NZ621872B2 - Formulations based on solid dispersions - Google Patents
Formulations based on solid dispersions Download PDFInfo
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- NZ621872B2 NZ621872B2 NZ621872A NZ62187212A NZ621872B2 NZ 621872 B2 NZ621872 B2 NZ 621872B2 NZ 621872 A NZ621872 A NZ 621872A NZ 62187212 A NZ62187212 A NZ 62187212A NZ 621872 B2 NZ621872 B2 NZ 621872B2
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- active agent
- solid dispersion
- moieties
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The present disclosure relates to formulations comprising a solid dispersion product of an active agent having at least one of a hydrogen bond donor moiety (e.g. ibuprofen, fenofibric acid or naproxen) and a proton donor moiety and a pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymer, and to methods for preparing such formulations. alkylene glycol) graft copolymer, and to methods for preparing such formulations.
Description
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Formulations based on solid dispersions
The present invention relates to formulations comprising a solid dispersion product of
an active agent having at least one hydrogen bond donor moiety or proton donor moie-
ty and a pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkylene
glycol) graft copolymer, and methods for preparing such formulations.
Pharmaceutical scientists increasingly face the challenge of delivering poorly water
soluble drugs. To meet this challenge, attempts have been made to use amorphous
solids in place of crystals in pharmaceutical formulations. Amorphous solids are pre
ferred physical forms because they dissolve more rapidly than crystalline solids when
contacted with a liquid medium such as gastric fluid. The ease of dissolution may be
attributed at least in part to the fact that the energy required for dissolution of an amor
phous drug is less than that required for the dissolution of a crystalline or microcrystal-
line solid phase.
Provisions must be made to stabilize amorphous drugs and counteract their tendency
to undergo physical and chemical changes. One way of stabilizing the amorphous state
of a drug involves forming solid solutions of the drug in polymeric matrices.
Water-soluble or water-dispersible polyvinyllactam polyvinylacetate poly(alkylene gly
col) graft copolymers have been reported to be able to form solid dispersions with
drugs, see and . Such graft copolymers form flow
able powders that can easily be mixed with liquid or solid active agents and processed
by melt extrusion. In particular polyvinylcaprolactam polyvinylacetate poly(ethylene
glycol) graft copolymer has shown excellent extrudability and easy processability. Poly
vinyllactam polyvinylacetate poly(alkylene glycol) graft copolymers can provide trans
parent and clear solid dispersion products that are stable and resistant to recrystalliza
tion of the active agent dispersed therein. Moreover, in many cases such graft copoly-
mers can improve solubility and bioavailability of poorly soluble drugs when used in
solid dispersions.
Nevertheless, it has been observed by the present inventors that with certain active
agents polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymers form
solid dispersions with only low dispersibility in aqueous media which impairs release
and bioavailability of the dispersed active agent. This particularly applies to active agents
having hydrogen bond donor moieties or proton donor moieties. It is believed that the
polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymer acts as a hydrogen bond
acceptor which forms strong hydrogen bonds to the dispersed active agent.
A major aim of the present invention is to provide desired release profiles of active agents
having hydrogen bond donor moieties or proton donor moieties from their solid dispersion
products with polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymers.
Surprisingly, it has now been found that this problem can be solved by incorporating an pH
modifier into the solid dispersion product.
In one aspect, the present invention provides use of a pharmaceutically acceptable pH modifier
for increasing the dispersion rate of a solid dispersion product in an aqueous medium
wherein the solid dispersion product comprises
(a) an active agent having at least one of a hydrogen bond donor moiety and a proton donor
moiety,
(b) a pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkyleneglycol)
graft copolymer, and
(c) a pharmaceutically acceptable pH modifier;
wherein the active agent is selected from the group consisting of pharmaceutically active agents,
cosmetically active agents and nutritional supplements, and is a compound with a solubility in
water at 25°C and pH 7.0 of 0.01 g/100 ml or less.
The invention also provides a formulation comprising a solid dispersion product comprising
formulation comprising a solid dispersion product comprising
(a) an active agent having at least one of a hydrogen bond donor moiety and a proton donor
moiety,
(b) a pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkylene glycol)
graft copolymer, and
(c) a pharmaceutically acceptable pH modifier.
AH26(10387204_1):JIN
The invention further provides a method for producing a formulation as described herein,
wherein an active agent having at least one hydrogen bond donor moiety or proton donor
moiety, a pharmaceutically acceptable pH modifier and a pharmaceutically acceptable
polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymer are intimately blended.
The term "pharmaceutically acceptable", as used herein, refers to a compound that does not
cause acute toxicity when the formulation of the invention comprising it is administered in an
amount that is required for medical or cosmetic treatment or medical prophylaxis, or that is
taken up by consumption of the maximum recommended intake of a nutritional product
comprising the formulation of the invention. Expediently, all components of the formulation of
the present invention are pharmaceutically acceptable.
AH26(10387204_1):JIN
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As used herein, the term "pH modifier" refers to compounds capable of creating an
alkaline ("alkaline pH modifier") or acidic ("acidic pH modifier") environment when dis
solved in water.
The term "hydrogen bond donor moiety", as used herein, refers to a moiety that com
prises a hydrogen atom attached to a relatively electronegative atom, such as an oxy
gen atom or a nitrogen atom, and does not dissociate (release a proton) in basic,
aqueous solutions.
Exemplary hydrogen bond donor moieties are selected from primary amino, secondary
amino, hydroxy, carbamoyl, thiocarbamoyl, sulfamoyl, sulfinamoyl and ureido.
The term "proton donor moiety", as used herein refers to a moiety that comprises an
acidic hydrogen atom and is able to dissociate in a basic, aqueous solution releasing a
proton. Preferably, the proton donor moieties of the active agents used in the present
invention have pKa values from 3.0 to 5.5, for example from 4.0 to 5.0.
The proton donor moiety may be an organic acid moiety, wherein the acidic hydrogen
is bound to a heteroatom such as oxygen or nitrogen. Examples of such proton donor
moieties include carboxy, sulfo and sulfino; carboxy being particularly preferred.
Alternatively, the proton donor moiety may be a CH-acidic moiety. The acidic hydrogen
atom in CH-acidic moieties is bound to a carbon atom adjacent, i.e. in alpha position, to
a strongly electron withdrawing group, such as a carbonyl (e.g., in an ester, ketone or
aldehyde), sulfonyl, cyano, trifluoromethyl or nitro group, which exerts an inductive ef
fect that polarises the bond between the alpha-carbon atom and the thus acidic hydro
gen atom. CH-acidic moieties include moieties, which, when deprotonized, form reso
nance-stabilized anions.
In preferred embodiments, the active agent has at least one carboxy group or CH
acidic moiety.
In one embodiment of the invention, the active agent is a non-ionic compound.
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In particular, the active agent(s) comprised in solid dispersion product described herein
may be selected from pharmaceutically active agents, cosmetically active agents and
nutritional supplements.
The invention is particularly useful for water-insoluble or poorly water-soluble (or "lipo
philic") compounds. Compounds are considered water-insoluble or poorly water-soluble
when their solubility in water at 25°C (at pH 7.0) is 1 g/1 00 ml or less, in particular
when it is 0.1 g/1 00 ml, 0.05 g/1 00 ml or even 0.01 g/1 00 ml, or less.
Examples of pharmaceutically active agents according to the invention include, but are
not limited to:
(RS)(4-(2-methylpropyl)phenyl)propanoic acid [ibuprofen],
2-{4-[(4-chlorophenyl)carbonyl]phenoxy}methylpropanoic acid [fenofibric acid],
(2$)(6-methoxynaphthalenyl) propanoic acid [naproxen]
and stereochemically isomeric forms thereof.
The term "stereochemically isomeric forms" defines all possible stereoisomeric forms
which the active ingredients may possess. In particular, stereogenic centers may have
the R- or S-configuration and active ingredients containing one or more double bonds
may have the E- or Z-configuration.
The solid dispersion product described herein may comprise from about 1 up to
60 wt%, for example up to 40 wt%, up to 30 wt%, up to 20 wt%, or from about 1 up to
about 10 wt%, of active agent(s) relative to the total weight of the product.
The pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkylene glycol)
graft copolymer used in the solid dispersion product described herein is a thermoplastic
polymer capable to act as a solid meltable solvent. It forms a matrix for dispersion, and
in particular for dissolution, of the active agent(s) and the pH modifier(s). Preferably,
said polymer is at least partly soluble or swellable in aqueous media, expediently under
the conditions of use, in particular under physiological conditions in the digestive tract if
the formulation is intended for oral administration. Most preferably, said polymer is a
water-soluble polymer.
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The term "graft copolymer" refers to a copolymer in which chains of a first polymer are
grafted onto a second polymer chain. In other words, a graft copolymer has polymer
chains of one kind "growing out" of the sides of polymer chains with a different chemi
cal composition.
The polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymer used in the
solid dispersion product described is a copolymer, wherein chains of an N
vinyllactam/vinylacetate copolymer grow out of the sides of polyalkylene glycol chains.
Method of producing such graft copolymers are generally known in the art. They are
obtainable by polymerization of N-vinyllactam and vinylacetate in the presence of an
poly(alkylene glycol). Polymerization is preferably initiated by free radicals, and is pref
erably performed in solution in non-aqueous organic solvents or mixtures of non
aqueous and aqueous solvents. Suitable methods for producing polyvinyllactam poly-
vinylacetate poly(alkylene glycol) graft copolymer useful for the present invention are
described, for example, in and .
The pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkylene glycol)
graft copolymer used in the solid dispersion product described herein comprises
(i) 10 to 50 wt% poly(alkylene glycol) moieties,
(ii) 30 to 80 wt% N-vinyllactam moieties, and
(iii) 1 0 to 50 wt% vinyl acetate moieties.
Preferably, said graft copolymer comprises
(i) 10 to 35 wt% poly(alkylene glycol) moieties,
(ii) 30 to 70 wt% N-vinyllactam moieties, and
(iii) 15 to 35 wt% vinyl acetate moieties.
More preferably, said graft copolymer comprises
(i) 10 to 30 wt% poly(alkylene glycol) moieties,
(ii) 40 to 60 wt% N-vinyllactam moieties, and
(iii) 15 to 35 wt% vinyl acetate moieties.
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It is particularly preferred that said graft copolymer comprises
(i) 10 to 20 wt% poly(alkylene glycol) moieties,
(ii) 50 to 60 wt% N-vinyllactam moieties, and
(iii) 25 to 35 wt% vinyl acetate moieties.
In each case the sum of (i), (ii) and (iii) makes up at least 95 wt%, at least 99 wt% and
preferably 100 wt% of the total weight of the polyvinyllactam polyvinylacetate
poly(alkylene glycol) graft copolymer.
The N-vinyllactam moieties of the graft copolymer may be N-vinylcaprolactam or N
vinylpyrrolidon moieties or mixtures thereof, and preferably are N-vinylcaprolactam
moieties.
Poly(alkylene glycol) constitutes the backbone of the graft copolymer. Poly(alkylene
glycols) having a number average molecular weight of from 1 ,000 to 100,000, from
1 ,500 to 35,000, or in particular from 1 ,500 to 10,000 are preferably used as grafting
base. The molecular weights are determined based on the hydroxyl value determined
according to DIN 53240. The alkyl moiety of the poly(alkylene glycol) may be selected
from branched or linear c1 to c22 alkyl moieties, in particular c1 to c18 alkyl moieties
such as methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl,
tridecyl and octadecyl. For example, the poly(alkylene glycol) is selected from
poly(ethylene glycols); poly(propylene glycols); polytetrahydrofurans; poly(butylene
glycols) obtained from 2-ethyloxirane or 2,3-dimethyloxirane; copolymers obtained of
ethylene oxide, propylene oxide and/or butylene oxides such as poly(ethylene glycol)
poly(propylene glycol) block copolymers; or mixtures thereof. Preferably, the
poly(alkylene glycol) is selected from poly(ethylene glycols) and mixtures thereof.
The graft copolymer used according to the invention suitably has a K value according
to Fikentscher of from 10 to 60, preferably from 15 to 40 (determined in a 1 wt% solu
tion in ethanol at 31-41 °C).
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In one embodiment of the invention, the polyvinyllactam polyvinylacetate poly(alkylene
glycol) graft copolymer is a polyvinylcaprolactam polyvinylacetate poly(ethylene glycol)
graft copolymer.
In a preferred embodiment of the invention, the polyvinyllactam polyvinylacetate
poly(alkylene glycol) graft copolymer is a polyvinylcaprolactam polyvinylacetate
poly( ethylene glycol) graft copolymer having a number average molecular weight de
termined by gel permeation chromatography in the range of 90,000 to 140,000 and a
glass transitions temperature of 70°C such as Soluplus® (available from BASF AG,
Ludwigshafen, Germany).
The solid dispersion product described herein comprises at least one pharmaceutically
acceptable pH modifier; for example from 0.5 to 20 wt%, from 0.5 to 10 wt% or from 1
to 6 wt% pH modifier(s) per total weight of the solid dispersion product.
Preferably, the pH modifier used in the present invention is a water-soluble compound
that is solid at ambient temperature.
According to one embodiment of the invention, the pharmaceutically acceptable pH
modifier is an acidic pH modifier. Such acidic pH modifiers include pharmaceutically
acceptable inorganic acids, e.g. sulfamic acid, and pharmaceutically acceptable organ
ic acids, e.g. mono-, di- or polybasic carboxylic acids and mono-, di- or poly-sulfonic
acids, as well as acidic salts thereof, e.g. acidic ammonium salts, acidic alkali metal
salts and acidic alkaline earth metal salts of organic or inorganic acids.
Pharmaceutically acceptable carboxylic acids useful as pH modifiers for the present
invention include aliphatic mono-, di- and tri-carboxylic acids, e.g. such having from 2
to 8 carbon atoms and in particular such having from 4 to 6 carbon atoms. Said car
boxylic acids may be saturated or unsatured. Examples of suitable mono-carboxylic
acids include sorbic acid, gluconic acid, lactic acid, glycolic acid and ascorbic acid. Ex
amples of suitable di-carboxylic acids include adipic acid, malonic acid, succinic acid,
glutaric acid, maleic acid, fumaric acid, malic acid, tartaric acid, tartronic acid, mucic
acid, glutamic acid and aspartic acid. Examples of suitable tri-carboxylic acids include
citric acid.
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In particular embodiments of the invention, the acidic pH modifier is citric acid (C6Ha07)
or ascorbic acid (CGHaOG).
According to another embodiment of the invention, the pharmaceutically acceptable pH
modifier is an alkaline pH modifier. Examples of such alkaline pH modifiers include
pharmaceutically acceptable basic salts of organic acids and inorganic acids, basic
amino acids, metal oxides and metal hydroxides.
Suitable pharmaceutically acceptable basic salts of organic acids include basic alkali
1 0 metal salts and basic alkaline earth metal salts of organic acids. Said organic acids
may be the organic acids which are described herein as acidic pH modifiers.
Suitable pharmaceutically acceptable salts of inorganic acids include basic alkaline
metal salts and alkaline earth metal salts of inorganic acids, and in particular basic
salts of phosphoric acid or carbonic acid. For example, said salt may be selected from
sodium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydro
gen carbonate, sodium hydrogen phosphate, and magnesium carbonate.
Suitable pharmaceutically acceptable metal oxides and metal hydroxides include basic
alkaline metal oxides and alkaline earth metal oxides, or alkaline metal hydroxides and
alkaline earth metal hydroxides, respectively. Examples of such compounds are mag
nesium oxide and magnesium hydroxide.
Suitable pharmaceutically acceptable basic amino acids include arginine and lysine,
and basic salts thereof.
In particular embodiments of the invention the alkaline pH modifier is trisodium citrate
(Na3C6H507), magnesium oxide (MgO) or sodium carbonate (Na2C03).
The solid dispersion product described herein comprises a matrix of at least one graft
copolymer (b), wherein at least one active agent (a) and at least one pH modifier (c)
are homogeneously distributed. Preferably, the sum of components (a), (b) and (c)
makes up at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, at least
99 wt%, and most preferably 100 wt% of the solid dispersion product.
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Various additives may be included in the formulation of the invention, for example lubri
cants, fillers, disintegrants, preservatives or stabilizers such as antioxidants, light stabi
lizers, radical scavengers and stabilizers against microbial attack, dyes such as azo
dyes, organic or inorganic pigments such as iron oxides or titanium dioxide, or dyes of
natural origin, as well as compounds which alter or mask flavor and/or odor of the for
mulation such as sweeteners, flavorings and odorants.
The matrix of the solid dispersion product is formed by the pharmaceutically acceptable
polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymer. It is particularly
preferred that the active agent(s) in the solid dispersion product is/are present in an
essentially non-crystalline state. This encompasses a state wherein essentially amor
phous domains of active agent(s) are interspersed in the matrix, and a state wherein
the active agent(s) are molecularly dispersed in the matrix. When said dispersion of the
active agent(s) in the polymer phase is such that the system of active agent and poly-
mer is chemically and physically uniform or homogeneous throughout, such a solid
dispersion will be called a "solid solution" or a "molecular dispersion". The state of mo
lecular dispersion corresponds to the maximum possible homogenization of the active
agent in the polymer phase.
Known analytical methods can be used to investigate the state of such solid disper
sions, for example differential scanning calorimetry (DSC) or wide angle X-ray scatter
ing measurements (WAXS measurements). The DSC analytical measurement of an
essentially non-crystalline state lacks the melting peak which occurs with the crystalline
pure substance and is usually endothermic. Another possibility for identifying an essen-
tially non-crystalline state is the reduction in intensity and/or absence of typical X-ray
diffraction signals in the WAXS analysis.
A variety of methods for producing solid dispersions that can be applied for producing
the solid dispersion product described herein are known in the art.
solid dispersion product can be produced by blending at least one active agent
having at least one hydrogen atom bound to an oxygen or a nitrogen atom, at least one
pharmaceutically acceptable pharmaceutically acceptable pH modifier and at least one
pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkylene glycol) graft
copolymer; heating the blend to obtain a homogeneous melt; and allowing the melt to
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solidify to obtain a solid dispersion product. The terms "melt" and "melting" should be
interpreted broadly. For the purposes herein, these terms not only mean the alteration
from a solid state to a liquid state, but can also refer to a transition to a glassy state or
a rubbery state, and in which it is possible for one component of the mixture to get em-
bedded more or less homogeneously into the other. In particular cases, one compo
nent will melt and the other component(s) will dissolve in the melt, thus forming a solu
tion, which, upon cooling, may form a solid dispersion having advantageous dissolution
properties. Blending and heating are conveniently performed in a mixer or kneader
which is jacketed for heating.
A preferred method for producing the formulation of present invention comprises:
(a) blending the active agent(s); the pH modifier(s) and the graft copolymer(s);
(b) heating the blend to obtain a homogeneous melt;
(c) forcing the thus obtained melt through one or more nozzles; and
(d) allowing the melt to solidify to obtain a solid dispersion product.
Steps a) to c) may be performed in one or more than one apparatus suitable for this
purpose, such as an extruder or kneader extruder. Preferably, the blend is subjected to
a mixing action in a mixing section of the extruder.
Extruders are known per se. An extruder comprises a housing or barrel divided into
several sections in a longitudinal direction. On the upstream side of the extruder, an
opening is provided for feeding the active agent(s), the pH modifier(s) and the graft
copolymer(s), and any further components such as the additives described herein.
Usually, a hopper is placed on this opening so that the ingredients, usually in the form
of powders, can be easily fed into the barrel of the extruder. The barrel ends in convey
ing direction in a die, where the dispersion is expelled.
The extruder comprises at least one rotating shaft. Alternatively, it may comprise two or
up to six rotating shafts. The shafts may be co-rotating or counter-rotating. Processing
elements disposed on adjacent shafts closely intermesh.
Each shaft carries a plurality of processing elements disposed axially one behind the
other. The processing elements define a feeding and conveying section, at least one
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mixing section, and a discharging section. The feeding and conveying section is posi
tioned farthest upstream, close to the hopper of the extruder, the at least one mixing
section is positioned downstream of the feeding and conveying section, and the dis
charging section is positioned farthest downstream, close to the discharge opening of
the extruder. The term "downstream" as used herein, refers to direction in which the
material is being conveyed in the extruder, i.e. the conveying direction.
The processing elements of the feeding and conveying section as well as the discharg
ing section are formed by screw-type elements. Preferably, these screw type elements
form an endless screw having the feed direction and a uniform pitch flight. Thus, in the
feeding and conveying section the powder is fed into the extruder and conveyed in the
downstream direction.
In the mixing section(s) the material to be processed is homogenized by mixing or
kneading. Paddle means or kneading blocks have conventionally been employed in
kneading and plasticizing pharmaceutical mixtures. These kneading blocks consist of
cam disks mutually offset at an angle in a peripheral direction. The cam disks have
abutting faces that are perpendicular to the general conveying direction in the extruder.
Alternatively, the mixing section(s) are defined by processing element(s) that com-
prise(s) a mixing element that is derived from a screw type element. A mixing element
"being derived from a screw type element" is intended to mean an element whose
basic shape is that of a screw element, but which has been modified such that it exerts
a compounding or mixing effect in addition to a conveying effect. The underlying screw
type element may have a positive-flight (positive-feed, "right-handed") screw element,
may have a reverse-flight (negative-feed, "left-handed") screw element or a combina
tion thereof. A preferred mixing element has a plurality of concentric ring portions
formed by grooves turned into a screw type element. Therefore, the mixing element
has a continuous screw flight, which is interrupted only by turned grooves with ring por
tions. Advantageously, the mixing element comprises screw portions between the ring
portions which first cause a pressure buildup that forces the substance through the
annular gap between the extruder housing and the ring portions with shearing action
and elongation; the pressure is then reduced again.
The extruder shaft may further comprise one or more than one reverse-flight section(s),
preferably arranged after the (last) mixing section and defined by reverse-flight ele-
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ments. A reverse-flight element has a screw with a reverse-flight relative to the screw
type elements which may be arranged in the feeding and conveying section which de
fine the general conveying direction of the extruder. Thus, the reverse-flight element
convey the material in an opposite direction relative to the general conveying direction
of the extruder and serves to create sufficient back-pressure to allow for a desired de
gree of mixing and/or homogenization. The reverse-flight element is designed to stow
the material conveyed in the extruder. Therefore it may also be called a back-pressure
element.
The substances which are fed to the extruder are melted in order to homogenize the
melt and to disperse or, preferably, dissolve the active agent in the matrix efficiently.
"Melting" means transition into a liquid or rubbery state in which it is possible for one
component to be homogeneously embedded in the other. Melting usually involves
heating above the softening point of the polymer. Usually, the maximum melt tempera-
ture is in the range of from 50 to 260°C, for example from 1 00 to 190°C, and is prefer
ably not more to 160°C, e.g. not more than 140°C, or not more than 120°C. The maxi
mum melt temperature that are optimal for forming the solid dispersion product depend
on the composition of the mixture to be melt extruded, e.g. on the amount and melting
point of the active agent to be incorporated into the product. At least part of the mixture
must plasticizable at the temperature used. Expediently, a temperature should be cho
sen, where none of the components of the mixture to be melt extruded is decomposed.
The glass transition temperature and melt viscosity of the mixture to be melt extruded
can be adjusted by adding thermoplastic polymers with a high glass transition tempera-
ture, for example polyvinylpyrrolidones, hydroxyalkylcelluloses or hydroxyalkylstarches.
Plasticizers, for example propylene glycol or polyethylene glycol 400, may be added to
achieve a lower glass transition temperature.
The extruder housing is heated in order to form a melt from the substances fed to the
extruder. It will be appreciated that the working temperatures will also be determined by
the kind of extruder or the kind of configuration within the extruder that is used. A part
of the energy needed to melt, mix and dissolve the components in the extruder can be
provided by heating elements, while the friction and shearing of the material in the ex
truder can also provide the mixture with a substantial amount of energy and aid in the
formation of a homogeneous melt of the components.
wo 2013/045365
In order to obtain a homogeneous distribution and a sufficient degree of dispersion of
the active agent, the melt is kept in the heated barrel of the melt extruder for a sufficient
length of time.
The extrudate exiting from the extruder ranges from pasty to viscous. Before allowing
the extrudate to solidify, the extrudate may be directly shaped into virtually any desired
shape. Shaping of the extrudate may be conveniently carried out by a calender with
two counter-rotating rollers with mutually matching depressions on their surface. A
broad range of tablet forms can be attained by using rollers with different forms of de
pressions. If the rollers do not have depressions on their surface, films can be ob
tained. Alternatively, the extrudate is moulded into the desired shape by injection
moulding. Alternatively, the extrudate is subjected to profile extrusion and cut into piec
es, either before (hot-cut) or after solidification (cold-cut).
Optionally, the solid dispersion product resulting from such process of melt extrusion is
milled or ground to granules. The granules may then be compacted. Compacting
means a process whereby a powder mass comprising the granules is condensed under
high pressure in order to obtain a compact with low porosity, e.g. a tablet. Compression
of the powder mass is usually done in a tablet press, more specifically in a steel die
between two moving punches.
Alternatively, the solid dispersion product can be produced by dissolving at least one
active agent having at least one hydrogen atom bound to an oxygen or a nitrogen at-
om, at least one pharmaceutically acceptable pharmaceutically acceptable pH modifier
and at least one pharmaceutically acceptable polyvinyllactam polyvinylacetate
poly(alkylene glycol) graft copolymer in a suitable solvent, and then removing the sol
vent. A suitable solvent may be an organic solvent, for example ethanol, isopropanol,
n-butanol, isobutanol, ethyl acetate, acetone and dimethylformamide. Any method of
drying may be used for removing the solvent, for example spray drying, fluidized-bed
drying, roller drying, supercritical drying, lyophilization, vacuum drying or evaporation.
For oral administration of the formulations of the invention a variety of dosage forms
may be used comprising granules, capsules, pellets, powders or tablets.
wo 2013/045365
Granules consist of solid grains of formulations of the invention, each grain represent
ing an agglomerate of powder particles. A lubricant is preferably used in compacting
the granules. Suitable lubricants are selected from polyethylene glycol (e.g., having a
Mw of from 1,000 to 6,000), magnesium and calcium stearates, sodium stearyl
fumarate, and the like. The user can be offered single-dose preparations, for example
granules packed in a small bag (sachet), a paper bag or a small bottle, or multidose
preparations which require appropriate dimensions. However, in many cases, such
granules do not represent the actual drug form, but are intermediates in the manufac
ture of particular drug forms, for example tablet granules to be compressed to tablets,
capsule granules to be packed into hard gelatin capsules, or instant granules or gran
ules for oral suspension to be put in water before intake.
As capsules, the formulations of the invention are usually packed into a hard shell
composed of two pieces fitted together or a soft, one-piece, closed shell, which may
vary in shape and size. It is likewise possible for formulations of the invention to be
encased or enveloped or embedded in a matrix in suitable polymers, i.e. micro
capsules and microspherules. Hard and soft capsules consist mainly of gelatin, while
the latter have a suitable content of plasticizing substances such as glycerol or sorbitol.
Hard gelatin capsules are used to receive formulations of the invention which have a
solid consistency, for example granules, powder or pellets. Soft gelatin capsules are
particularly suitable for formulations with a semisolid consistency and, if required, also
viscous liquid consistency.
Pellets are granules of formulations of the invention in the particle size range from
about 0.5 to 2 mm in diameter. Both with a narrow particle size distribution, preferably
from 0.8 to 1.2 mm, and with an essentially round shape, are preferred.
Tablets are solid preparations in particular for oral use. The meaning of "oral admin
istration" within the framework of the present invention is, in particular, that of the term
"peroral administration" or "ingestion", thus the tablets are for absorption or action of
the active agent in the gastrointestinal tract. Particular embodiments are coated tablets,
layered tablets, laminated tablets, tablets with modified release of the active agent,
matrix tablets, effervescent tablets, chewable tablets or pills. The formulations of the
invention usually comprise at least a part of the necessary tablet excipients, such as
binders, fillers, glidants and lubricants, and disintegrants. Tablets of formulations of the
wo 2013/045365
invention may also, if necessary, comprise other suitable excipients, for example excip
ients which assist tableting such as lubricants and glidants, e.g. talc and silicones, ani
mal or vegetable fats, especially in hydrogenated form and those which are solid at
room temperature. Coated tablets additionally comprise suitable coating materials, for
example film coating agents with coating aids, especially those mentioned below.
Coated tablets include, in particular, sugar-coated tablets and film-coated tablets.
Powders are finely dispersed solids of formulations of the invention with particle sizes
usually of less than 1 mm. The above statements about granules apply corresponding-
ly.
The solid dispersion products described herein have a higher dispersion rate in aque
ous media and a higher release rate of the comprised active agent(s) into the aqueous
media compared to solid dispersions which do not comprise pH modifier(s). Release of
active agents from solid dispersion products may be determined according to chapter
<711 > Dissolution of United States Pharmacopeia (USP 33, 201 0) using USP appa
ratus 2 (paddle) and 500 ml dissolution medium at a temperature of 3rC and a stirring
speed of 50 rpm. Dissolved active agent(s) may be detected by means of HPLC and
UVNis photometry.
The invention is further illustrated by the following, non-limiting, examples.
EXAMPLE 1: Preparation of solid dispersion products using a DSC (differential scan
ning calorimetry) apparatus
The appropriate amounts of active agent (fenofibric acid or naproxen), pharmaceutical
ly acceptable polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymer
(Soluplus®) and pharmaceutically acceptable pH modifier (trisodium citrate, sodium
carbonate, magnesium oxide or citric acid) were weighed into a sample vessel to give a
total weight of about 200 mg for each sample. After addition of approximately 0.50 to
0.75 ml tetrahydrofuran each sample was stirred for 2 h. A few drops of deionized wa
ter were added to samples containing sodium carbonate or trisodium citrate to facilitate
dissolution of the pH modifier. The samples were then evaporated to dryness in vacuo
at room temperature to form solid dispersion films. Approximately 70 mg of each solid
dispersion film was collected, loaded into a 160 1-11 aluminum DSC pan and heated to
wo 2013/045365
154 oc at a heating rate of 3°C/min. Thus, cylindrical solid dispersion samples were
obtained.
EXAMPLE 2: Preparation of solid dispersion products by hot melt extrusion
The appropriate amounts of active agent (fenofibric acid or naproxen), pharmaceutical
ly acceptable polyvinyllactam polyvinylacetate poly(alkylene glycol) graft copolymer
(Soluplus®, available from BASF AG, Ludwigshafen, Germany) and pharmaceutically
acceptable pH modifier (trisodium citrate, sodium carbonate, magnesium oxide or citric
acid) for each sample and 1 wt% Aerosil were mixed. The mixtures were processed by
hot melt extrusion using an extruder with the temperature profile Z1 =11 0°C, Z2=
170°C, Z3= 170°C.
EXAMPLE 3: Dispersibility of solid dispersion products
Solid dispersion products were prepared from fenofibric acid and Soluplus® with or
without the pH modifier trisodium citrate. The compositions of said solid dispersion
products are indicated in Table 1. Dispersibility of the solid dispersion products was
determined in de-ionized water at room temperature.
Table 1: Compositions of solid dispersion products
Reference product Product #1 Product #2
fenofibric acid 10 wt% 10 wt% 10 wt%
Soluplus® 90 wt% 88wt% 85wt%
trisodium citrate - 2wt% 5wt%
While products #1 and #2 were completely dispersed after 4 h or 0.5 h, respectively, no
dispersion of the reference product was observed even after 24 h.
EXAMPLE 4: Drug release from solid dispersion products
Solid dispersion products were prepared from fenofibric acid ("Feno acid") or naproxen,
and Soluplus® with or without a pH modifier selected from citric acid, sodium carbonate
and magnesium oxide. Of each solid dispersion product a cylindrical sample of about
70 mg was placed in a vessel containing 75 ml de-ionized water or phosphate buffer
wo 2013/045365
(pH 6.8). The vessel was shaken on a Heidolph platform shaker at a rotation speed of
250 rpm and a temperature of 3rC. At regular time intervals a sample of 500 1-11 was
taken from each solution, diluted with methanol and analyzed for the amount of diluted
drug it contained by UV spectroscopy on a Shimadzu UVNis-1800 apparatus.
Each sample comprising a pH modifier showed a significantly improved rate of drug
release compared to a corresponding sample without pH modifier (see Figures 1-8).
I/WE
Claims (14)
1. Use of a pharmaceutically acceptable pH modifier for increasing the dispersion rate of a solid dispersion product in an aqueous medium wherein the solid dispersion product comprises (a) an active agent having at least one of a hydrogen bond donor moiety and a proton donor moiety, (b) a pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkyleneglycol) graft copolymer, and (c) a pharmaceutically acceptable pH modifier; wherein the active agent is selected from the group consisting of pharmaceutically active agents, cosmetically active agents and nutritional supplements, and is a compound with a solubility in water at 25°C and pH 7.0 of 0.01 g/100 ml or less.
2. Use of a pharmaceutically acceptable pH modifier for increasing the release rate of an active agent from a solid dispersion product in an aqueous medium wherein the solid dispersion product comprises (a) an active agent having at least one of a hydrogen bond donor moiety and a proton donor moiety, (b) a pharmaceutically acceptable polyvinyllactam polyvinylacetate poly(alkyleneglycol) graft copolymer, and (c) a pharmaceutically acceptable pH modifier; wherein the active agent is selected from the group consisting of pharmaceutically active agents, cosmetically active agents and nutritional supplements, and is a compound with a solubility in water at 25°C and pH 7.0 of 0.01 g/100 ml or less.
3. The use of either claims 1 or 2, wherein the hydrogen bond donor moiety is selected from primary amino, secondary amino, hydroxy, carbamoyl, thiocarbamoyl, sulfamoyl, sulfinamoyl and ureido.
4. The use of either claims 1 to 3, wherein the proton donor moiety is selected from organic acid moieties and CH-acidic moieties.
5. The use of either claims 1 to 4, wherein the active agent is non-ionic. AH26(10387204_1):JIN
6. The use of either claims 1 to 5, wherein the active agent is selected from (RS)(4-(2- methylpropyl)phenyl)propanoic acid, 2-{4-[(4-chlorophenyl)carbonyl]phenoxy} methylpropanoic acid and (2S)(6-methoxynaphthalenyl) propanoic acid.
7. The use of either claims 1 to 6, wherein the graft copolymer comprises (i) from 10 to 50 wt% poly(alkylene glycol) moieties, (ii) from 30 to 80 wt% N-vinyllactam moieties, and (iii) from 10 to 50 wt% vinyl acetate moieties.
8. The use of claim 7, wherein the N-vinyllactam moieties are N-vinylcaprolactam moieties.
9. The use of either claims 1 to 8, wherein the pH modifier is an alkaline pH modifier.
10. The use of claim 9, wherein the alkaline pH modifier is selected from basic salts of organic acids and inorganic acids, basic amino acids, metal oxides and metal hydroxides.
11. The use of either claims 1 to 8, wherein the pH modifier is an acidic pH modifier.
12. The use of claim 11, wherein the acidic pH modifier is selected from mono-,di- and polybasic carboxylic acids, mono-, di- and poly-sulfonic acids, and acidic salts thereof.
13. The use of either claims 1 to 12, comprising 0.5 to 20 wt% of the pH modifier relative to the weight of the solid dispersion product.
14. The use of either claims 1 to 13, wherein the sum of components (a), (b) and (c) makes up at least 80% of the solid dispersion product. AbbVie Deutschland GmbH & Co. KG By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(10387204_1):JIN
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11182792A EP2572731A1 (en) | 2011-09-26 | 2011-09-26 | Formulations based on solid dispersions |
EP11182792.9 | 2011-09-26 | ||
PCT/EP2012/068661 WO2013045365A1 (en) | 2011-09-26 | 2012-09-21 | Formulations based on solid dispersions |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ621872A NZ621872A (en) | 2015-10-30 |
NZ621872B2 true NZ621872B2 (en) | 2016-02-02 |
Family
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