steps of heating and cooling are repeated.
Another aspect of the present disclosure provides for a method of preparing a
co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is
represented by the following structural formula:
wherein the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
comprising the steps of:
(a) preparing a mixture comprising Compound 1 and the co-former;
(b) heating the mixture to about 80ºC;
(c) cooling the mixture down; and
(d) repeating step (b) and (c).
In another embodiment, Compound 1 and the co-former are cooled down to
40ºC.
Another aspect of the present disclosure provides for a method of preparing a
co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is
represented by the following structural formula:
wherein the co-former is chosen from the following structural formula:
R O O R
wherein R , R , and R are independently C aliphatic,
1 2 3 1-29
comprising the steps of:
(a) adding Compound 1 and the triglyceride;
(b) heating to about 80ºC;
(c) cooling down to about 40ºC; and
(d) repeating step (b) and (c).
In some embodiments, co-crystals can be prepared by slurrying Compound 1
and a co-former in a suitable solvent at a slurry composition at which the co-crystal is
stable in the ternary phase diagram, for example: by co-grinding Compound 1 and a
co-former, by co-grinding Compound 1 and a co-former and adding a small amount of
suitable solvent, by co-grinding Compound 1 and a co-former and subsequently
annealing, by co-grinding Compound 1 and a co-former and subsequently annealing
at elevated temperature, by co-grinding Compound 1 and a co-former and
subsequently annealing at elevated humidity, by co-grinding Compound 1 and a co-
former and subsequently annealing at elevated temperature and humidity, by mixing
Compound 1 and a co-former at a temperature where at least the co-former is liquid,
by mixing Compound 1 and a co-former at a temperature where at least the co-former
is liquid and subsequent cooling after a crystallization period, by extruding
Compound 1 and a co-former at a temperature and conformer composition at which
the co-crystal is stable, or by dissolving Compound 1 and a co-former in suitable
solvent, and evaporating the solvent. Co-crystals may be made with multiple co-
formers in a similar manner.
In one embodiment, the co-crystals are collected by centrifugal filtration at a
temperature above the melting temperature of the co-former.
In another embodiment, the co-crystals are washed after filtration to remove
excess co-former.
Co-crystals produced by any of the methods above are isolated or purified.
Co-crystals are pure as measured by HPLC. In one embodiment, the co-crystal is
over 99% (w/w). In another embodiment, the Compound 1:triglyceride co-crystal is
over 99.5% (w/w). In one embodiment, the Compound 1:triglyceride co-crystal is
99.5% (w/w). In another embodiment, the Compound 1:triglyceride co-crystal is
99.6% (w/w). In another embodiment, the Compound 1:triglyceride co-crystal is
99.7% (w/w). In another embodiment, the Compound 1:triglyceride co-crystal is
99.8% (w/w). In another embodiment, the Compound 1:triglyceride co-crystal is
99.9% (w/w)). In one embodiment, the Compound 1:glyceryltrioctanoate co-crystal is
99.9% (w/w). In another embodiment, the Compound 1:glyceryltrioleate co-crystal is
99.9% (w/w). In yet another embodiment, the Compound 1:glyceryltrilinoleate co-
crystal is 99.5% (w/w). The detection limit for impurities by HPLC is 0.005%.
The present disclosure also provides a method of preparing a co-crystal
comprising Compound 1 and a co-crystal former selected from the group consisting of
glyceryltrioctanoate, glyceryltrioleate, and glyceryltrilinoleate, wherein Compound 1
is represented by the following structural formula:
comprising the step of:
stirring Compound 1 and the co-crystal former to form the co-crystal.
In some embodiments, the co-crystal former is glyceryltrioctanoate.
In some embodiments, the co-crystal former is glyceryltrioleate.
In some embodiments, the co-crystal former is glyceryltrilinoleate.
The present disclosure also provides a method of preparing a co-crystal
comprising Compound 1 and a co-crystal former selected from the group consisting of
glyceryltrioctanoate, glyceryltrioleate, and glyceryltrilinoleate, wherein Compound 1
is represented by the following structural formula:
comprising the steps of:
adding Compound 1 and the co-former together; and
heating.
Uses, Formulation and Administration
Pharmaceutically acceptable compositions
In one aspect of the present disclosure, pharmaceutically acceptable
compositions are provided, wherein these compositions comprise co-crystal of any
one of the embodiments above and a pharmaceutically acceptable carrier or excipient.
In some embodiments, at least 30% of Compound 1 present in the
pharmaceutically acceptable compositions are in the form of Compound 1:triglyceride
co-crystals described herein. As non-limiting example, at least 30%, 40%, 50%, 60%,
70%, 80%, 85%, 90%, 92.5%, 95%, 97.5%, 98%, or 99% of Compound 1 are present
in the form of Compound 1:triglyceride co-crystals described herein.
In certain embodiments, these compositions optionally further comprise one
or more additional therapeutic agents.
As described above, the pharmaceutically acceptable compositions of the
present disclosure additionally comprise a pharmaceutically acceptable carrier,
adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or
other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic
agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980)
discloses various carriers used in formulating pharmaceutically acceptable
compositions and known techniques for the preparation thereof. Except insofar as any
conventional carrier medium is incompatible with the compounds of the disclosure,
such as by producing any undesirable biological effect or otherwise interacting in a
deleterious manner with any other component(s) of the pharmaceutically acceptable
composition, its use is contemplated to be within the scope of this disclosure. Some
examples of materials which can serve as pharmaceutically acceptable carriers
include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin,
serum proteins, such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,
colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato starch; cellulose and its
derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and
suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil;
olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene
glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as
magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as
well as other non-toxic compatible lubricants such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, releasing agents, coating agents,
sweetening, flavoring and perfuming agents, preservatives and antioxidants can also
be present in the composition, according to the judgment of the formulator.
Uses of Compounds and Pharmaceutically Acceptable Compositions
In addition to cystic fibrosis, modulation of CFTR activity may be beneficial
for other diseases not directly caused by mutations in CFTR, such as secretory
diseases and other protein folding diseases mediated by CFTR. These include, but are
not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and
Sjögren’s Syndrome. COPD is characterized by airflow limitation that is progressive
and not fully reversible. The airflow limitation is due to mucus hypersecretion,
emphysema, and bronchiolitis. Activators of mutant or wild-type CFTR offer a
potential treatment of mucus hypersecretion and impaired mucociliary clearance that
is common in COPD. Specifically, increasing anion secretion across CFTR may
facilitate fluid transport into the airway surface liquid to hydrate the mucus and
optimized periciliary fluid viscosity. This would lead to enhanced mucociliary
clearance and a reduction in the symptoms associated with COPD. Dry eye disease is
characterized by a decrease in tear aqueous production and abnormal tear film lipid,
protein and mucin profiles. There are many causes of dry eye, some of which include
age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and
diseases, such as cystic fibrosis and Sjögrens's syndrome. Increasing anion secretion
via CFTR would enhance fluid transport from the corneal endothelial cells and
secretory glands surrounding the eye to increase corneal hydration. This would help
to alleviate the symptoms associated with dry eye disease. Sjögrens's syndrome is an
autoimmune disease in which the immune system attacks moisture-producing glands
throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina,
and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease.
The disease is also associated with rheumatoid arthritis, systemic lupus, systemic
sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is
believed to cause the disease, for which treatment options are limited. Augmenters or
inducers of CFTR activity may hydrate the various organs afflicted by the disease and
help to elevate the associated symptoms.
In one aspect, the disclosure provides a method of treating or lessening the
severity of a disease in a patient comprising administering to said patient co-crystals
of any one of the embodiments described above, and said disease is selected from
cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis,
constipation, pancreatitis, pancreatic insufficiency, male infertility caused by
congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease,
idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver
disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis
deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid
processing deficiencies, such as familial hypercholesterolemia, Type 1
chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell
disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar
type II, polyendocrinopathy/hyperinsulinemia, Diabetes mellitus, Laron dwarfism,
myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis
CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurohypophyseal DI,
nephrogenic DI, Charcot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease,
neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease,
amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick’s disease, several
polyglutamine neurological disorders such as Huntington’s, spinocerebellar ataxia
type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and
myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary
Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease,
Sträussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren’s disease,
Osteoporosis, Osteopenia, bone healing and bone growth (including bone repair, bone
regeneration, reducing bone resorption and increasing bone deposition), Gorham's
Syndrome, chloride channelopathies such as myotonia congenita (Thomson and
Becker forms), Bartter's syndrome type III, Dent's disease, epilepsy, hyperekplexia,
lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia
(PCD), a term for inherited disorders of the structure and/or function of cilia,
including PCD with situs inversus (also known as Kartagener syndrome), PCD
without situs inversus and ciliary aplasia. In some embodiments, the co-crystal is a
Compound 1:triglyceride co-crystal as described herein.
In some embodiments, the method includes treating or lessening the severity
of cystic fibrosis in a patient comprising administering to said patient a co-crystal of
any one of the embodiments described above. In some embodiments, the co-crystal is
a Compound 1:triglyceride co-crystal as described herein. In certain embodiments,
the patient possesses mutant forms of human CFTR. In other embodiments, the
patient possesses one or more of the following mutations ΔF508, R117H, and G551D
of human CFTR. In one embodiment, the method includes treating or lessening the
severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR
comprising administering to said patient Compound 1:triglyceride co-crystals
described herein. In one embodiment, the method includes treating or lessening the
severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR
comprising administering to said patient Compound 1:triglyceride co-crystals
described herein. In one embodiment, the method includes treating or lessening the
severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR
on one allele comprising administering to said patient Compound 1:triglyceride co-
crystals described herein. In one embodiment, the method includes treating or
lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of
human CFTR on both alleles comprising administering to said patient Compound
1:triglyceride co-crystals described herein. In one embodiment, the method includes
treating or lessening the severity of cystic fibrosis in a patient possessing the G551D
mutation of human CFTR on allele comprising administering to said patient
Compound 1:triglyceride co-crystals described herein. In one embodiment, the
method includes treating or lessening the severity of cystic fibrosis in a patient
possessing the G551D mutation of human CFTR on both alleles comprising
administering to said patient Compound 1:triglyceride co-crystals described herein.
In yet another aspect, the present disclosure provides a method of treating or
lessening the severity of a condition, disease, or disorder implicated by CFTR
mutation. In certain embodiments, the present disclosure provides a method of
treating a condition, disease, or disorder implicated by a deficiency of the CFTR
activity, the method comprising administering a composition comprising co-crystals
of any one of the embodiments described above, to a subject, preferably a mammal, in
need thereof. In some embodiments, the co-crystal is a Compound 1:triglyceride co-
crystal as described herein.
In certain embodiments, the present disclosure provides a method of treating
diseases associated with reduced CFTR function due to mutations in the gene
encoding CFTR or environmental factors (e.g., smoke). These diseases include,
cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male
infertility caused by congenital bilateral absence of the vas deferens (CBAVD),
female infertility caused by congenital absence of the uterus and vagina (CAUV),
idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic
acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic
bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic
bronchopulmonary aspergillosis (ABPA), bone diseases (e.g., osteoporosis), and
asthma, comprising administering to said patient a co-crystal of any one of the
embodiments described above. In some embodiments, the co-crystal is a Compound
1:triglyceride co-crystal as described herein.
In certain embodiments, the present disclosure provides a method for treating
diseases associated with normal CFTR function. These diseases include, chronic
obstructive pulmonary disease (COPD), chronic bronchitis, recurrent bronchitis, acute
bronchitis, rhinosinusitis, constipation, pancreatitis including chronic pancreatitis,
recurrent pancreatitis, and acute pancreatitis, pancreatic insufficiency, male infertility
caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary
disease, idiopathic pancreatitis, liver disease, hereditary emphysema, gallstones,
gastroesophageal reflux disease, gastrointestinal malignancies, inflammatory bowel
disease, constipation, diabetes, arthritis, osteoporosis, and osteopenia, comprising
administering to said patient co-crystals of any one of the embodiments described
above. In some embodiments, the co-crystals are Compound 1:triglyceride co-
crystals as described herein.
In certain embodiments, the present disclosure provides a method for treating
diseases associated with normal CFTR function including hereditary
hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency,
Type 1 hereditary angioedema, lipid processing deficiencies, such as familial
hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal
storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses,
Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia,
Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary
hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism,
osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes
insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie Tooth
syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, progressive
supranuclear palsy, Pick’s disease, several polyglutamine neurological disorders such
as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy,
dentatorubral pallidoluysian atrophy, and myotonic dystrophy, as well as spongiform
encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein
processing defect), Fabry disease, Sträussler-Scheinker syndrome, Gorham’s
Syndrome, chloride channelopathies, myotonia congenita (Thomson and Becker
forms), Bartter’s syndrome type III, Dent’s disease, epilepsy, hyperekplexia,
lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD),
PCD with situs inversus (also known as Kartagener syndrome), PCD without situs
inversus and ciliary aplasia, or Sjogren’s disease, comprising the step of administering
to said mammal an effective amount of co-crystals of any of the embodiments
described above. In some embodiments, the co-crystals are Compound 1:triglyceride
co-crystals as described herein.
According to an alternative embodiment, the present disclosure provides a
method of treating cystic fibrosis comprising the step of administering to said
mammal a composition comprising the step of administering to said mammal an
effective amount of a composition comprising Compound 1:triglyceride co-crystals
described herein.
According to the disclosure an “effective amount” of Compound
1:triglyceride co-crystals, or a pharmaceutically acceptable composition thereof is that
amount effective for treating or lessening the severity of one or more of the diseases,
disorders or conditions as recited above.
Compound 1:triglyceride co-crystals described herein, or a pharmaceutically
acceptable composition thereof may be administered using any amount and any route
of administration effective for treating or lessening the severity of one or more of the
diseases, disorders or conditions as recited above.
In certain embodiments, Compound 1:triglyceride co-crystals described
herein, or a pharmaceutically acceptable composition thereof is useful for treating or
lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity
in the apical membrane of respiratory and non-respiratory epithelia. The presence of
residual CFTR activity at the epithelial surface can be readily detected using methods
known in the art, e.g., standard electrophysiological, biochemical, or histochemical
techniques. Such methods identify CFTR activity using in vivo or ex vivo
electrophysiological techniques, measurement of sweat or salivary Cl- concentrations,
or ex vivo biochemical or histochemical techniques to monitor cell surface density.
Using such methods, residual CFTR activity can be readily detected in patients
heterozygous or homozygous for a variety of different mutations, including patients
homozygous or heterozygous for the most common mutation, ΔF508.
In another embodiment, Compound 1:triglyceride co-crystals described
herein, described herein or a pharmaceutically acceptable composition thereof, is
useful for treating or lessening the severity of cystic fibrosis in patients who have
residual CFTR activity induced or augmented using pharmacological methods or gene
therapy. Such methods increase the amount of CFTR present at the cell surface,
thereby inducing a hitherto absent CFTR activity in a patient or augmenting the
existing level of residual CFTR activity in a patient.
In one embodiment, Compound 1:triglyceride co-crystals described herein,
or a pharmaceutically acceptable composition thereof, is useful for treating or
lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting
residual CFTR activity, e.g., class III mutations (impaired regulation or gating), class
IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R.
Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis
Transmembrane Conductance Regulator Defects and Opportunities of Therapy;
Current Opinion in Pulmonary Medicine 6:521 – 529, 2000). Other patient genotypes
that exhibit residual CFTR activity include patients homozygous for one of these
classes or heterozygous with any other class of mutations, including class I mutations,
class II mutations, or a mutation that lacks classification.
In one embodiment, Compound 1:triglyceride co-crystals described herein,
or a pharmaceutically acceptable composition thereof, is useful for treating or
lessening the severity of cystic fibrosis in patients within certain clinical phenotypes,
e.g., a moderate to mild clinical phenotype that typically correlates with the amount of
residual CFTR activity in the apical membrane of epithelia. Such phenotypes include
patients exhibiting pancreatic insufficiency or patients diagnosed with idiopathic
pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease.
The exact amount required will vary from subject to subject, depending on
the species, age, and general condition of the subject, the severity of the infection, the
particular agent, its mode of administration, and the like. The compounds of the
disclosure are preferably formulated in dosage unit form for ease of administration
and uniformity of dosage. The expression “dosage unit form” as used herein refers to
a physically discrete unit of agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds and compositions of
the present disclosure will be decided by the attending physician within the scope of
sound medical judgment. The specific effective dose level for any particular patient
or organism will depend upon a variety of factors including the disorder being treated
and the severity of the disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general health, sex and diet of
the patient; the time of administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed, and like factors
well known in the medical arts. The term "patient", as used herein, means an animal,
preferably a mammal, and most preferably a human.
The pharmaceutically acceptable compositions of this disclosure can be
administered to humans and other animals orally, rectally, parenterally,
intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments,
drops or patch), bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments, the compounds of the
disclosure may be administered orally or parenterally at dosage levels of about 0.01
mg/kg to about 50 mg/kg and preferably from about 0.5 mg/kg to about 25 mg/kg, of
subject body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
Liquid dosage forms for oral administration include, but are not limited to,
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-
butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn,
germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides
inert diluents, the oral compositions can also include adjuvants such as wetting agents,
emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing
or wetting agents and suspending agents. The sterile injectable preparation may also
be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally
acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are water, Ringer’s solution,
U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this purpose any
bland fixed oil can be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration
through a bacterial-retaining filter, or by incorporating sterilizing agents in the form
of sterile solid compositions which can be dissolved or dispersed in sterile water or
other sterile injectable medium prior to use.
In order to prolong the effect of a compound of the present disclosure, it is
often desirable to slow the absorption of the compound from subcutaneous or
intramuscular injection. This may be accomplished by the use of a liquid suspension
of crystalline or amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of dissolution that, in turn,
may depend upon crystal size and crystalline form. Alternatively, delayed absorption
of a parenterally administered compound form is accomplished by dissolving or
suspending the compound in an oil vehicle. Injectable depot forms are made by
forming microencapsule matrices of the compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the
nature of the particular polymer employed, the rate of compound release can be
controlled. Examples of other biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared by entrapping the
compound in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this disclosure with
suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol
or a suppository wax which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and release the active
compound.
Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound is mixed
with inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol, and silicic acid, b) binders such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and
acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium
carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators
such as quaternary ammonium compounds, g) wetting agents such as, for example,
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite
clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of
capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft
and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well
as high molecular weight polyethylene glycols and the like. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared with coatings and
shells such as enteric coatings and other coatings well known in the pharmaceutical
formulating art. They may optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-
filled gelatin capsules using such excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols and the like.
The active compounds can also be in microencapsulated form with one or
more excipients as noted above. The solid dosage forms of tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells such as enteric coatings,
release controlling coatings and other coatings well known in the pharmaceutical
formulating art. In such solid dosage forms the active compound may be admixed
with an inert diluent such as sucrose, lactose or starch. Such dosage forms may also
comprise additional substances other than inert diluents, e.g., tableting lubricants and
other tableting aids such a magnesium stearate and microcrystalline cellulose. In the
case of capsules, tablets and pills, the dosage forms may also comprise buffering
agents. They may optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of
this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions,
sprays, inhalants or patches. The active component is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also
contemplated as being within the scope of this disclosure. Additionally, the present
disclosure contemplates the use of transdermal patches, which have the added
advantage of providing controlled delivery of a compound to the body. Such dosage
forms are prepared by dissolving or dispensing the compound in the proper medium.
Absorption enhancers can also be used to increase the flux of the compound across
the skin. The rate can be controlled by either providing a rate controlling membrane
or by dispersing the compound in a polymer matrix or gel.
It will also be appreciated that the co-crystals of any one of the embodiments
described above (e.g., Compound 1:triglyceride co-crystals described herein) or a
pharmaceutically acceptable composition thereof can be employed in combination
therapies, that is, co-crystals of any of the embodiments described above (e.g.,
Compound 1:triglyceride co-crystals described herein) or a pharmaceutically
acceptable composition thereof, can be administered concurrently with, prior to, or
subsequent to, one or more other desired therapeutics or medical procedures. The
particular combination of therapies (therapeutics or procedures) to employ in a
combination regimen will take into account compatibility of the desired therapeutics
and/or procedures and the desired therapeutic effect to be achieved. It will also be
appreciated that the therapies employed may achieve a desired effect for the same
disorder (for example, an inventive compound may be administered concurrently with
another agent used to treat the same disorder), or they may achieve different effects
(e.g., control of any adverse effects). As used herein, additional therapeutic agents
that are normally administered to treat or prevent a particular disease, or condition,
are known as “appropriate for the disease, or condition, being treated.”
In one embodiment, the additional therapeutic agent is selected from a
mucolytic agent, bronchodilator, an anti-biotic, an anti-infective agent, an anti-
inflammatory agent, a CFTR modulator other than a compound of the present
disclosure, or a nutritional agent.
In one embodiment, the additional therapeutic agent is a compound that
stabilizes the presence of CFTR at the cell surface such as activators of Rac1
signaling, of which hepatocyte growth factor (HGF) is an example.
In one embodiment, the additional therapeutic agent is an antibiotic.
Examplary antibiotics useful herein include tobramycin, including tobramycin inhaled
powder (TIP), azithromycin, cayston, aztreonam, including the aerosolized form of
aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin,
including formulations thereof suitable for administration by inhalation, levoflaxacin,
including aerosolized formulations thereof, and combinations of two antibiotics, e.g.,
fosfomycin and tobramycin.
In another embodiment, the additional therapeutic agent is a mucolyte.
Examplary mucolytes useful herein includes Pulmozyme®.
In another embodiment, the additional therapeutic agent is a bronchodilator.
Examplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol
acetate, salmeterol, or tetrabuline sulfate.
In another embodiment, the additional therapeutic agent is effective in
restoring lung airway surface liquid. Such agents improve the movement of salt in
and out of cells, allowing mucus in the lung airway to be more hydrated and,
therefore, cleared more easily. Examplary such agents include hypertonic saline,
denufosol tetrasodium ([[(3S,5R)(4-aminooxopyrimidinyl)hydroxyoxolan-
2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4R,5R)(2,4-dioxopyrimidinyl)-3,
4-dihydroxyoxolanyl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]
hydrogen phosphate), or bronchitol (inhaled formulation of mannitol).
In another embodiment, the additional therapeutic agent is an anti-
inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs.
Examplary such agents useful herein include ibuprofen, docosahexanoic acid (DHA),
sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.
In another embodiment, the additional therapeutic agent is a compound that
augments or induces CFTR activity other than a co-crystal of Compound 1.
Examplary such agents include ataluren (“PTC124®”; 3-[5-(2-fluorophenyl)-1,2,4-
oxadiazolyl]benzoic acid), sinapultide, lancovutide, depelestat (a human
recombinant neutrophil elastase inhibitor), and cobiprostone (7-{(2R, 4aR, 5R, 7aR)-
2-[(3S)-1,1-difluoromethylpentyl]hydroxyoxooctahydrocyclopenta[b]pyran-
-yl}heptanoic acid).
In another embodiment, the additional therapeutic agent is a nutritional
agent. Examplary nutritional agents include pancrelipase (pancreating enzyme
replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®,
Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one
embodiment, the additional nutritional agent is pancrelipase.
In another embodiment, the additional therapeutic agent is a compound
selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat,
felodipine, nimodipine, Philoxin B, geniestein, Apigenin, cAMP/cGMP augmenters
or inducers such as rolipram, sildenafil, milrinone, tadalafil, amrinone, isoproterenol,
albuterol, and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors,
proteosome inhibitors such as epoxomicin, lactacystin, etc.
In another embodiment, the additional therapeutic agent reduces the activity
of the epithelial sodium channel blocker (ENaC) either directly by blocking the
channel or indirectly by modulation of proteases that lead to an increase in ENaC
activity (e.g., seine proteases, channel-activating proteases). Examplary such agents
include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-
4995, Aerolytic, and amiloride. Additional therapeutic agents that reduce the activity
of the epithelial sodium channel blocker (ENaC) can be found, for example in PCT
Publication No. WO2009/074575, the entire contents of which are incorporated herein
in their entirety.
Amongst other diseases described herein, combinations of CFTR
modulators, such as Compound 1:triglyceride co-crystals described herein, and agents
that reduce the activity of ENaC are used for treating Liddle’s syndrome, cystic
fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary
disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and
keratoconjunctivitis sire, respiratory tract infections (acute and chronic; viral and
bacterial) and lung carcinoma.
Combinations of CFTR modulators, such as Compound 1:triglyceride co-
crystals described herein, and agents that reduce the activity of ENaC are also useful
for treating diseases mediated by blockade of the epithelial sodium channel also
include diseases other than respiratory diseases that are associated with abnormal
fluid regulation across an epithelium, perhaps involving abnormal physiology of the
protective surface liquids on their surface, e.g., xerostomia (dry mouth) or
keratoconjunctivitis sire (dry eye). Furthermore, blockade of the epithelial sodium
channel in the kidney could be used to promote diuresis and thereby induce a
hypotensive effect.
Chronic obstructive pulmonary disease includes chronic bronchitis or
dyspnea associated therewith, emphysema, as well as exacerbation of airways
hyperreactivity consequent to other drug therapy, in particular, other inhaled drug
therapy. In some embodiments, the combinations of CFTR modulators, such as
Compound 1:triglyceride co-crystals described herein, and agents that reduce the
activity of ENaC are useful for the treatment of bronchitis of whatever type or genesis
including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
In another embodiment, the additional therapeutic agent is a CFTR
modulator other than Compound 1:triglyceride co-crystals described herein, i.e., an
agent that has the effect of modulating CFTR activity. Examplary such agents include
ataluren ("PTC124®"; 3-[5-(2-fluorophenyl)-1,2,4-oxadiazolyl]benzoic acid),
sinapultide, lancovutide, depelestat (a human recombinant neutrophil elastase
inhibitor), cobiprostone (7-{(2R, 4aR, 5R, 7aR)[(3S)-1,1-difluoromethylpentyl]-
2-hydroxyoxooctahydrocyclopenta[b]pyranyl}heptanoic acid), (3-(6-(1-(2,2-
difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido)methylpyridin
yl)benzoic acid, or (R)(2,2-difluorobenzo[d][1,3]dioxolyl)-N-(1-(2,3-
dihydroxypropyl)fluoro(1-hydroxymethylpropanyl)-1H-indol
yl)cyclopropanecarboxamide. In one embodiment, the additional therapeutic agent is
(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido)
methylpyridinyl)benzoic acid, or (R)(2,2-difluorobenzo[d][1,3]dioxolyl)-N-
(1-(2,3-dihydroxypropyl)fluoro(1-hydroxymethylpropanyl)-1H-indol
yl)cyclopropanecarboxamide. In another embodiment, the additional therapeutic
agent is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido)-
3-methylpyridinyl)benzoic acid. In another embodiment, the additional therapeutic
agent is (R)(2,2-difluorobenzo[d][1,3]dioxolyl)-N-(1-(2,3-dihydroxypropyl)
fluoro(1-hydroxymethylpropanyl)-1H-indolyl)cyclopropanecarboxamide.
In one embodiment, the additional therapeutic agent is a CFTR modulator
other than a compound of the present disclosure.
The amount of additional therapeutic agent present in the compositions of
this disclosure will be no more than the amount that would normally be administered
in a composition comprising that therapeutic agent as the only active agent.
Preferably the amount of additional therapeutic agent in the presently disclosed
compositions will range from about 50 % to 100 % of the amount normally present in
a composition comprising that agent as the only therapeutically active agent.
Co-crystals of any of the embodiments described above (e.g., Compound
1:triglyceride co-crystals described herein) or a pharmaceutically acceptable
composition thereof, may also be incorporated into compositions for coating an
implantable medical device, such as prostheses, artificial valves, vascular grafts,
stents and catheters. Accordingly, the present disclosure, in another aspect, includes a
composition for coating an implantable device comprising a compound of the present
disclosure as described generally above, and in classes and subclasses herein, and a
carrier suitable for coating said implantable device. In still another aspect, the present
disclosure includes an implantable device coated with a composition comprising a
compound of the present disclosure as described generally above, and in classes and
subclasses herein, and a carrier suitable for coating said implantable device. Suitable
coatings and the general preparation of coated implantable devices are described in
US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically
biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane,
polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and
mixtures thereof. The coatings may optionally be further covered by a suitable
topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or
combinations thereof to impart controlled release characteristics in the composition.
In one embodiment, the disclosure features a kit comprising a tablet of the
present disclosure, and a separate therapeutic agent or pharmaceutical composition
thereof. In one embodiment, the additional therapeutic agent is a CFTR corrector. In
another embodiment, the therapeutic agent is (3-(6-(1-(2,2-
difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido)methylpyridin
yl)benzoic acid or (R)(2,2-difluorobenzo[d][1,3]dioxolyl)-N-(1-(2,3-
dihydroxypropyl)fluoro(1-hydroxymethylpropanyl)-1H-indol
yl)cyclopropanecarboxamide. In another embodiment, the therapeutic agent is (3-(6-
(1-(2,2-difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido)
methylpyridinyl)benzoic acid. In another embodiment, the therapeutic agent is
(R)(2,2-difluorobenzo[d][1,3]dioxolyl)-N-(1-(2,3-dihydroxypropyl)fluoro
(1-hydroxymethylpropanyl)-1H-indolyl)cyclopropanecarboxamide. In
another embodiment, the tablet and the therapeutic agent are in separate containers.
In another embodiment, the kits of the present disclosure are drawn to kits wherein
the compounds or pharmaceutical compositions of the present disclosure and the one
or more additional therapeutic agents) are in separate containers. In one embodiment,
the separate containers are bottles. In another embodiment, the separate containers
are vials. In another embodiment, the separate containers are blister packs. In
another embodiment, the container is a bottle, vial, or blister pack or combination
thereof.
Another aspect of the disclosure relates to modulating CFTR activity in a
biological sample or a patient (e.g., in vitro or in vivo), which method comprises
administering to the patient, or contacting said biological sample co-crystals of any of
the embodiments described above (e.g., Compound 1:triglyceride co-crystals
described herein) or a pharmaceutically acceptable composition thereof. The term
“biological sample”, as used herein, includes, without limitation, cell cultures or
extracts thereof; biopsied material obtained from a mammal or extracts thereof; and
blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
Modulation of CFTR in a biological sample is useful for a variety of
purposes that are known to one of skill in the art. Examples of such purposes include,
but are not limited to, the study of CFTR in biological and pathological phenomena;
and the comparative evaluation of new modulators of CFTR.
In yet another embodiment, a method of modulating activity of an anion
channel in vitro or in vivo, is provided comprising the step of contacting said channel
with Compound 1:triglyceride co-crystals described herein or a pharmaceutically
acceptable composition thereof. In some embodiments, the anion channel is a
chloride channel or a bicarbonate channel. In other embodiments, the anion channel
is a chloride channel.
According to an alternative embodiment, the present disclosure provides a
method of increasing the number of functional CFTR in a membrane of a cell,
comprising the step of contacting said cell with co-crystals of any one of the
embodiments described above (e.g., Compound 1:triglyceride co-crystals described
herein) or a pharmaceutically acceptable composition thereof.
According to another embodiment, the activity of the CFTR is measured by
measuring the transmembrane voltage potential. Means for measuring the voltage
potential across a membrane in the biological sample may employ any of the known
methods in the art, such as optical membrane potential assay or other
electrophysiological methods.
The optical membrane potential assay utilizes voltage-sensitive FRET
sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995)
"Voltage sensing by fluorescence resonance energy transfer in single cells." Biophys J
69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997); "Improved indicators of
cell membrane potential that use fluorescence resonance energy transfer" Chem Biol
4(4): 269-77) in combination with instrumentation for measuring fluorescence
changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K.
Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel
targets" Drug Discov Today 4(9): 431-439).
These voltage sensitive assays are based on the change in fluorescence
resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive
dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to
the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in
membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistribute
across the plasma membrane and the amount of energy transfer from CC2-DMPE
changes accordingly. The changes in fluorescence emission can be monitored using
VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to
conduct cell-based screens in 96- or 384-well microtiter plates.
In another aspect the present disclosure provides a kit for use in measuring
the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo
comprising (i) a composition comprising any of the co-crystals of the embodiments
described above (e.g., Compound 1:triglyceride co-crystals described herein); and (ii)
instructions for a) contacting the composition with the biological sample and b)
measuring activity of said CFTR or a fragment thereof. In one embodiment, the kit
further comprises instructions for a) contacting an additional composition with the
biological sample; b) measuring the activity of said CFTR or a fragment thereof in the
presence of said additional compound, and c) comparing the activity of the CFTR in
the presence of the additional compound with the density of the CFTR in the presence
of co-crystals of any of the embodiments described above (e.g., Compound
1:triglyceride co-crystals described herein). In some embodiments, the kit is used to
measure the density of CFTR.
In another aspect, the disclosure provides a kit for use in measuring the
activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo,
comprising:
(i) a composition comprising co-crystals of any of the
embodiments described above (e.g., Compound 1:triglyceride co-crystals);
(ii) instructions for:
(a) contacting the composition with the biological sample;
(b) measuring activity of said CFTR or a fragment thereof.
In one embodiment, the kit further comprises instructions for:
i. contacting an additional composition with the biological
sample;
ii. measuring the activity of said CFTR, or a fragment thereof, in
the presence of said additional compound; and
iii. comparing the activity of the CFTR, or fragment thereof, in the
presence of the additional compound with the density of CFTR,
or fragment thereof, in the presence of co-crystals of any of the
embodiments described above (e.g., Compound 1:triglyceride
co-crystals).
In another embodiment, the step of comparing the activity of said CFTR, or
fragment thereof, provides a measure of the density of said CFTR, or fragment thereof
In order that the disclosure described herein may be more fully understood,
the following examples are set forth. It should be understood that these examples are
for illustrative purposes only and are not to be construed as limiting this disclosure in
any manner.
EXAMPLES
Initial Preparation of Compound 1
Compound 1 was prepared as described in , US
2010/0267768 and US 8,476,442, which are incorporated by reference herein. The
preparation is also described below.
Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor.
2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50%
solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5
vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to
45.0 to 50.0 °C and held at this temperature for 15 hours. A sample was taken and
checked for completion by HPLC. Once complete, the resulting mixture was cooled
to 20.0 °C +/- 5.0 °C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The
reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged
to bring the total volume of reaction to 40.0 vol. (~16.5 vol. charged). Residual water
was removed by continuous distillation at 35.0 °C +/- 5 °C from 40 vol. to 30 vol.
with 2-MeTHF until in-process control testing using the Karl Fisher method shows
the water content to be no more than 1.0% w/w. The solution was cooled to 20.0 °C
+/- 5.0 °C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the
hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and
checked for completion by HPLC. Once complete, the reaction was quenched with 1
N HCl / H O (10.0 vol.), and washed with 0.1 N HCl (10.0 vol.). The organic
solution was polish filtered to remove any particulates and placed in a second flask.
The filtered solution was concentrated at 25.0 °C +/- 5.0 °C under reduced pressure to
vol. CH CN was added to 40 vol. and the solution concentrated at 25.0 °C +/-
.0 °C to 20 vol. The addition of CH CN and concentration was repeated 2 more
times for a total of 3 additions of CH CN and 4 concentrations to 20 vol. After the
final concentration to 20 vol., 16.0 vol. of CH CN was charged followed by 4.0 vol.
of H O to make a final concentration of 40 vol. of 10% H O/CH CN relative to
2 2 3
Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 °C
+/- 5 °C and filtered. The cake was washed with CH CN (5 vol.) 2 times. The
resulting solid was dried in a vacuum oven at 50.0 °C +/- 5.0 °C until a constant
weight is attained.
Preparation of Neat Amorphous Compound 1
The following solution was prepared by stirring Compound 1, as prepared
above, into 90% MEK/10% water according to Table A.
Table A
(MEK/Water = 90/10) Weight (g)
MEK 360.00
Water 40.00
Compound 1 (as prepared above) 35.00
Total Solution Weight 400.00
Solids Loading 35.00
Spray drying was performed on a Buchi Mini Spray Dryer B-290 with
dehumidifier B-296 and Inert Loop B-295 using the parameters used in Table B. The
system was saturated with solvent that was to be sprayed, and inlet and outlet
temperatures were allowed to equilibrate before spray drying. The powder from the
collection vessel and the cyclone were combined in a shallow dish and dried in a
vacuum oven with slight nitrogen purge for 7 days. The amorphous material was then
dried in a vacuum oven at 75 to 80 °C and a pressure of approximately 0.1 mmHg
until the MEK concentration was reduced to <1.0% w/w by 1H NMR (50 hours). The
material was removed from the vacuum after cooling under N2 50°C.
Table B: Spray Drying Parameters
INLET Temperature 110 ºC
OUTLET Temperature 50-60 ºC
Nitrogen Pressure 120 psi
Aspirator 100 %
Pump Rate 45 %
Nozzle 1mm
Atomizer 35 mm
Filter Pressure -50 to -70 mbar
Condenser Temperature -5 ºC
Run Time 40 min.
Preparation of Co-Crystals of Compound 1
Method 1: All pure Compound 1 co-crystals were prepared by slurrying or
stirring neat amorphous Compound 1 in neat triglyceride at a 5%-10% weight to
volume solids load for at least 18 hours at 40°C or 5°C -10 °C above the triglyceride
melting point in a HEL Polyblock synthesizer. The completion of the conversion was
determined by birefringence of the suspended particles with polarized light
microscopy. Crude co-crystals were isolated by centrifugal filtration using Millipore
2ml centrifugation devices.
In some cases the mother liquor was collected for preparation of additional
Compound 1 co-crystal to increase yield with respect to the triglyceride. This was
achieved by slurrying or stirring neat amorphous Compound 1 at a 5%-10% weight to
volume ratio in the mother liquor for at least 18 hours. The mother liquor was used
not more than two times for additional conversions. The crude co-crystals of
subsequent conversions were combined into 2ml centrifugation devices and heptane
was added at a 1.5 to 2 volume to weight ratio. After briefly vortexing of the mixture,
the heptane was filtered by centrifugal filtration and the solids collected. Excess
heptane was removed by drying in vacuum at 40 to 45°C for at least 18 hours. The
heptane content was checked periodically by 1H solution state NMR and drying was
continued until the heptane was at acceptable levels, e.g., until there was no further
decrease in the overlapping triglyceride and heptane CH3 resonance observed.
Method 2: Approximately 50 mg neat amorphous Compound 1 was added
to approximately 1 g triglyceride, heated to 80 ºC and kept at this temperature for at
least 1 hour. The solution was then cooled to a temperature above the melting point of
the triglyceride to crystallize the Compound 1 co-crystal. In order to improve crystal
quality and size the system was heated again to 80 ºC and cooled down. The
temperature cycling was repeated until crystals of suitable size for analysis were
obtained. All Compound 1 co-crystals were isolated by centrifugal filtration at
temperatures above the melting point of the triglyceride.
Characterization of Compound 1 Co-Crystals
Characterization Techniques Used:
X-Ray Powder Diffraction (XRPD) Analysis: The XRPD patterns were
acquired at room temperature in reflection mode using a Pananalytical Empyrean II or
a Bruker D8 Advance diffractometer. The powder sample were placed in a
Pananalytical stainless steel sample holder or a Bruker shallow cavity sample holder
and spun at 15 rpm, respectively. Instrument parameters are listed in the table below.
XRD System Bruker D8 Panalytical
Advance Empyrean
Generator Voltage, kV 40 45
Generator Current, mA 40 40
Incident beam Variable at 12 Programmable at
Divergence slit mm 14 mm
Scan start (°2 Θ) 3 2.9989
Scan end (°2 Θ) 40 40
Step size (°2 Θ) 0.0144531 0.0131303
Nominal number of detector Default 255
channels
Detector VANTEC-1 PIXcel 1D
Scan Type Locked Coupled Locked Coupled
Number of Steps 2560 2818
Time per step (sec) 0.25 49.725
Incident Anti Scatter Slit (°) 0.5 2
Rotation Speed (rpm) 15 7.5
Filter Nickel Nickel
Beam Knife Yes Yes
Incident Solar Slit (RAD) N/A 0.04
Incident Mask (mm) N/A 10
Diffracted Anti Scatter Slit Default Automatic @ 14
Diffracted Solar Slit (RAD) N/A 0.04
Scan Speed (°/sec) Default 0.067335
13 13
C Solid State Nuclear Magnetic Resonance Spectroscopy ( C ssNMR):
A Bruker-Biospin 400 MHz wide-bore AVance III spectrometer equipped with
Bruker-Biospin 4mm HFX probe was used for all C ssNMR experiments. Samples
were packed into 4mm ZrO2 rotors and spun under magic angle spinning (MAS)
condition with spinning speed of 12.5 kHz. The CP contact time of carbon CPMAS
experiment was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%)
was employed. The Hartmann-Hahn match was optimized on external reference
sample (glycine). TPPM15 decoupling sequence was used with the field strength of
approximately 100 kHz. The relaxation delay was set to 5s in all 13C CPMAS
experiments. 1H T1 values were measured using a saturation recovery sequence. All
spectra were reference externally to the upfield resonance of adamantine at 29.5 ppm.
The temperature of the sample was controlled to 275 K.
Thermogravimetric Analysis (TGA): Thermal gravimetric analysis (TGA)
was conducted on a TA Instruments model Q5000 V3.8 thermogravimetric analyzer.
Approximately 5-15 mg of solid sample was placed in a platinum sample pan and
heated in a 60 mL/min sample and a 40mL/min balance nitrogen stream at 10°C/min
from ambient to 350 °C. All thermograms were analyzed using TA Instruments
Universal Analysis 2000 software V4.4A.
Differential Scanning Calorimetry (DSC): The DSC traces were obtained
using TA Instruments DSC Q2000 equipped with Universal Analysis 2000 software.
An amount of 0.5 - 2 mg of Compound 1 co-crystal was weighed into an aluminum
pan and sealed with a pinhole lid. The samples were heated from ambient to 350°C or
300 °C at 10 °C/min.
H solution Nuclear Magnetic Resonance Spectroscopy ( H NMR): A
Bruker narrow bore 400MHz AvanceIII Nanobay spectrometer equipped with a
Bruker-Biospin 5mm broadband probe was used for all experiments. Approximately
0.5 - 2mg of Compound 1 co-crystal samples were dissolved in 0.65ml acetone-d6
(for Compound 1:glycereyltrioleate and Compound 1:glyceryltrilinoleate) or DMSO-
d6 (for Compound 1:glyceryltrioctanoate) in a 5mm NMR tube. A relaxation delay of
60 s was chosen to minimize differential relaxation of 1H between different proton
positions on Compound 1 and triglyceride. All spectra are referenced using a
tetramethylsilane internal standard at 0.0 ppm.
All H NMR solution state spectra are in accord with the presence of both
Compound 1 and the respective triglyceride co- former and are consistent with
chemically pure co-crystals. Significant shifts are absent in the spectra of the
dissolved co-crystals for both Compound 1 and the triglycerides when compared to
the spectra of the pure components individually. This provides evidence for
dissociation of the co-crystals components in solution and confirms the weak
association of Compound 1 and triglyceride association in the solid. The ratio of
integrated intensity for protons in Compound 1:glyceryltrioctanoate in the H NMR
spectra indicate a stoichiometry of 3:1 (Compound 1:triglyceride) in the co-crystal,
whereas the integrated intensity of the Compound 1:glyceryltrioleate and Compound
1:glyceryltrilinoleate integrated intensities indicate a 6:1 (Compound 1:triglyceride)
stoichiometry in the respective co-crystals. The stoichiometry determined by solution
state H NMR is consistent with the stoichiometry determined by thermogravimetric
analysis for the Compound 1:glyceryltrioctanoate co-crystal.
The H NMR results are consistent with high performance liquid
chromatography analysis of the co-crystals. The assay values were determined to be
72.1 % (w:w), 72.4 % (w:w) and 68.6 % (w:w) Compound 1 for the Compound
1:glyceryltrioctanoate, Compound 1:glyceryltrioleate and Compound 1:trilinoleate co-
crystals. Impurities were found to be less than 0.5 % total using UV detection.
Mass Spectrometry Analysis: The mass spectrometry analysis was done as
outlined for each complex below.
Single Crystal X-Ray Crystallography: The single crystal was prepared by
dissolving 56 mg of amorphous Compound 1 in 1000 mg triglyceride in an oven set to
80°C. Upon crystallization, a few crystals were removed for single crystal X-ray
analysis. Diffraction data were acquired at ESFR synchrotron source with wavelength
0.70158Å at 100K temperature (reference number Phil Pattison 130813). The
structure was solved and refined using SHELX program (Sheldrick, G.M., Acta
Cryst., (2008) A64, 112-122).
Characterization of Compound 1:glyceryltrioctanoate
XRPD for Compound 1:glyceryltrioctanoate:
An examplary X-Ray Powder Diffraction (XRPD) pattern of Compound
1:glyceryltrioctanoate in Figure 3 was acquired using the Panalytical Empyrean II
diffractometer. XRPD Representative peaks for Compound 1:glyceryltrioctanoate as
observed in the XRPD pattern are provided in Table C below. All peaks listed below
are greater than 5% of the maximum peak intensity.
Table C
Peak # Angle 2 θ, in degrees
(±0.2°)
1 3.5
2 6.0
3 6.9
4 9.1
10.9
6 12.0
7 12.5
8 13.2
9 13.7
15.0
11 16.2
12 16.9
13 18.0
14 19.3
20.2
16 21.7
17 22.5
18 23.8
19 25.8
27.0
21 27.6
22 28.3
23 30.0
24 31.0
32.6
C ssNMR for Compound 1:glyceryltrioctanoate:
An examplary C solid state nuclear magnetic resonance spectroscopy
( C ssNMR) spectrum of Compound 1:glyceryltrioctanoate is shown in Figure 4. A
listing of some of the C ssNMR peaks for Compound 1:glyceryltrioctanoate are
provided in Table D below.
Table D
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.6
2 172.9
3 171.6
4 169.9
165.1
6 155.0
7 143.2
8 139.4
9 137.3
134.6
11 133.0
12 126.0
13 119.4
14 117.7
112.1
16 67.3
17 64.0
18 62.0
19 59.6
54.2
21 35.8
22 34.8
23 31.7
24 30.5
23.5
26 14.6
TGA for Compound 1:glyceryltrioctanoate:
An examplary thermal gravimetric analysis (TGA) trace of Compound
1:glyceryltrioctanoate is shown in Figure 5. A weight loss of 28.3% corresponding to
the evaporation of glyceryltriocanoate was observed from 150°C to 300°C for
Compound 1:glyceryltrioctanoate. The calculated Compound 1 to
glyceryltrioctanoate mole ratio based on the weight loss in the material is 1:3.1.
DSC for Compound 1:glyceryltrioctanoate:
An examplary Differential Scanning Calorimetry (DSC) thermogram of
Compound 1:glyceryltrioctanoate is shown in Figure 6. The thermogram had an
endotherm at 186.7°C that corresponds to the melting of the Compound
1:glyceryltrioctanoate. The error in the thermogram measurement is ±0.2 ºC. This
endotherm was followed by an exotherm corresponding to a recrystallization to a neat
form of Compound 1 which then melted in a later endothermic event.
H NMR for Compound 1:glyceryltrioctanoate:
An examplary 1H Nuclear Magnetic Resonance (1H NMR) spectrum of
Compound 1:glyceryltrioctanoate in DMSO-d6 is shown in Figure 7.
Table E and Table F summarize the H NMR data and assign the Compound
1 and glyceryltrioctanoate hydrogens, respectively. The numbering system used for
assignment of hydrogens in Compound 1 is as follows:
The numbering system used for assignment of hydrogens in
glyceryltrioctanoate is as follows:
Table E
Atom H- Chemical Multiplicity
# of Protons
Number Shift (ppm) (J value)
3 1 s
7.17
6 7.11 1 s
8 3x3 s
1.36
1.38 3x3 s
11 9.18 1 s
12 11.81 1 s
17 8.33 1 d, J = 8.01 Hz
18 7.52 1 t, J = 7.46 Hz
19 1 t, J = 7.91 Hz
7.80
7.75 1 d, J = 8.21 Hz
22 12.86 1 s, broad
23 1 s
8.87
Table F
Theoretical Measured
signal integrated
Atom Chemical # of Multiplicity
intensity for signal
Number Shift Protons (J value)
3:1 intensity
(ppm)
stoichiometry
0.85 3 t, J=7 Hz 3.00 3.06
6-9 1.24 8 m, 8.00 8.39
(overlapped)
1.5 2 m, 2.00 2.19
(overlapped)
4 2.27 0.67 t, J=7.3 Hz 0.67 2.03
combined
value
4 2.28 1.33 t, J=7.3 Hz 1.33
reported
above
2a 4.12 0.67 dd (J=6.6, 0.67 0.68
J=12.0)
2b 4.26 0.67 dd (J=12.0, 0.67 0.68
J=3.6 Hz)
1 5.19 0.33 tt (J=3.6Hz, 0.33 0.33
J=6.6 Hz)
Integration was calibrated to yield 2.00 units for the combined integrated
intensity for position 3 and 6 of Compound 1.
Mass Spectrometry Analysis: The accurate mass of Compound
1:glyceryltrioctanoate was determined on the Agilent 6210 time of flight mass
spectrometer. The sample was dissolved to approximately 0.1 mg/ml in MeOH and
injected by direct flow injection using a syringe pump. A zero volume blank nut was
used to do direct inject analysis.
The following masses were found and confirm the identity of the molecular
components of the Compound 1:glyceryltriocanoate:
Compound 1: HRMS (ESI-TOF) m/z: [M + H] Calculated for
C24H29N2O3 393.2173; Found 393.2179.
Glyceryltrioctanoate: HRMS (ESI-TOF) m/z: [M + NH3]+ Calculated for
C27H54NO6+ 488.3947; Found 488.3951
Molecular Ions and Exact Masses for Compound 1:glyceryltrioctanoate:
Characterization of Compound 1:glyceryltrioleate
XRPD for Compound 1:glyceryltrioleate:
An examplary XRPD pattern for Compound 1:glyceryltrioleate shown in
Figure 8 was acquired using the Panalytical Empyrean II diffractometer.
Representative peaks for Compound 1:glyceryltrioleate as observed in the XRPD
pattern are provided in Table G below. All peaks listed below are greater than 5% of
the maximum peak intensity.
Table G
Peak # Angle 2 θ, in degrees
(±0.2°)
1 3.5
2 6.9
3 9.2
4 9.8
10.4
6 10.9
7 12.0
8 12.7
9 13.3
13.8
11 15.1
12 16.3
13 16.9
14 18.1
18.5
16 19.4
17 19.9
18 20.2
19 21.2
21.8
21 22.6
22 23.8
23 26.0
24 27.0
27.8
26 28.5
27 30.0
28 30.6
29 32.7
C ssNMR for Compound 1:glyceryltrioleate:
An examplary C ssNMR spectrum for Compound 1:glyceryltrioleate is
shown in Figure 9. A listing of some of the C ssNMR peaks for Compound
1:glyceryltrioleate are provided in Table H below.
Table H
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.6
2 172.9
3 171.6
4 169.9
165.0
6 155.0
7 142.9
8 139.3
9 137.4
134.5
11 133.0
12 130.5
13 127.3
14 126.0
119.3
16 117.7
17 112.1
18 67.2
19 63.9
59.6
21 35.8
22 34.8
23 31.7
24 30.5
28.2
26 24.6
27 23.6
28 14.7
TGA for Compound 1:glyceryltrioleate:
An examplary TGA trace of Compound 1:glyceryltrioleate is shown in
Figure 10. A weight loss of 1.1% was observed from 150°C to 300°C for Compound
1:glyceryltrioleate. Evaporation of glyceryltrioleate was not observed due to its high
boiling point.
DSC for Compound 1:glyceryltrioleate:
An examplary DSC thermogram of Compound 1:glyceryltrioleate is shown
in Figure 11. The thermogram had an endotherm at 197.5°C that corresponds to the
melting of Compound 1:glyceryltrioleate. The error in the endotherm measurement is
±0.2 ºC. This endothermic event was followed by an exotherm, corresponding to the
crystallization of a neat form of Compound 1. Another endotherm corresponding to
the melting of this neat form of Compound 1 was observed. Another later exothermic
recrystallization to a second neat form of Compound 1 was observed. A later
endotherm corresponds to melting of this second form of Compound 1.
1H NMR for Compound 1:glyceryltrioleate:
An examplary 1H NMR spectrum of Compound 1:glyceryltrioleate is shown
in Figure 12.
Table I and Table J summarize the 1H NMR data and assign the Compound
1 and glyceryltrioleate hydrogens, respectively. The numbering system used for
assignment of hydrogens in Compound 1 was as previously shown above.
The numbering system used for assignment of hydrogens in glyceryltrioleate
is as follows:
Table I
Atom H- Chemical Multiplicity
# of Protons
Number Shift (ppm) (J value)
3 7.34 1 d (1.1Hz)
6 7.29 1 s
8 1.41 3x3 s
1.47 3x3 s
23 8.95 1 d, J=6.8 Hz
(overlapped)
22 11.7 1 s, broad
17 8.44 1 d, J = 8.2 Hz
18 7.53 1 ddd, J = 1.6 Hz, J =
6.6 Hz, J = 8.2 Hz
19 7.8 1 t, J = 7.6 Hz
7.75 1 d, J = 8.21 Hz
12 11.9 1 s
11 8.18 1 s
Table J
# of Theoretical Measured
Protons signal integrated
Atom H- Chemical Multiplicity
intensity for signal
Number Shift (ppm) (J value)
6:1 intensity
stoichiometry
0.89 t, J=7 Hz 9 1.50 1.69
6-9,14- 1.34/1.30 m, 60 10.00 11.34
19 (overlapped)
1.61 m, 6 1.00 1.18
(overlapped)
,13 overlapped m, overlapped 12 2.00 n/a
w/solvent with acetone-
2.06 d6
4 2.32 t, J=7.4 Hz 6 1.00 1.06
2a 4.18 dd, J=6.1, 2 0.33 0.36
J=12.0
2b 4.34 dd, J=4.0, 2 0.33 0.36
J=12.0
1 5.28 m 1 0.17 0.19
11,12 5.36 m 6 1.00 1.06
Integration was calibrated to yield 2.00 units for the combined integrated
intensity for position 3 and 6 of Compound 1. Slow H-D exchange at position 22 of
Compound 1 results in observation of both doublet (position 22 H) and singlet
(position 22 D) for H23 for Compound 1.
Mass Spectrometry Analysis for Compound 1:glyceryltrioleate:
The accurate mass of this complex was determined on a Thermo LTQ Orbi
Trap XL mass spectrometer. The sample was dissolved to approximately 0.1 mg/ml in
MeOH and infused by direct flow injection using a syringe pump at a rate of 50µl/s.
50 scans were collected using the FTMS analyzer at a 30000 resolution setting.
The following masses were found and confirm the identity of the molecular
components of the Compound 1:glyceryltrioleate:
Compound 1: HRMS (ESI-TOF) m/z: [M + H]+ Calculated for
C24H29N2O3+ 393.2173; Found 393.2170.
Glyceryltrioleate: HRMS (ESI-TOF) m/z: [M + Compound 1 + H]+
Calculated for C81H133N2O9+ 1278.0006; Found 1277.9991.
Molecular ions and exact masses Compound 1:glyceryltrioleate:
Characterization of Compound 1:glyceryltrilinoleate
XRPD for Compound 1:glyceryltrilinoleate:
An examplary XRPD pattern for Compound 1:glyceryltrilinoleate shown in
Figure 13 was acquired using the Panalytical Empyrean II diffractometer.
Representative peaks for Compound 1:glyceryltrilinoleate as observed in the XRPD
pattern are provided in Table K below. All peaks listed below are greater than 5% of
the maximum peak intensity.
Table K
Peak # Angle 2 θ, in degrees
(±0.2°)
1 3.5
2 6.0
3 6.9
4 9.2
10.9
6 12.0
7 12.5
8 13.8
9 15.1
16.3
11 16.9
12 18.1
13 19.4
14 20.2
21.8
16 22.6
17 23.8
18 25.9
19 27.1
27.8
21 28.4
22 32.7
C ssNMR for Compound 1:glyceryltrilinoleate:
An examplary C ssNMR spectrum for Compound 1:glyceryltrilinoleate is
shown in Figure 14. A listing of some of the C ssNMR peaks for Compound
1:glyceryltrilinoleate are provided in Table L below.
Table L
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.5
2 172.8
3 171.5
4 169.8
165.1
6 155.0
7 142.9
8 139.3
9 137.4
134.4
11 133.1
12 130.6
13 126.0
14 119.3
117.6
16 112.0
17 86.5
18 67.2
19 63.9
59.7
21 35.8
22 34.8
23 31.7
24 30.6
28.2
26 14.8
TGA for Compound 1:glyceryltrilinoleate:
An examplary TGA trace of Compound 1:glyceryltrilinoleate is shown in
Figure 15. A weight loss of 1.7% was observed from 40 °C to 190 °C for Compound
1:glyceryltrlinioleate. Evaporation of glyceryltrilinoleate was not observed due to its
high boiling point.
DSC for Compound 1:glyceryltrilinoleate:
An examplary DSC thermogram for Compound 1:glyceryltrilinoleate is
shown in Figure 16. The thermogram of Compound 1:glyceryltrilinoleate in Figure
16 had an endotherm at 182.3°C that corresponds to the melting of Compound
1:glyceryltrilinoleate. The error in the endotherm measurement is ±0.2 ºC. This
endothermic event was followed by an exotherm, corresponding to the crystallization
of a neat form of Compound 1. Another endotherm corresponding to the melting of
this neat form was observed. Another later exothermic recrystallization to a second
neat form of Compound 1 was observed. A later endotherm corresponds to melting of
this second form of Compound 1.
H NMR for Compound 1:glyceryltrilinoleate:
An examplary 1H NMR spectrum of Compound 1:glyceryltrioleate is shown
in Figure 17.
Table M and Table N summarize the 1H NMR data and assign the
Compound 1 and glyceryltrioleate hydrogens, respectively. The numbering system
used for assignment of hydrogens in Compound 1 was previously shown above.
Integration was calibrated to yield 2.00 units for the combined integrated intensity for
position 3 and 6 of Compound 1.
The numbering system for the assignment of hydrogens in glyceryltrioleate
is as follows:
O 39
10
11 11
13 13
14 14
18 18
Table M
Atom H- Chemical Multiplicity
# of Protons
Number Shift (ppm) (J value)
3 7.33 1 s
6 7.29 1 s
8 1.4 3x3 s
1.47 3x3 s
23 8.95 1 d, J=6.8 Hz
(overlapped)
22 11.7 1 s, broad
17 8.44 1 d, J = 8.2 Hz
18 7.53 1 ddd, J = 1.6 Hz, J =
6.6 Hz, J = 8.2 Hz
19 7.8 1 t, J = 7.6 Hz
7.76 1 d, J = 7.8 Hz
12 11.9 1 s
11 8.2 1 s
Table N
Theoretical
Measured
H- signal
Atom Multiplicity # of integrated
Chemical intensity for
Number (J value) Protons signal
Shift (ppm) 6:1
intensity
stoichiometry
0.89 t, J=7 Hz 9 1.50 1.42
6-9, 17-19 1.34 42 7.00 6.01
(overlapped)
1.61 6 1.00 1.33
(overlapped)
overlapped
,16 2.08 with acetone- 12 2.00 n/a
4 2.32 t, J=7.4 Hz 6 1.00 0.91
2.80
13 overlapped D, J=12Hz 6 1.00 n/a
w/HOD
dd, J=6.1,
2a 4.18 2 0.33 0.31
J=12.0
dd, J=4.0,
2b 4.34 2 0.33 0.34
J=12.0
1 5.28 m 1 0.17 0.14
11,12,13,14 5.36 m 12 2.00 1.08
Integration was calibrated to yield 2.00 units for the combined integrated
intensity for position 3 and 6 of Compound 1. Slow H-D exchange at position 22 of
Compound 1 results in observation of both doublet (position 22 H) and singlet
(position 22 D) for H23 for Compound 1.
Mass Spectrometry Analysis for Compound 1:glyceryltrilinoleate:
The accurate mass of this complex was determined on a LTQ Orbi Trap XL
mass spectrometer. The sample was dissolved to approximately 0.1 mg/ml in MeOH
and infused by direct flow injection using a syringe pump at a rate of 2µl/s. 50 scans
were collected using the FTMS analyzer at a 30000 resolution setting.
The following masses were found and confirm the identity of the molecular
components of Compound 1:glyceryltrilinoleate:
Compound 1: HRMS (ESI-TOF) m/z: [M + H]+ Calculated for
C24H29N2O3+ 393.2173; Found 393.2176.
Glyceryltrilinoleate: HRMS (ESI-TOF) m/z: [M + Compound 1 + H]+
Calculated for C81H127N2O9+ 1271.9536; Found 1271.9541
Molecular ions and exact masses Compound 1:glyceryltrilinoleate:
Characterization of Compound 1:triacetin
XRPD for Compound 1:triacetin:
An examplary XRPD pattern for Compound 1:triacetin shown in Figure 18
was acquired using the Panalytical Empyrean II diffractometer. Representative peaks
for Compound 1:triacetin as observed in the XRPD pattern are provided in Table O
below. All peaks listed below are greater than 5% of the maximum peak intensity.
Table O
Peak # Angle 2 θ, in degrees
(±0.2°)
1 4.9
2 9.5
3 9.8
4 14.7
16.5
6 18.2
7 23.1
C ssNMR for Compound 1:triacetin:
C ssNMR spectrum for Compound 1:triacetin is shown in
An examplary
Figure 19. A listing of some of the C ssNMR peaks for Compound
1:glyceryltriacetate are provided in Table P below.
Table P
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.2
2 165.4
3 164.3
4 155.1
154.8
6 154.1
7 149.4
8 146.8
9 145.6
140.0
11 134.1
12 133.2
13 132.3
14 127.0
125.9
16 125.6
17 124.3
18 120.6
19 119.7
119.2
21 118.3
22 117.6
23 111.9
24 111.1
110.4
26 35.3
27 35.0
28 31.8
29 29.8
21.9
31 20.4
32 18.9
DSC for Compound 1:triacetin:
An examplary DSC thermogram for Compound 1:triacetin is shown in
Figure 20. The thermogram of Compound 1:triacetin an endotherm at 123.9°C that
corresponds to the melting of the Compound 1:glyceryltritriacetin co-crystal. This
event is followed by another endotherm at 141.9°C and yet another endotherm at
193.8 °C.
Characterization of Compound 1:glyceryltributyrate
XRPD for Compound 1:glyceryltributyrate:
An examplary XRPD pattern for Compound 1:glyceryltributyrate shown in
Figure 21 was acquired using the Panalytical Empyrean II diffractometer.
Representative peaks for Compound 1:glyceryltributyrate as observed in the XRPD
pattern are provided in Table Q below. All peaks listed below are greater than 5% of
the maximum peak intensity.
Table Q
Peak # Angle 2 θ, in degrees
(±0.2°)
1 4.8
2 4.9
3 6.8
4 9.5
9.6
6 14.3
7 18.0
8 19.0
9 19.8
21.4
11 22.6
12 23.8
Characterization of Compound 1:glyceryltristearate
XRPD for Compound 1:glyceryltristearate:
An examplary XRPD pattern for Compound 1:glyceryltristearate shown in
Figure 22 was acquired using the Bruker D8 Advance diffractometer. Representative
peaks for Compound 1:glyceryltristearate as observed in the XRPD pattern are
provided in Table R below. All peaks listed below are equal to or greater than 1% of
the maximum peak intensity.
Table R
Peak # Angle 2 θ, in degrees
(±0.2°)
1 3.6
2 5.4
3 6.2
4 6.9
9.3
6 11.0
7 12.1
8 12.6
9 13.4
13.9
11 15.4
12 16.4
13 17.0
14 18.2
18.5
16 19.4
17 20.0
18 20.4
19 21.8
23.8
21 26.0
22 27.0
23 28.4
24 29.1
29.9
26 31.2
27 32.8
C ssNMR for Compound 1:glyceryltristearate:
An examplary C ssNMR spectrum for Compound 1:glyceryltristearate is
shown in Figure 23. A listing of some of the C ssNMR peaks for Compound
1:glyceryltristearate are provided in Table S below.
Table S
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.5
2 172.9
3 171.6
4 169.9
165.0
6 155.0
7 143.6
8 139.4
9 137.2
135.1
11 134.4
12 133.0
13 127.3
14 126.1
119.5
16 117.6
17 112.0
18 67.3
19 64.1
59.6
21 35.7
22 34.7
23 31.7
24 30.6
23.6
26 14.8
DSC for Compound 1:glyceryltristearate:
An examplary DSC thermogram for Compound 1:glyceryltristearate is
shown in Figure 24. The thermogram of Compound 1:glyceryltristearate in Figure 24
has an endotherm at 55.1°C that corresponds to the eutectic melt of Compound
1:glyceryltrilstearate co-crystal and glyceryltristearate. This event is followed by
another endotherm at 71.3 °C, corresponding to the melt of neat glyceryltristearate.
Overlapping endotherm at 201.3°C and exotherm at 208.1°C (peak) correspond to the
cocrystal melt and crystallization of neat Compound 1, respectively. Another
endotherm at 284.7°C corresponds to the melt of a neat form of Compound 1.
Characterization of Compound 1:glyceryltripalmitate
XRPD for Compound 1:glyceryltripalmitate:
An examplary XRPD pattern for Compound 1:glyceryltripalmitate shown in
Figure 25 was acquired using the Bruker D8 Advance diffractometer. Representative
peaks for Compound 1:glyceryltripalmitate as observed in the XRPD pattern are
provided in Table T below. All peaks listed below are greater than 1% of the
maximum peak intensity.
Table T
Peak # Angle 2 θ, in degrees
(±0.2°)
1 3.5
2 6.0
3 6.9
4 9.3
11.0
6 13.8
7 15.1
8 16.3
9 17.0
18.2
11 19.4
12 19.9
13 20.3
14 21.8
23.7
C ssNMR for Compound 1:glyceryltripalmitate:
An examplary C ssNMR spectrum for Compound 1:glyceryltripalmitate is
shown in Figure 26. A listing of some of the C ssNMR peaks for Compound
1:glyceryltripalmitate are provided in Table U below.
Table U
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.4
2 173.0
3 169.9
4 165.0
155.0
6 144.0
7 139.5
8 137.2
9 134.5
133.0
11 127.2
12 126.0
13 119.6
14 117.5
112.0
16 67.2
17 64.0
18 59.7
19 35.7
34.6
21 31.7
22 30.6
23 23.7
24 14.8
DSC for Compound 1:glyceryltripalmitate:
An examplary DSC thermogram for Compound 1:glyceryltripalmitate is
shown in Figure 27. The thermogram of Compound 1:glyceryltripalmitate in Figure
27 has an endotherm at 47.7°C that corresponds to the eutectic melt of Compound
1:glyceryltripalmitate co-crystal and glyceryltripalmitate. This event is followed by
another endotherm at 63.0 °C, corresponding to the melt of neat glyceryltripalmitate.
Overlapping endotherm at 174.9°C and exotherm at 186.7°C correspond to the
cocrystal melt and crystallization of neat Compound 1, respectively. Another
endotherm at 266.2°C corresponds to the melt of a neat form of Compound 1.
Characterization of Compound 1:glyceryltridodecanoate
XRPD for Compound 1:glyceryltridodecanoate:
An examplary XRPD pattern for Compound 1:glyceryldodecanoate is shown
Figure 28 was acquired using the Bruker D8 Advance diffractometer. Representative
peaks for Compound 1:glyceryltridodecanoate as observed in the XRPD pattern are
provided in Table V below. All peaks listed below are equal to or greater than 1% of
the maximum peak intensity.
Table V
Peak # Angle 2 θ, in degrees
(±0.2°)
1 3.5
2 6.1
3 6.9
4 9.2
6 10.9
7 11.8
8 12.1
9 12.6
13.2
11 13.8
12 14.9
13 16.3
14 16.9
18.1
16 18.5
17 19.4
18 19.8
19 20.3
21.7
21 23.4
22 23.9
23 25.2
24 25.8
27.2
26 28.4
C ssNMR for Compound 1:glyceryltridodecanoate:
An examplary C ssNMR spectrum for
Compound 1:glyceryltridodecanoate is shown in Figure 29. A listing of some of the
C ssNMR peaks for Compound 1:glyceryltridodecanoate are provided in Table W
below.
Table W
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.4
2 173.1
3 171.5
4 169.8
165.0
6 155.0
7 143.0
8 139.4
9 137.2
134.6
11 133.0
12 127.3
13 126.1
14 119.6
117.6
16 112.1
17 67.1
18 63.9
19 59.7
35.6
21 31.7
22 30.6
23 23.6
Single Crystal X-Ray Crystallography for Compound
1:glyceryltridodecanoate
Representative single crystal x-ray crystallography data for Compound
1:glyceryl tridodecanoate is provided in Tables X-i to X-vii.
Table X-i: Crystal data
C H N O F(000) = 3944
37 52.67 2 5
M = 605.48 D = 1.099 g cm
Hexagonal, P¯31c
Synchrotron radiation, λ = 0.70158 Å
a = 29.1507 (10) Å
μ = 0.07 mm
c = 14.9118 (6) Å T = 100 K
V = 10973.8 (7) Å Rod, colorless
Z = 12
Table X-ii: Data collection
Radiation source: synchrotron R = 0.076
Graphite monochromator
θ = 24.3°, θ = 1.6°
max min
66577 measured reflections
h = -34→32
5709 independent reflections
k = -33→34
4610 reflections with I > 2σ(I) l = -17→14
Table X-iii: Refinement
Refinement on F Primary atom site location: structure-invariant
direct methods
Least-squares matrix: full Secondary atom site location: difference
Fourier map
R[F > 2 (F )] = 0.226 Hydrogen site location: inferred from
neighbouring sites
wR(F ) = 0.545 H atoms treated by a mixture of independent
and constrained refinement
2 2 2
S = 2.03
w = 1/[σ (F ) + (0.2P) ]
where P = (F + 2F )/3
5709 reflections
(Δ/σ) = 3.947
361 parameters
Δ = 0.54 e Å
19 restraints
Δ = -0.35 e Å
Table X-iv: Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are
estimated using the full covariance matrix. The cell esds are taken into account
individually in the estimation of esds in distances, angles and torsion angles;
correlations between esds in cell parameters are only used when they are defined by
crystal symmetry. An approximate (isotropic) treatment of cell esds is used for
estimating esds involving l.s. planes.
Refinement. Refinement of F against ALL reflections. The weighted R-factor wR and
goodness of fit S are based on F , conventional R-factors R are based on F, with F set to
2 2 2
zero for negative F . The threshold expression of F > 2sigma(F ) is used only for
calculating R-factors(gt) etc. and is not relevant to the choice of reflections for
refinement. R-factors based on F are statistically about twice as large as those based on
F, and R- factors based on ALL data will be even larger.
Table X-v: Fractional atomic coordinates and isotropic or equivalent
isotropic displacement parameters (Å )
x y z U */U
iso eq
C1 0.2708 (3) 0.8168 (4) 0.1302 (11) 0.197 (5)
C2 0.3516 (3) 0.8099 (3) 0.1185 (11) 0.197 (5)
C3 0.2429 (3) 0.7620 (4) 0.1281 (9) 0.183 (4)
N1 0.4387 (3) 0.8802 (2) 0.0983 (10) 0.226 (5)
H1 0.4223 0.8979 0.0865 0.271*
C4 0.4097 (3) 0.8311 (3) 0.1168 (11) 0.209 (6)
C5 0.3276 (3) 0.8423 (3) 0.1157 (13) 0.217 (6)
O2 0.4277 (2) 0.7989 (2) 0.1347 (11) 0.274 (6)
C6 0.3197 (3) 0.7569 (3) 0.1298 (9) 0.173 (4)
H6 0.3356 0.7356 0.1372 0.208*
O1 0.3551 (2) 0.8934 (2) 0.1076 (9) 0.228 (5)
N2 0.2668 (2) 0.7333 (2) 0.1311 (6) 0.164 (3)
H2 0.2477 0.6986 0.1340 0.197*
C7 0.1863 (4) 0.7341 (5) 0.1360 (15) 0.244 (8)
H7 0.1667 0.6965 0.1396 0.292*
C8 0.5250 (4) 0.9194 (3) 0.1741 (16) 0.228 (8)
H8 0.5060 0.9049 0.2282 0.274*
C9 0.2438 (4) 0.8470 (4) 0.1279 (14) 0.233 (7)
H9 0.2629 0.8843 0.1202 0.280*
O3 0.6057 (3) 0.9569 (3) 0.2587 (12) 0.253 (6)
H3 0.5836 0.9407 0.2996 0.380*
C10 0.1619 (5) 0.7629 (6) 0.1383 (17) 0.270 (9)
H10 0.1243 0.7450 0.1410 0.324*
C11 0.1907 (4) 0.8204 (5) 0.1369 (16) 0.263 (9)
H11 0.1721 0.8393 0.1422 0.316*
C12 0.6673 (4) 1.0096 (4) 0.1039 (14) 0.227 (7)
C13 0.6068 (4) 0.9709 (4) 0.1014 (15) 0.220 (7)
C14 0.6792 (3) 1.0569 (4) 0.1638 (14) 0.229 (7)
H14A 0.6564 1.0445 0.2170 0.344*
H14B 0.6723 1.0818 0.1304 0.344*
H14C 0.7164 1.0747 0.1823 0.344*
C15 0.5781 (4) 0.9486 (3) 0.1736 (16) 0.228 (8)
C37 0.5243 (15) 0.9305 (18) -0.1442 (11) 0.57 (3)
H37A 0.5473 0.9689 -0.1506 0.857*
H37B 0.4974 0.9174 -0.1915 0.857*
H37C 0.5457 0.9132 -0.1493 0.857*
C17 0.5782 (4) 0.9571 (5) 0.0208 (16) 0.279 (12)
H17 0.5998 0.9664 -0.0312 0.334*
C18 0.5182 (5) 0.9296 (5) 0.0001 (12) 0.289 (10)
C19 0.6974 (4) 0.9824 (4) 0.1357 (16) 0.247 (8)
H19A 0.7322 1.0090 0.1585 0.371*
H19B 0.7020 0.9634 0.0855 0.371*
H19C 0.6774 0.9572 0.1836 0.371*
C20 0.6882 (5) 1.0244 (10) 0.007 (2) 0.336 (17)
H20A 0.6658 0.9950 -0.0336 0.504*
H20B 0.7247 1.0313 0.0039 0.504*
H20C 0.6873 1.0562 -0.0118 0.504*
C21 0.4997 (5) 0.9114 (4) 0.0947 (14) 0.209 (7)
C22 0.5057 (8) 0.9220 (8) -0.0808 (11) 0.266 (9)
C23 0.4695 (12) 0.864 (2) -0.109 (5) 0.68 (7)
H23A 0.4703 0.8408 -0.0635 1.018*
H23B 0.4818 0.8581 -0.1666 1.018*
H23C 0.4332 0.8577 -0.1161 1.018*
C24 0.4561 (6) 0.9358 (7) -0.0824 (14) 0.252 (8)
H24A 0.4709 0.9742 -0.0812 0.378*
H24B 0.4334 0.9199 -0.0298 0.378*
H24C 0.4351 0.9212 -0.1370 0.378*
C31 0.3177 (9) 0.7343 (12) 0.873 (2) 0.333 (15)
C32 0.2650 (16) 0.731 (2) 0.856 (6) 0.64 (7)
C33 0.267 (2) 0.7790 (16) 0.891 (2) 0.78 (9)
C35 0.190 (2) 0.8034 (12) 0.892 (4) 1.05 (18)
C36 0.1312 (16) 0.7838 (11) 0.889 (3) 0.325 (16)
C34 0.214 (2) 0.770 (2) 0.864 (2) 0.53 (4)
C38 0.3078 (14) 0.6793 (14) 0.898 (3) 0.40 (2)
C41 0.1040 (18) 0.8161 (9) 0.885 (2) 1.05 (7)
C42 0.077 (3) 0.846 (3) 0.884 (5) 0.73 (8)
O51 0.3333 0.6667 0.024 (2) 0.325 (13)
O52 0.152 (5) 0.937 (4) 0.186 (6) 0.97 (13)
Table X-vi: Atomic displacement parameters (Å )
11 22 33 12 13 23
U U U U U U
C1 0.058 (4) 0.076 (5) 0.449 (17) 0.027 (4) 0.016 (7) 0.001 (7)
C2 0.075 (4) 0.062 (4) 0.453 (16) 0.033 (3) -0.024 (7) -0.083 (7)
C3 0.060 (4) 0.077 (5) 0.400 (14) 0.026 (4) 0.019 (6) -0.012 (7)
N1 0.054 (3) 0.062 (3) 0.550 (16) 0.020 (3) 0.024 (6) -0.045 (6)
C4 0.058 (4) 0.059 (4) 0.501 (17) 0.022 (3) 0.005 (7) -0.063 (7)
C5 0.059 (4) 0.057 (4) 0.527 (19) 0.023 (3) -0.009 (7) -0.036 (7)
O2 0.065 (3) 0.067 (3) 0.684 (19) 0.030 (3) -0.002 (6) -0.084 (6)
C6 0.067 (4) 0.060 (4) 0.380 (13) 0.023 (3) 0.001 (6) 0.006 (6)
O1 0.067 (3) 0.059 (3) 0.555 (14) 0.029 (2) 0.057 (5) -0.008 (5)
N2 0.066 (3) 0.054 (3) 0.359 (9) 0.022 (3) 0.033 (4) 0.016 (4)
C7 0.056 (4) 0.104 (7) 0.56 (2) 0.030 (5) 0.017 (9) 0.026 (11)
C8 0.067 (5) 0.052 (4) 0.57 (3) 0.036 (4) 0.000 (10) -0.038 (8)
C9 0.061 (4) 0.092 (6) 0.54 (2) 0.032 (4) 0.034 (9) 0.023 (9)
O3 0.054 (4) 0.077 (4) 0.614 (19) 0.022 (3) 0.042 (7) 0.033 (7)
C10 0.076 (6) 0.127 (9) 0.57 (3) 0.020 (7) 0.021 (11) 0.021 (14)
C11 0.072 (5) 0.108 (7) 0.62 (3) 0.050 (5) 0.050 (11) 0.021 (12)
C12 0.059 (5) 0.100 (7) 0.52 (2) 0.036 (5) 0.049 (9) 0.004 (10)
C13 0.050 (5) 0.074 (5) 0.53 (2) 0.022 (5) 0.024 (10) -0.057
(10)
C14 0.061 (4) 0.077 (5) 0.53 (2) 0.016 (4) 0.009 (8) -0.061 (9)
C15 0.050 (5) 0.041 (4) 0.58 (3) 0.014 (4) 0.073 (11) -0.022 (8)
C37 0.55 (5) 1.09 (9) 0.138 (9) 0.46 (6) 0.021 (16) -0.21 (2)
C17 0.057 (6) 0.150 (10) 0.58 (3) 0.017 (6) 0.097 (12) -0.125
(15)
C18 0.239 (14) 0.157 (8) 0.45 (2) 0.085 (8) 0.227 (15) -0.110
(10)
C19 0.065 (4) 0.096 (6) 0.59 (3) 0.046 (4) -0.008 (9) -0.014
(10)
C20 0.072 (7) 0.26 (3) 0.63 (5) 0.053 (11) 0.022 (15) -0.10 (3)
C21 0.080 (6) 0.090 (6) 0.48 (2) 0.057 (5) 0.005 (10) -0.056 (9)
C22 0.314 (17) 0.332 (18) 0.194 (10) 0.193 (14) 0.098 (11) -0.123
(11)
C23 0.25 (4) 1.05 (18) 0.89 (11) 0.45 (8) -0.23 (6) -0.40 (12)
C24 0.136 (10) 0.189 (13) 0.384 (18) 0.046 (10) 0.038 (11) -0.106
(14)
C31 0.159 (17) 0.27 (3) 0.48 (3) 0.035 (19) 0.089 (18) 0.06 (3)
C32 0.20 (3) 0.28 (6) 1.3 (2) -0.01 (3) -0.09 (6) 0.16 (9)
C33 1.19 (18) 0.21 (3) 0.32 (3) -0.11 (6) -0.30 (6) 0.11 (3)
C35 2.0 (4) 0.083 (14) 0.53 (7) 0.12 (6) -0.40 (17) 0.00 (2)
C36 0.33 (4) 0.136 (18) 0.53 (4) 0.13 (2) -0.06 (3) -0.07 (2)
C34 0.78 (11) 0.36 (5) 0.41 (4) 0.26 (6) -0.34 (6) -0.05 (4)
C38 0.25 (3) 0.29 (3) 0.58 (5) 0.07 (2) 0.11 (3) 0.26 (4)
C41 1.81 (15) 0.26 (2) 0.64 (5) 0.19 (5) -0.35 (7) 0.34 (3)
C42 0.78 (13) 0.47 (9) 0.86 (13) 0.25 (9) 0.12 (10) 0.45 (10)
O51 0.274 (18) 0.274 (18) 0.43 (3) 0.137 (9) 0.000 0.000
O52 1.3 (4) 1.1 (3) 0.99 (16) 1.0 (3) -0.23 (16) -0.40 (15)
Table X-vii: Geometric parameters (Å, º) for (hexe)
C1—C3 1.383 (13) C12—C14 1.531 (19)
C1—C9 1.445 (14) C12—C20 1.55 (3)
C1—C5 1.453 (12) C13—C15 1.32 (2)
C2—C6 1.357 (12) C13—C17 1.40 (2)
C2—C5 1.431 (12) C37—C22 1.06 (2)
C2—C4 1.483 (11) C17—C18 1.55 (2)
C3—N2 1.332 (10) C18—C22 1.25 (2)
C3—C7 1.433 (13) C18—C21 1.51 (2)
N1—C4 1.276 (12) C22—C23 1.53 (4)
N1—C21 1.541 (15) C22—C24 1.68 (2)
C4—O2 1.311 (13) C31—C32 1.51 (4)
C5—O1 1.296 (10) C31—C38 1.53 (4)
C6—N2 1.337 (11) C32—C33 1.47 (5)
C7—C10 1.35 (2) C33—C34 1.49 (5)
C8—C15 1.342 (15) C35—C34 1.50 (4)
C8—C21 1.35 (2) C35—C36 1.51 (5)
C9—C11 1.348 (15) C36—C41 1.51 (4)
O3—C15 1.46 (2) C38—C38 1.70 (6)
C10—C11 1.45 (2) C38—C38 1.70 (6)
C12—C19 1.524 (16) C41—C42 1.45 (5)
C12—C13 1.546 (15)
C3—C1—C9 121.1 (7) C15—C13—C17 114.7 (13)
C3—C1—C5 116.8 (7) C15—C13—C12 123.4 (18)
C9—C1—C5 120.9 (8) C17—C13—C12 121.9 (16)
C6—C2—C5 118.1 (7) C13—C15—C8 124 (2)
C6—C2—C4 117.9 (7) C13—C15—O3 117.9 (11)
C5—C2—C4 123.9 (7) C8—C15—O3 117.8 (18)
N2—C3—C1 122.2 (7) C13—C17—C18 132.6 (14)
N2—C3—C7 117.1 (8) C22—C18—C21 145.1 (12)
C1—C3—C7 120.1 (8) C22—C18—C17 116.1 (12)
C4—N1—C21 126.4 (8) C21—C18—C17 96.2 (15)
N1—C4—O2 124.6 (7) C8—C21—C18 133.6 (13)
N1—C4—C2 116.8 (8) C8—C21—N1 116.1 (14)
O2—C4—C2 118.6 (8) C18—C21—N1 110.1 (15)
O1—C5—C2 122.4 (7) C37—C22—C18 139 (2)
O1—C5—C1 119.6 (7) C37—C22—C23 90 (3)
C2—C5—C1 117.8 (8) C18—C22—C23 116 (3)
N2—C6—C2 123.1 (7) C37—C22—C24 110 (2)
C6—N2—C3 120.5 (6) C18—C22—C24 100.4 (10)
C10—C7—C3 117.6 (9) C23—C22—C24 93.1 (17)
C15—C8—C21 117.5 (19) C32—C31—C38 109 (3)
C11—C9—C1 117.9 (9) C33—C32—C31 109 (5)
C11—C10—C7 122.8 (10) C32—C33—C34 102 (3)
C10—C11—C9 119.9 (9) C34—C35—C36 123 (3)
C19—C12—C13 111.8 (9) C35—C36—C41 128 (3)
C19—C12—C14 111.0 (14) C35—C34—C33 126 (4)
C13—C12—C14 109.5 (10) C31—C38—C38 155 (2)
C19—C12—C20 100.8 (14) C31—C38—C38 99 (3)
i ii
C13—C12—C20 109.1 (15) C38 —C38—C38 60.000 (18)
C14—C12—C20 114.5 (14) C42—C41—C36 178 (3)
Symmetry codes: (i) -y+1, x-y+1, z; (ii) -x+y, -x+1, z.
Characterization of Compound 1:glyceryltrimyristate
XRPD for Compound 1: glyceryltrimyristate:
An examplary XRPD pattern for Compound 1: glyceryltrimyristate shown in
Figure 30 was acquired using the Panalytical Empyrean II diffractometer.
Representative peaks for Compound 1: glyceryltrimyristate as observed in the XRPD
pattern are provided in Table X below. All peaks listed below are greater than 1% of
the maximum peak intensity.
Table X
Peak # Angle 2 θ, in degrees
(±0.2°)
1 3.5
2 6.0
3 6.8
4 7.4
8.3
6 9.2
7 9.9
8 10.9
9 12.0
12.5
11 13.2
12 13.7
13 14.9
14 16.2
16.9
16 17.6
17 18.0
18 18.5
19 19.4
20.0
21 21.2
22 22.1
23 23.2
24 24.1
25.1
26 26.4
27 27.2
28 27.7
29 28.3
29.2
31 29.7
32 31.0
36 32.7
C ssNMR for Compound 1:glyceryltrimyristate:
An examplary C ssNMR spectrum for Compound 1:glyceryltrimyristate is
shown in Figure 31. A listing of some of the C ssNMR peaks for Compound
1:glyceryltrimyristate are provided in Table Y below.
Table Y
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.1
2 171.4
3 169.8
4 165.0
155.0
6 142.9
7 139.5
8 137.2
9 134.6
133.1
11 127.3
12 126.0
13 119.9
14 117.4
112.0
16 67.0
17 63.7
18 61.4
19 35.6
DSC for Compound 1:glyceryltrimyristate:
An examplary DSC thermogram for Compound 1:glyceryltristearate is
shown in Figure 32. The thermogram of Compound 1:glyceryltrimyristate in Figure
32 has an endotherm at 59.2°C that corresponds to the melt of glyceryltrimyristate.
This event is followed by a broad exotherm at 134.4 °C that is overlapping with an
endotherm. This event is followed by an exotherm at 171.3 °C corresponding to the
crystallization of neat Compound 1. Another endotherm at 280.1°C corresponds to
the melt of a neat form of Compound 1.
Characterization of Compound 1:glyceryltrihexanoate
XRPD for Compound 1: glyceryltrihexanoate:
An examplary XRPD pattern for Compound 1: glyceryltrihexanoate
shown in Figure 33 was acquired using the Panalytical Empyrean II diffractometer .
Representative peaks for Compound 1: glyceryltrihexanoate as observed in the XRPD
pattern are provided in Table Z below. All peaks listed below are greater than 1% of
the maximum peak intensity.
Table Z
Peak # Angle 2 θ, in degrees
(±0.2°)
1 4.7
2 6.5
3 9.2
4 9.9
11.8
6 12.5
7 14.5
8 15.1
9 15.6
17.4
11 18.7
12 19.9
13 21.4
14 23.0
24.4
16 25.2
17 26.5
18 28.3
19 29.1
30.5
21 35.6
Characterization of Compound 1:glyceryltridecanoate
XRPD for Compound 1: glyceryltridecanoate:
An examplary XRPD pattern for Compound 1: glyceryltridecanoate shown
in Figure 34 was acquired using the Bruker D8 Advance diffractometer.
Representative peaks for Compound 1: glyceryltridecanoate as observed in the XRPD
pattern are provided in Table AA below. All peaks listed below are greater than 1% of
the maximum peak intensity.
Table AA
Angle 2 θ, in degrees
(±0.2°)
1 3.5
2 6.1
3 6.9
4 9.2
6 10.9
7 11.8
8 12.1
9 12.6
13.2
11 13.8
12 14.9
13 16.3
14 16.9
18.1
16 18.5
17 19.4
18 19.8
19 20.3
21.7
21 23.4
22 23.9
23 25.2
24 25.8
27.2
26 28.4
C ssNMR for Compound 1:glyceryltridecanoate:
An examplary C ssNMR spectrum for Compound 1:glyceryltridecanoate is
shown in Figure 35. A listing of some of the C ssNMR peaks for Compound
1:glyceryltridodecanoate are provided in Table AB below.
Table AB
Peak # C Chemical Shift
(± 0.1 ppm)
1 178.5
2 171.6
3 169.9
4 165.0
155.0
143.3
7 139.5
8 137.2
9 134.9
133.0
11 127.3
12 126.1
13 119.5
14 117.6
112.1
16 67.2
17 64.0
18 59.8
19 35.7
34.7
21 31.7
22 30.5
23 25.8
24 23.5
HPLC Analysis of Compound 1-Triglyceride Co-crystals
Sample Preparation
30 mg Compound 1-triglyceride co-crystal samples were weighed and
quantitatively transferred into a 100 mL amber volumetric flasks. 50ml of diluent was
added, and the sample preparation was sonicated for 15 minutes. Each sample
preparation was then shaken on a mechanical shaker for 30 minutes at 200
motion/sec. Another 40ml of diluent was added and the sample preparation was
shaken on a mechanical shaker for 30 minutes at 200 motion/sec. The Compound 1-
glyceryltrioctanoate sample preparation dissolved completely, was allowed to return
to room temperature, then diluted to volume with diluent, and mixed well. The
Compound 1-glyceryltrioleate and Compound 1-glyceryltrilinoleate sample
preparations did not dissolve completely. These two sample preparations were each
sonicated for 15 minutes and then shaken for 30 minutes at 200 motion/sec. The two
sample preparations were still not dissolved. 8 ml of acetonitrile was added to each
and the sample preparations were sonicated for 15 minutes and then shaken for 30
minutes at 200 motion/sec. The two sample preparations were still not dissolved. 1ml
of methanol was added to each and the two sample preparations were sonicated for 15
minutes and then shaken for 30 minutes at 200 motion/sec. The two sample
preparations were still not dissolved. The sample preparations were allowed to return
to room temperature, diluted to volume with methanol and mixed well. Both sample
preparations were cloudy. An aliquot of the solutions were filtered through a 0.45 µm
Whatman PVDF filter. The first 2 mL of the filtrate was discarded before collecting
in amber HPLC vials for analysis.
Sample preparations were made for the HPLC method described below.
HPLC Method
Samples were analyzed using the method parameters described below.
Mobile Phase A was 0.1% Phosphoric Acid in Water. Mobile Phase B was 0.1%
Phosphoric Acid in Acetonitrile. Table AC below shows the gradient program used.
Table AC: Gradient program for the HPLC method.
Time (min.) %A %B
0.0 80 20
7.0 40 60
9.0 40 60
9.1 0 100
12.0 0 100
12.1 80 20
16.0 80 20
The HPLC was done using a Waters Symmetry Shield RP18, 4.6 x 50 mm,
3.5 µm column (P/N 186000177) column on an Agilent 1260 HPLC instrument. The
diluent was 70:30 Acetonitrile:Water. The flow rate was 1.5 mL/minute. Column
temperature was 35 °C. The needle wash used was 90:10 (Acetonitrile: Water).
Injection volume was 10 µL. The detector wavelength was 235 nM. Data acquisition
time was 10.0 minutes. The vial temperature was ambient or 25 °C. Run time was 16
minutes. The syringe filter used was a 0.45µm PVDF Syringe Filter. Sample and
standard stability were both 2 days. Two standards of Compound 1 were prepared
and used (75.12 mg of Compound 1 in 250 mL of diluent and 75.29 mg of Compound
1 in 250 mL of diluent).
The purity was determined for each co-crystal by totaling the relative
integrated intensities of the impurity peaks and subtracting from 100%. The
Compound 1:glyceryltrioctanoate co-crystal and the Compound 1:glyceryltrioleate
co-crystal were each 99.9% (w/w). The Compound 1:glyceryltrilinoleate co-crystal
was 99.5% (w/w). The detection limit for impurities by HPLC is 0.005%.
The stoichiometry for each co-crystal was also determined from this HPLC
assay. As shown in Table AD below, the stoichiometry determined was consistent
with the results from solution state H NMR and thermogravimetric analysis.
TABLE AD
Compound 1:glyceryltrioctanoate
Compound 1 Stoichiometry Note
% w:w Compound
1:Triglyeride
Solution 1H 71.9 3.1 Compound 1 % w:w
NMR calculated based on
observed stoichiomtry
TGA weight loss 71.8 3.1 Stoichiometry calculated
based on
observed
glyceryltrioctanoate %
weight loss
HPLC Assay 72.1 3.1 Stoichiometry calculated
based on
observed Ivacaftor %w:w
Compound 1:glyceryltrioleate
Compound 1 % Stoichiometry Note
w:w Compound
1:Triglyeride
Solution 1H NMR 71.4 5.6 Compound 1 % w:w
calculated based on
observed stoichiomtry
HPLC Assay 72.4 5.9 Stoichiometry calculated
based on
observed Ivacaftor %w:w
Compound 1:glyceryltrilinoleate
Compound 1 % Stoichiometry Note
w:w Compound
1:Triglyeride
Solution 1H NMR 71.6 5.7 Compound 1 % w:w
calculated based on
observed stoichiometry
HPLC Assay 68.6 4.9 Stoichiometry calculated
based on
observed Ivacaftor %w:w
ACTIVITY ASSAYS
A. PROTOCOL 1
Assays for Detecting and Measuring ΔF508-CFTR Potentiation
Properties of Compounds
Membrane potential optical methods for assaying ΔF508-CFTR modulation
properties of compounds
The assay utilizes fluorescent voltage sensing dyes to measure changes in
membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular
Devices, Inc.) as a readout for increase in functional ΔF508-CFTR in NIH 3T3 cells.
The driving force for the response is the creation of a chloride ion gradient in
conjunction with channel activation by a single liquid addition step after the cells
have previously been treated with compounds and subsequently loaded with a voltage
sensing dye.
Identification of Potentiator Compounds
To identify potentiators of ΔF508-CFTR, a double-addition HTS assay
format was developed. This HTS assay utilizes fluorescent voltage sensing dyes to
measure changes in membrane potential on the FLIPR III as a measurement for
increase in gating (conductance) of ΔF508 CFTR in temperature-corrected ΔF508
CFTR NIH 3T3 cells. The driving force for the response is a Cl ion gradient in
conjunction with channel activation with forskolin in a single liquid addition step
using a fluorescent plate reader such as FLIPR III after the cells have previously been
treated with potentiator compounds (or DMSO vehicle control) and subsequently
loaded with a redistribution dye.
Solutions
Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl 2, MgCl 1, HEPES
, pH 7.4 with NaOH.
Chloride-free bath solution: Chloride salts in Bath Solution #1 (above) are
substituted with gluconate salts.
Cell Culture
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for
optical measurements of membrane potential. The cells are maintained at 37 ºC in 5%
CO and 90 % humidity in Dulbecco’s modified Eagle’s medium supplemented with
2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25
mM HEPES in 175 cm culture flasks. For all optical assays, the cells were seeded at
~20,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 °C before
culturing at 27 °C for 24 hrs. for the potentiator assay. For the correction assays, the
cells are cultured at 27 °C or 37 °C with and without compounds for 16 – 24 hours.
Electrophysiological Assays for assaying ΔF508-CFTR modulation
properties of compounds.
Ussing Chamber Assay
Ussing chamber experiments were performed on polarized airway epithelial
cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators
identified in the optical assays. Non-CF and CF airway epithelia were isolated from
bronchial tissue, cultured as previously described (Galietta, L.J.V., Lantero, S.,
Gazzolo, A., Sacco, O., Romano, L., Rossi, G.A., & Zegarra-Moran, O. (1998) In
vitro Cell. Dev. Biol. 34, 478-481), and plated onto Costar® Snapwell filters that
were precoated with NIH3T3-conditioned media. After four days the apical media
was removed and the cells were grown at an air liquid interface for >14 days prior to
use. This resulted in a monolayer of fully differentiated columnar cells that were
ciliated, features that are characteristic of airway epithelia. Non-CF HBE were
isolated from non-smokers that did not have any known lung disease. CF-HBE were
isolated from patients homozygous for ΔF508-CFTR.
HBE grown on Costar® Snapwell™ cell culture inserts were mounted in an
Using chamber (Physiologic Instruments, Inc., San Diego, CA), and the
transepithelial resistance and short-circuit current in the presence of a basolateral to
apical Cl- gradient (ISC) were measured using a voltage-clamp system (Department
of Bioengineering, University of Iowa, IA). Briefly, HBE were examined under
voltage-clamp recording conditions (Vhold = 0 mV) at 37 oC. The basolateral
solution contained (in mM) 145 NaCl, 0.83 K2HPO4, 3.3 KH2PO4, 1.2 MgCl2, 1.2
CaCl2, 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical
solution contained (in mM) 145 NaGluconate, 1.2 MgCl2, 1.2 CaCl2, 10 glucose, 10
HEPES (pH adjusted to 7.35 with NaOH).
Identification of Potentiator Compounds
Typical protocol utilized a basolateral to apical membrane Cl concentration
gradient. To set up this gradient, normal ringers was used on the basolateral
membrane, whereas apical NaCl was replaced by equimolar sodium gluconate
(titrated to pH 7.4 with NaOH) to give a large Cl concentration gradient across the
epithelium. Forskolin (10 μM) and all test compounds were added to the apical side
of the cell culture inserts. The efficacy of the putative ΔF508-CFTR potentiators was
compared to that of the known potentiator, genistein.
Patch-clamp Recordings
Total Cl current in ∆F508-NIH3T3 cells was monitored using the
perforated-patch recording configuration as previously described (Rae, J., Cooper, K.,
Gates, P., & Watsky, M. (1991) J. Neurosci. Methods 37, 15-26). Voltage-clamp
recordings were performed at 22 ºC using an Axopatch 200B patch-clamp amplifier
(Axon Instruments Inc., Foster City, CA). The pipette solution contained (in mM)
150 N-methyl-D-glucamine (NMDG)-Cl, 2 MgCl , 2 CaCl , 10 EGTA, 10 HEPES,
and 240 µg/mL amphotericin-B (pH adjusted to 7.35 with HCl). The extracellular
medium contained (in mM) 150 NMDG-Cl, 2 MgCl , 2 CaCl , 10 HEPES (pH
adjusted to 7.35 with HCl). Pulse generation, data acquisition, and analysis were
performed using a PC equipped with a Digidata 1320 A/D interface in conjunction
with Clampex 8 (Axon Instruments Inc.). To activate ΔF508-CFTR, 10 μM forskolin
and 20 μM genistein were added to the bath and the current-voltage relation was
monitored every 30 sec.
Identification of Potentiator Compounds
The ability of ΔF508-CFTR potentiators to increase the macroscopic ΔF508-
CFTR Cl current (IΔ ) in NIH3T3 cells stably expressing ΔF508-CFTR was also
F508
investigated using perforated-patch-recording techniques. The potentiators identified
from the optical assays evoked a dose-dependent increase in I Δ with similar
F508
potency and efficacy observed in the optical assays. In all cells examined, the
reversal potential before and during potentiator application was around -30 mV,
which is the calculated ECl (-28 mV).
Cell Culture
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for
whole-cell recordings. The cells are maintained at 37 ºC in 5% CO and 90 %
humidity in Dulbecco’s modified Eagle’s medium supplemented with 2 mM
glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25 mM
HEPES in 175 cm culture flasks. For whole-cell recordings, 2,500 - 5,000 cells were
seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C
before use to test the activity of potentiators; and incubated with or without the
correction compound at 37 °C for measuring the activity of correctors.
Single-channel recordings
Gating activity of wt-CFTR and temperature-corrected ∆F508-CFTR
expressed in NIH3T3 cells was observed using excised inside-out membrane patch
recordings as previously described (Dalemans, W., Barbry, P., Champigny, G., Jallat,
S., Dott, K., Dreyer, D., Crystal, R.G., Pavirani, A., Lecocq, J-P., Lazdunski, M.
(1991) Nature 354, 526 – 528) using an Axopatch 200B patch-clamp amplifier (Axon
Instruments Inc.). The pipette contained (in mM): 150 NMDG, 150 aspartic acid, 5
CaCl , 2 MgCl , and 10 HEPES (pH adjusted to 7.35 with Tris base). The bath
contained (in mM): 150 NMDG-Cl, 2 MgCl , 5 EGTA, 10 TES, and 14 Tris base (pH
adjusted to 7.35 with HCl). After excision, both wt- and ∆F508-CFTR were activated
by adding 1 mM Mg-ATP, 75 nM of the catalytic subunit of cAMP-dependent protein
kinase (PKA; Promega Corp. Madison, WI), and 10 mM NaF to inhibit protein
phosphatases, which prevented current rundown. The pipette potential was
maintained at 80 mV. Channel activity was analyzed from membrane patches
containing ≤ 2 active channels. The maximum number of simultaneous openings
determined the number of active channels during the course of an experiment. To
determine the single-channel current amplitude, the data recorded from 120 sec of
ΔF508-CFTR activity was filtered “off-line” at 100 Hz and then used to construct all-
point amplitude histograms that were fitted with multigaussian functions using Bio-
Patch Analysis software (Bio-Logic Comp. France). The total microscopic current
and open probability (P ) were determined from 120 sec of channel activity. The P
was determined using the Bio-Patch software or from the relationship P = I/i(N),
where I = mean current, i = single-channel current amplitude, and N = number of
active channels in patch.
Cell Culture
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for
excised-membrane patch-clamp recordings. The cells are maintained at 37 ºC in 5%
CO and 90 % humidity in Dulbecco’s modified Eagle’s medium supplemented with
2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25
mM HEPES in 175 cm culture flasks. For single channel recordings, 2,500 - 5,000
cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48
hrs at 27 °C before use.
Activity of the Compound 1
Compounds of the present disclosure are useful as modulators of ATP
binding cassette transporters. Table AD below illustrates the EC50 and relative
efficacy of certain embodiments in Table 1. In Table AE below, the following
meanings apply. EC50: “+++” means <10 uM; “++” means between 10uM to 25
uM; “+” means between 25 uM to 60uM. % Efficacy: “+” means < 25%; “++”
means between 25% to 100%; “+++” means > 100%.
TABLE AE
% Activity
Cmpd # EC50 (uM)
1 +++ ++
B. PROTOCOL 2
Assays for Detecting and Measuring ΔF508-CFTR Potentiation
Properties of Compounds
Membrane potential optical methods for assaying ΔF508-CFTR
modulation properties of compounds
The assay utilizes fluorescent voltage sensing dyes to measure changes in
membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular
Devices, Inc.) as a readout for increase in functional ΔF508-CFTR in NIH 3T3 cells.
The driving force for the response is the creation of a chloride ion gradient in
conjunction with channel activation by a single liquid addition step after the cells
have previously been treated with compounds and subsequently loaded with a voltage
sensing dye.
Identification of Potentiator Compounds
To identify potentiators of ΔF508-CFTR, a double-addition HTS assay
format was developed. This HTS assay utilizes fluorescent voltage sensing dyes to
measure changes in membrane potential on the FLIPR III as a measurement for
increase in gating (conductance) of ΔF508 CFTR in temperature-corrected ΔF508
CFTR NIH 3T3 cells. The driving force for the response is a Cl ion gradient in
conjunction with channel activation with forskolin in a single liquid addition step
using a fluorescent plate reader such as FLIPR III after the cells have previously been
treated with potentiator compounds (or DMSO vehicle control) and subsequently
loaded with a redistribution dye.
Solutions
Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl 2, MgCl 1, HEPES
, pH 7.4 with NaOH.
Chloride-free bath solution: Chloride salts in Bath Solution #1 (above) are
substituted with gluconate salts.
Cell Culture
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for
optical measurements of membrane potential. The cells are maintained at 37 ºC in 5%
CO and 90 % humidity in Dulbecco’s modified Eagle’s medium supplemented with
2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25
mM HEPES in 175 cm culture flasks. For all optical assays, the cells were seeded at
~20,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 °C before
culturing at 27 °C for 24 hrs. for the potentiator assay. For the correction assays, the
cells are cultured at 27 °C or 37 °C with and without compounds for 16 – 24 hours.
Electrophysiological Assays for assaying ΔF508-CFTR modulation
properties of compounds.
Ussing Chamber Assay
Ussing chamber experiments were performed on polarized airway epithelial
cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators
identified in the optical assays. Non-CF and CF airway epithelia were isolated from
bronchial tissue, cultured as previously described (Galietta, L.J.V., Lantero, S.,
Gazzolo, A., Sacco, O., Romano, L., Rossi, G.A., & Zegarra-Moran, O. (1998) In
vitro Cell. Dev. Biol. 34, 478-481), and plated onto Costar® Snapwell filters that
were precoated with NIH3T3-conditioned media. After four days the apical media
was removed and the cells were grown at an air liquid interface for >14 days prior to
use. This resulted in a monolayer of fully differentiated columnar cells that were
ciliated, features that are characteristic of airway epithelia. Non-CF HBE were
isolated from non-smokers that did not have any known lung disease. CF-HBE were
isolated from patients homozygous for ΔF508-CFTR.
HBE grown on Costar® Snapwell™ cell culture inserts were mounted in an
Using chamber (Physiologic Instruments, Inc., San Diego, CA), and the
transepithelial resistance and short-circuit current in the presence of a basolateral to
apical Cl gradient (I ) were measured using a voltage-clamp system (Department of
Bioengineering, University of Iowa, IA). Briefly, HBE were examined under voltage-
clamp recording conditions (V = 0 mV) at 37 C. The basolateral solution
hold
contained (in mM) 145 NaCl, 0.83 K2HPO4, 3.3 KH2PO4, 1.2 MgCl2, 1.2 CaCl2, 10
Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical solution
contained (in mM) 145 NaGluconate, 1.2 MgCl , 1.2 CaCl , 10 glucose, 10 HEPES
(pH adjusted to 7.35 with NaOH).
Identification of Potentiator Compounds
Typical protocol utilized a basolateral to apical membrane Cl concentration
gradient. To set up this gradient, normal ringers was used on the basolateral
membrane, whereas apical NaCl was replaced by equimolar sodium gluconate
(titrated to pH 7.4 with NaOH) to give a large Cl concentration gradient across the
epithelium. Forskolin (10 μM) and all test compounds were added to the apical side
of the cell culture inserts. The efficacy of the putative ΔF508-CFTR potentiators was
compared to that of the known potentiator, genistein.
Patch-clamp Recordings
Total Cl current in ∆F508-NIH3T3 cells was monitored using the
perforated-patch recording configuration as previously described (Rae, J., Cooper, K.,
Gates, P., & Watsky, M. (1991) J. Neurosci. Methods 37, 15-26). Voltage-clamp
recordings were performed at 22 ºC using an Axopatch 200B patch-clamp amplifier
(Axon Instruments Inc., Foster City, CA). The pipette solution contained (in mM)
150 N-methyl-D-glucamine (NMDG)-Cl, 2 MgCl , 2 CaCl , 10 EGTA, 10 HEPES,
and 240 µg/mL amphotericin-B (pH adjusted to 7.35 with HCl). The extracellular
medium contained (in mM) 150 NMDG-Cl, 2 MgCl , 2 CaCl , 10 HEPES (pH
adjusted to 7.35 with HCl). Pulse generation, data acquisition, and analysis were
performed using a PC equipped with a Digidata 1320 A/D interface in conjunction
with Clampex 8 (Axon Instruments Inc.). To activate ΔF508-CFTR, 10 μM forskolin
and 20 μM genistein were added to the bath and the current-voltage relation was
monitored every 30 sec.
Identification of Potentiator Compounds
The ability of ΔF508-CFTR potentiators to increase the macroscopic ΔF508-
CFTR Cl current (IΔF508) in NIH3T3 cells stably expressing ΔF508-CFTR was also
investigated using perforated-patch-recording techniques. The potentiators identified
from the optical assays evoked a dose-dependent increase in I Δ with similar
F508
potency and efficacy observed in the optical assays. In all cells examined, the
reversal potential before and during potentiator application was around -30 mV,
which is the calculated E (-28 mV).
Cell Culture
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for
whole-cell recordings. The cells are maintained at 37 ºC in 5% CO and 90 %
humidity in Dulbecco’s modified Eagle’s medium supplemented with 2 mM
glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25 mM
HEPES in 175 cm culture flasks. For whole-cell recordings, 2,500 - 5,000 cells were
seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C
before use to test the activity of potentiators; and incubated with or without the
correction compound at 37 °C for measuring the activity of correctors.
Single-channel recordings
Gating activity of wt-CFTR and temperature-corrected ∆F508-CFTR
expressed in NIH3T3 cells was observed using excised inside-out membrane patch
recordings as previously described (Dalemans, W., Barbry, P., Champigny, G., Jallat,
S., Dott, K., Dreyer, D., Crystal, R.G., Pavirani, A., Lecocq, J-P., Lazdunski, M.
(1991) Nature 354, 526 – 528) using an Axopatch 200B patch-clamp amplifier (Axon
Instruments Inc.). The pipette contained (in mM): 150 NMDG, 150 aspartic acid, 5
CaCl2, 2 MgCl2, and 10 HEPES (pH adjusted to 7.35 with Tris base). The bath
contained (in mM): 150 NMDG-Cl, 2 MgCl , 5 EGTA, 10 TES, and 14 Tris base (pH
adjusted to 7.35 with HCl). After excision, both wt- and ∆F508-CFTR were activated
by adding 1 mM Mg-ATP, 75 nM of the catalytic subunit of cAMP-dependent protein
kinase (PKA; Promega Corp. Madison, WI), and 10 mM NaF to inhibit protein
phosphatases, which prevented current rundown. The pipette potential was
maintained at 80 mV. Channel activity was analyzed from membrane patches
containing ≤ 2 active channels. The maximum number of simultaneous openings
determined the number of active channels during the course of an experiment. To
determine the single-channel current amplitude, the data recorded from 120 sec of
ΔF508-CFTR activity was filtered “off-line” at 100 Hz and then used to construct all-
point amplitude histograms that were fitted with multigaussian functions using Bio-
Patch Analysis software (Bio-Logic Comp. France). The total microscopic current
and open probability (P ) were determined from 120 sec of channel activity. The P
was determined using the Bio-Patch software or from the relationship P = I/i(N),
where I = mean current, i = single-channel current amplitude, and N = number of
active channels in patch.
Cell Culture
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for
excised-membrane patch-clamp recordings. The cells are maintained at 37 ºC in 5%
CO and 90 % humidity in Dulbecco’s modified Eagle’s medium supplemented with
2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25
mM HEPES in 175 cm culture flasks. For single channel recordings, 2,500 - 5,000
cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48
hrs at 27 °C before use.
DISSOLUTION
Dissolution in fed intestinal fluid (FeSSIF)
Dissolution tests of Compound 1 co-crystals were run in 50ml amber bottles
placed in jacketed vessels. The temperature of the jacketed vessel was controlled by
an Iso Temp 360 water bath/chiller and set to 37°C. Twenty milliliters of simulated
fed intestinal fluids were placed in the bottles and allowed to equilibrate to 37°C for
one hour while stirring at 125 rpm. Pre-weighed amounts (See Table AD, target
concentration of Compound 1 ~ 1mg/ml) of Compound 1:triglyceride co-crystal
were then added to each bottle and allowed to stir at 37°C for the duration of the
dissolution study. One microliter samples were collected at selected time points (5
and 30 minutes, and 1, 2, 3, 4, 6, 16, and 24 hours). The samples were filtered using
Millex®-LH 0.45 µm PTFE syringe filters and analyzed by HPLC for concentration
levels.
Dissolution tests of Compound 1 SDD and Compound 1 amorphous were
run in a Varian VK700 dissolution system. The temperature of the dissolution bath
was controlled and set to 37°C. Five hundred milliliters of simulated fed intestinal
fluids were placed in the dissolution vessels and allowed to equilibrate to 37°C while
stirring. Pre-weighed amounts (target concentration of Compound 1 ~ 1mg/mL) of
Compound 1 were then added to each vessel and allowed to stir at 37°C for the
duration of the dissolution study. Three milliliter samples were collected at selected
time points (0.5, 1, 1.5, 3, 6, 9, 12, 18, 24, 48 hours). The samples were filtered using
Whatman 25mm with 0.45 µm PTFE syringe filters and analyzed by HPLC for
concentration levels.
Table AF: Weights of Compound added to each vessel for dissolution
Weight of Compound
experiment # 1:triglyceride co-
crystal [mg]
1 31.9
2 31.6
3 32.0
4 33.1
32.5
6 31.2
7 30.2
8 32.0
9 34.1
Figure 36 shows the comparison of dissolution profiles up to 24 hours of
Compound 1:glyceryltrioctanoate, Compound 1:glyceryltrioleate and Compound
1:glyceryltrilinoleate with amorphous Compound 1 and Compound 1 SDD in FeSSIF.
Solid materials isolated from the mixture of infant formula and
amorphous Compound 1
Abbot Iron fortified infant formula was mixed with amorphous Compound 1
at approximate 7% w/v solids ratio (i.e., 7g of amorphous Compound 1 in 100 ml of
reconstituted formula). The suspension was slurried at ambient conditions and solids
were isolated by vacuum filtration. The recovered solids were air dried for at least 1
hour prior to analysis.
Figure 37 shows examplary low angle XRPD patterns of co-crystals of
Compound 1 with different pure triglycerides and solid materials isolated from the
mixture of infant formula and Compound 1. Based on the data shown in Figure 37,
the solid materials isolated from the mixture of infant formula and Compound 1 may
consist either of a mixture of different cocrystals of Compound 1:triglycerides or a
cocrystal of Compound 1 with a range of triglycerides in the crystal structure.
In addition, based on aromatic Compound 1 signal intensity in 13C CPMAS
spectra, an average amount of 22% of Compound 1 was present in the form of the
solid materials isolated from the mixture of infant formula during contacts ranging
from 1 hour to 24 hours.
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, or such sources of
information, 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.
Claims (21)
1. A pharmaceutical composition comprising a co-crystal of Compound 1 and only one triglyceride, wherein the triglyceride is chosen from the following structural formula: R O O R wherein R , R , and R are independently C aliphatic, 1 2 3 1-29 and wherein Compound 1 is represented by the following structural formula: and wherein the pharmaceutical composition is a solid formulated for oral administration.
2. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
3. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ± 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.0, and 23.8.
4. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having a C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the following positions: 178.6, 155.0, and 119.4.
5. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having a C ssNMR spectrum with characteristic peaks expressed in ppm ± 0.1 at the following positions: 178.6, 155.0, 130.5, and 119.4.
6. The pharmaceutical composition of any one of claims 1-5, wherein the stoichiometry of Compound 1 to the triglyceride in the co-crystal is 3 to 1.
7. The pharmaceutical composition of any one of claim 1-5, wherein the stoichiometry of Compound 1 to the triglyceride in the co-crystal is 6 to 1.
8. The pharmaceutical composition of any one of claims 1-7, wherein Compound 1 forms a hexamer in the co-crystal and further wherein R1, R2, and R are independently C aliphatic. 3 7-29
9. The pharmaceutical composition of any one of claims 1-8, wherein the co- crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is maintained for at least 10 hours.
10. The pharmaceutical composition of any one of claims 1-8, wherein the triglyceride is chosen from: glyceryl trioleate, glyceryl tristearate, glycerol tridecanoate, glycerol trihexanoate, glyceryl tritridecanoate, glycerol trioctanoate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tributyrate, glyceryl trilinoleate, glyceryl tridodecanoate, glyceryl decanoate, glyceryl tripalmitoleate, glycerol trierucate, glyceryl tripropionate, palmitodiolein, triarachidonin, glyceryl trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cisdocosenoate), glyceryl tripetroselinate, glyceryl tribehenate, glyceryl trielaidate, and triacetin.
11. A pharmaceutical composition comprising a therapeutically effective amount of Compound 1 and a pharmaceutically acceptable carrier or excipient, wherein Compound 1 is represented by the following structural formula: , and further wherein at least 30% of Compound 1 is present as a co-crystal comprising Compound 1 and a triglyceride, wherein the triglyceride is chosen from the following structural formula: wherein R , R , and R are independently C aliphatic, and wherein 1 2 3 1-29 the pharmaceutical composition is a solid formulated for oral administration.
12. The pharmaceutical composition according to claim 11, further comprising an additional therapeutic agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1, or a nutritional agent, or combinations thereof.
13. The pharmaceutical composition according to claim 12, wherein the additional therapeutic agent is a CFTR modulator other than Compound 1.
14. The pharmaceutical composition according to claim 13, wherein the CFTR modulator is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido)methylpyridinyl)benzoic acid or (R)(2,2- difluorobenzo[d][1,3]dioxolyl)-N-(1-(2,3-dihydroxypropyl)fluoro(1- hydroxymethylpropanyl)-1H-indolyl)cyclopropanecarboxamide.
15. The pharmaceutical composition according to any one of claims 1-14, wherein the solid formulated for oral administration is a capsule, a tablet, a pill, a powder, or a granule.
16. Use of a co-crystal of Compound 1 and only one triglyceride, wherein the triglyceride is chosen from the following structural formula: wherein R1, R2, and R3 are independently C1-29 aliphatic, and wherein Compound 1 is represented by the following structural formula: in the manufacture of a medicament for treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, and wherein the medicament is a solid formulated for oral administration.
17. The use according to claim 16, wherein the disease is cystic fibrosis.
18. The use according to any one of claims 16 and 17, wherein the medicament is formulated for co-administration with one or more additional therapeutic agents.
19. The use according claim 18, wherein the additional therapeutic agent is (3-(6- (1-(2,2-difluorobenzo[d][1,3]dioxolyl) cyclopropanecarboxamido) methylpyridinyl)benzoic acid or (R)(2,2-difluorobenzo[d][1,3]dioxol yl)-N-(1-(2,3-dihydroxypropyl)fluoro(1-hydroxymethylpropan yl)-1H-indolyl)cyclopropanecarboxamide.
20. The use according to claim 19, wherein the additional therapeutic agent is formulated for administration concurrently with, prior to, or subsequent to the medicament.
21. A method of preparing a co-crystal comprising Compound 1 and a triglyceride, wherein Compound 1 is represented by the following structural formula: and wherein the triglyceride is chosen from the following structural formula: R O O R wherein R , R , and R are independently C aliphatic; 1 2 3 1-29 comprising the steps of: (a) preparing a mixture comprising Compound 1 and the triglyceride ; and
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PCT/US2015/054577 WO2016057730A1 (en) | 2014-10-07 | 2015-10-07 | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
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