NZ507162A - Gamma-aminobutyric acid derivatives containing solid compositions and process for preparing the same - Google Patents
Gamma-aminobutyric acid derivatives containing solid compositions and process for preparing the sameInfo
- Publication number
- NZ507162A NZ507162A NZ507162A NZ50716299A NZ507162A NZ 507162 A NZ507162 A NZ 507162A NZ 507162 A NZ507162 A NZ 507162A NZ 50716299 A NZ50716299 A NZ 50716299A NZ 507162 A NZ507162 A NZ 507162A
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- NZ
- New Zealand
- Prior art keywords
- group
- amino
- substituted
- humectant
- butanoic acid
- Prior art date
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- 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
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- 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
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- Veterinary Medicine (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
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Abstract
A stabilised solid composition containing a 4-amino-3- substituted-butanoic acid derivative that can be obtained by incorporating a humectant as a stabilizer, and a process for stabilising a solid composition containing a 4-amino-3- substituted-butanoic acid derivative is disclosed.
Description
New Zealand Paient Spedficaiion for Paient Number 507162
507162
WO 99/59572 PCT/US99/10186
GAMMA-AMINOBUTYRIC ACID DERIVATIVES CONTAINING, SOLID COMPOSITIONS AND
PROCESS FDR PREPARING THE SAME
FIELD OF THE INVENTION 5 This invention relates to a stabilized solid composition comprising a 4-amino-3-substituzeci-butanoic acid derivative and a process for the preparation cf the same.
Also, this invention relates to a solid pharmaceutical preparation of the 4-amino-3-substituted-10 butanoic acid derivative comprising the stabilize solid composition and a process for the preparation of the same.
More particularly, the invention is concerned with a stabilized solid pharmaceutical preparation of the 4-amino-3-substituted-butanoic acid derivative, including 15 gabepentin, pregabalin, baclofen, 3-amAno-.ethyi-4-
cyclohexyl-butanoic acid, 3-aminomethyl-5-cyciohexyl pentanoic acid, 3-amj.nomethyl-4-phenyl-butar.oic acid or 3-aminomeChyl-5-phenyl-pentanoic acid/ in the dosage forms of tablets, powders, granules and capsules, as well as a process 20 for the preparation of the same.
BACKGROUND OF THE INVENTION 1- (Aminomethyl)cyclohexaneacetic acid, one of the 4~amino-3-substituted-butanoic acid derivatives, having the
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following structural formula is disclosed in U.S. Patent Nos. 4,024,175 and 4,087,544 and has been called "gabapentin", a generic name, due to its structural relation to Y~aminobutyric acid (GAHA) .
Gabapentin easily passes across the brain barrier. Owing to this, the compound is used as a medicine for tie treatment of certain cerebral diseases such as certain forms cf epilepsy, faint and hypokinesia as well as cranial traumas, and also for improving the cerebral functions in senile patients.
Moreover, U.S. Patent No. 5,084,479 discloses that gabapentin is used for the treatment of neurodegenerative disorders such as Alzheimer's disease, Hur.zingtor.'s chorea or Parkinson's disease and amyotrophic lateral sclerosis. U.S. Patent No. 5,025,035 discloses that gabapentin is used for the treatment of depression. U.5. Patent No. 5,bl0,381 discloses that this compound is used for the treatment of mania and bipolar disorder. Furthermore, this compound, having an analgesic activity, is expected to be used as analgesics. Under those circumstances, there has been a
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greatly increased utility of gabapentin as the therapeutic agents for those diseases or disorders or conditions as recited above, in addition to csrebral diseases such as epilepsy and the like.
As stated above, gabapentin is a very effective drug for cerebral diseases such as epilepsy and the like, and it has an extremely low toxicity. However, in order to maintain the effect as expected, it has been administered to adults usually at a single daily dose of 900 - 1800 mg or in 10 some cases a daily dose of up to 2400 mg in three divided doses. Thus, a single dose will be in the range of 300 - 60C mg or in some cases up to 800 mg.
Further, gabapentin has difficulties in that it is a drug having a strongly bitter taste and also a very poor IS fluidity and that an extremely high dosage should be required for administration in the dosage forit of powders. Since gabapentin is very difficult to formulate because of its instability, gabapentin eapsules now available in the oversea markets are those manufactured by a simple dry 20 blending of gabapentin with necessary auxiliaries and subsequent encapsulating into hard capsules.
However, a single dose is as high as 300 - 600 mg or in some cases up to 800 mg as stated above, which
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necessitates large-sized capsules; for example. Capsule No. 0 should be applied to capsules having a concent of 400 mg per capsule. Consequently, ingesting such capsules is difficult aven for adults, much more for children. Although 5 gabapentin capsules have already been marketed, it is still indispensable to attempt any improvement in compliance and easy administration of gabapentin, and a demand for a smaller-sized pharmaceutical preparation of gabapentin exists in the clinical field.
Gabapentin itself is a powdery material having very poor compression-moldability and fluidity. Compression molding or granulation has been usually employed for small-sizing or fluidizing of the drug having such powder properties and the molding properties should be improved with 15 che aid of pharmaceutical auxiliaries. However, many of the auxiliaries to be applied for compression molding tend to react with gabapentin with lapse of time zc 'orm 4-cyclohexylpyrrolidone (the corresponding lactam form) by accelerating the dehydration reaction between the amino 20 group and the carboxyl group within the molecule of gabapentin. This dehydration reaction would be far more accelerated as the gabapentin powder is being more tightly compressed. Moreover, the reaction between gabapentin and
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such auxiliaries with lapse of time would be further accelerated by the use of water or an organic solvent in manufacturing a pharmaceutical preparation.
It has been standardized in commercially available gabapentin capsules that an allowable content of the lactam up to the beyond-use date should be no more than 1.0% in view of safety. Accordingly, it is necessary in manufacturing a pharmaceutical preparation of gabapentin to prevent the formation of the lactam by retarding the dehydration reaction between the amino group and the carboxyl group within the molecule of gabapentin. On the other hand, there has been a demand for a small-sized dosage form for easier ingesting as discussed above. Under such circumstances,
there have been attempted over years various methods.
However, none of these attempts has succeeded either because a large-sized dosage form resulted due tc a large amount of the auxiliaries used or because an increased amount of the lactam formed or both of them.
Such instability as encountered in manufacturing a gabapentin preparation has been also observed in other 4-amino-3-substituted-butanoic acid derivatives which are structurally analogous to gabapentin and have a structurally
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. - 6 -
bulky substituent at the 3-position thereof similarly to gabapentin.
Tor example, 4-amino-3-p-chloropner.yl)butanoic acid, which is represented by the following structural formula and called "baclofen" in a generic name.
CI
HJN-HjC-CH-CHJ-COOH
and 5-methyl-3-aminomethyl-hexanoic acid, which is represented by the following structural formula and called "pregabalin" in a generic name/
ch,-ch (chj) a hsn-h,c-!:h-ch,-cooh are also a drug which has very poor compression-raoldability and fluidity like gabapentin. Compression molding or granulation used for small-sizing or fluiaizir.g the drug should be improved with the aid of pharmaceutical auxiliaries. However, many of the auxiliaries to be applied to compression molding tend to react with gabapentin with lapse of time to form 4-cyclohexylpyrrolidone (the
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WO 99/59572 PCT/US99/10186
corresponding lactam form) by accelerating the dehydration reaction between the amino group and the carboxyl group within the molecule of the compound. This dehydration reaction would ba far more accelerated as the compound is 5 being more tightly compressed and would be further accelerated by the use of. water or an organic solvent in manufacturing a pharmaceutical preparation, as is the case of gabapentin. It may be said that the mechanism of degradation by the autoeondensation is peculiar to the 4-10 amino-3~substituted-butanoic acid derivatives having a structurally bulky substituent at the 3-position thereof.
To the contrary, in Y'&ninobutyric acid derivatives having no or a less bulky substituent at the 3-position thereof, such as Y-aminobutyric acid or 4-amino-3-15 hydroxy-butanoic acid, the dehydration reaction is not brought about even when maintained in a dried state such as at a temperature of 105°C over 2-3 hours, and the formation of 4-cyclohexylpyrrolidone (the corresponding iactam form) is not observed. In other words, in the 4-amino-3-20 substituted-butanoic acid derivative wherein the substituent at the 3-position thereof has a bulky structure, the dehydration reaction could easily be brought about between the amino group and the carboxyl group within the molecule.
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PCT/US99/I0186
In view of the aforesaid background, it is an object of the invention to provide, for drugs which are 4-amino-3-substituted-butanoic acid derivatives, including gabapentin, having a structurally bulky substituent at the 3-position thereof, a new pharmaceutical preparation containing said drugs which may be small-sized or fluidized in a dosage form such as tablets or granules and may have a comparable storage stability to commercially available, pharmaceutical preparations including commercially available gabapentin capsules, and a process for manufacturing the same, or at least to provide a useful alternative.
SUMMARY OF THE INVENTION
We have made earnest studies to solve the prior art problems as stated above and, as a result, have now found that the degradation of 4-amino-3-substituted-butanoic acid derivatives including gabapentin owing to the lactam formation during the formulation and storage can be prevented by blocking the evaporation and movement of a very small amount of residual water in a solid composition containing the 4-amino-3-substituted-butanoic acid derivative manufactured, irrespective of formulation methods employed, that it is effective to add a humectant as a stabilizer against degradation and that a solid composition
Intellectual Property Office of NZ
\ & SEP 2003
containing the 4-amino-3-substituted-butanoic acid derivative stabilized by said humectant and a solid pharmaceutical preparation using said composition such as tablets, granules or the like have an excellent storage stability, on the basis of which this invention has been completed.
The present invention therefore provides a stabilized solid composition comprising a 4-amino-3-substituted butanoic acid derivative, a humectant, and an optional auxiliary agent for manufacturing a pharmaceutical preparation, wherein the 4-amino-3-substituted butanoic acid derivative is gabapentin or pregabalin or a combination thereof and the humectant is one or more compounds selected from ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerol, and a lower aliphatic acid ester of glycerol, provided that when the 4-amino-3-substitued butanoic acid derivative is gabapentin, the humectant is not sorbitol.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a stabilized solid composition containing a 4-amino-3-substituted-butanoic acid derivative which comprises a 4-amino-3-substituted-butanoic acid derivative having the general formula
NH2CH2—C—CHjCOOH
Rl Rj wherein,
Rl is a hydrogen atom, a hydroxyl group, a methyl group or an ethyl group;
R2 is a monovalent group selected from:
a straight or branched alkyl group of 3 - 8 carbon atoms;
a straight or branched alkylene group of 3 - 8 carbon atoms;
Intellectual Property Office of NZ
18 SEP 2003
a straight or branched alkyl group of 3 - 8 carbon atoms which is mono- or di-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkoxy group, an alkylthib group, an amino group, a nitro group, an oxo 5 group, a carboxyl group or a carboalkoxy group;
a cycloalkyl group of 3 - 8 carbon atoms;
a cycloalkyl group of 3 - 6 carbor. atoms which is mono-, di- or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an ;.0 alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkyl group of 4 - a carbon atoms;
a condensed ring group formed by ortho-fusion of a 15 phenyl ring with a cycloalkyl group of 4 - 8 carbon atoms wherein said phenyl ring is mono*-, di- or tri-substituted with a h&loger. atom, a trifluoromethyl group, a hydroxy! group, an alkyl group, an alkoxy group, an alkyj.-hio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy ZO group;
a condensed ring group formed by crthc-fusion of a phenyl ring with a cycloalkenyl group of 5 - 8 carbon atoms or a cycloalkanedienyl group of 5 - 8 carbon atoms;
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- il -
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - B carbon atoms or a cycloalkanedienyl group of 5 - 6 carbon atoms wherein said phenyl ring is mono-, di- or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group an alkylcycloalkyl group wherein said cycloalkyl has 3-8 carbon atoms and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -O-, -5- or -SS-;
an alkylcycloalkyl group wherein said cycloalkyl has 3-8 carbon atoms, is linked to an alkylene group having 1 - 4 carbon atoms optionally interrupted with -0-, -5- or -SS- and is mono-, di- or tri-substitutsd with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a cycloalkyl group of 5 - 8 carbon atoms wherein one of the methylene groups (-CH2-) is replaced by -o-, -NH-, —S —, —SO— or —5 (O) 2—;
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WO 99/59572 PCT/US99/10186
a cycloalkyl group of 5 - 8 carbon atoms wherein one of the methylene groups (-CHZ-) is replaced by -0-, -NH-, -S-, -SO- or -S(0)2-/ and one or two of the unsubstituted methylene groups (-CHZ~) are mono- or di-substituted with a 5 halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a cycloalkenyl group of 5 - 8 carbon atoms or a 10 cycloalkanedienyl group of 5 - 8 carbon atoms, one of the methylene groups (-CHZ-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by -0-, -NH-, "N-, -S-, -SO- or -S(0)2-;
a cycloalkenyl group of 5 - 6 carbon atoms or a 15 cycloalkanedienyl group of 5 - 8 carbon atoms, one of the methylene groups (-CH,-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by -0-, -NH-, -N-, -3-, -SO- or -5(0)2-, and one or two of the unsubstituted methylene groups (-CH,-) being mono- or di-substituted with a 20 halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
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a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkyl group of 5 - 9 carbon atoms wherein one of the methylene groups (-CH--j is replaced by -0-, -NH-, -S-, -SO- or -S(0)
a condensed ring group formed by crtho-fusion of a phenyl ring with a cycloalkyl group of 5 - 9 carbon atoms wherein one of the methylene groups (-CK2~) is replaced by —0— / -NH-, -S-, -SO- or -S(0)j-, said phenyl group being mono- or di-substituted with a halogen atom, a 10 trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - B carbon atoms 15 or a cycloalkanedienyl group of 5 - 8 carbon atoms, one of the methylene groups (-CH,-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by -0-, -NH-, -N-, -s -SO- or -5(0),-;
a condensed ring group formed by ortho-fusion of a 20 phenyl ring with a cycloalkenyl group of 5 - 8 carbon atoms or a cycloalkanedienyl group of 5 - 8 carbon atoms, one of the methylene groups (-CHZ-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by -0-, -NH-, -N-, -S
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-SO- or -S(0)Z-, said phenyl ring being mono- or di-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group;
an alkylcycloalkyl group wherein said cycloalkyl has 5-8 carbon atons and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -0-, -s- or -5S-, one cf the methylene groups (-CH2~) m said cycloalkyl ring being replaced by -0-, -NH-, -S-, -SO- cr -S(0)j-;
an alkylcycloalkyl group wherein said cycloalkyl has 5-8 carbon atoms and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -O-, -s- or -SS-, and one of the methylene groups (-CK.-) in said cycloalkyl ring being replaced by -0-, -NH-, -S-, -SO- or -S(0)2- and one or two of the unsubstituted methylene groups (-CH.-) beir.g mono-, di- or tri-substituted wj.~h a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a phenyl or naphthyl group;
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. - 15 -
a phenyl group substituted with a nethylenedioxy group;
a phenyl or naphthyl group which is mono-/ di- or tri-substituted with a halogen atom, a trifluoromethyl group/ a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group, a carboxyl group, a phenoxy group, a pnenylmethoxy group, a phenylmethoxy group wherein said phenyl ring is mono-substituted with a halogen atom, trifluoromethyl group, an alkoxy group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group, a cycloalkylmethoxy group having 5-8 carbon atoms in the cycloalkyl ring, a cycloalkenylmethoxy group having S - 8 carbon atoms in the cycloalkenyl ring, a cycloalkanedienylmethoxy group having 5 - B carbon atoms in the cycloalkanedienyl ring, a cycloalkylmethoxy group wherein one of the methylene groups (-CH,-! in said cycloalkyl ring having 5-8 carbon atoms is replaced by -O-, -NH-, -5-, -SO- or -5(0)z-, a cycloalkenylmethoxy group wherein one of the methylene groups (-CH2~) in said cycloalkenyl ring having 5 - B carbon atoms is replaced by -0-, -NH-, =N-, -S-, -SO- or -S (0) z-, a cycloalkanedienylmethoxy group wherein one of the methylene groups (-CHZ-) in said cycloalkanedienyl ring having 5-8 carbon atoms is
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replaced by -0-, -NH-, -N-, -S-, -SO- or -5(0)2- group, a cycloalkylmethoxy group havxng 5-8 carbon atoms in the cycloalkyl ring wherein said cycloalkyl ring is mono-substituted with a halogen atom, trifluoromethyl group a hydroxy group, an alkyl group, an alkoxy group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group and one of the methylene groups (-CHZ~) in said cycloalkyl ring is replaced by -0-, -NH-, -S-, -SO- or -s (O) t-, a cycloalkenylmethoxy group having 5 - B carbon atoms in the cycloalkenyl ring wherein said cycloalkenyl ring is mono-substituted with a halogen atom, a trifluoromethyl group, a hydroxy group, an alkyl group, an alkoxy group, an amino group, a nitro group, an oxo group, carboxyl group or a carboalkoxy group and one of the methylene groups (-CH,-) in said cycloalkenyl ring is replaced by -0-, -NH-, =N-, -S-, -SO- or -5(0),-, or a cycLoalkaneaienylmethoxy group having 5-8 carbon atoms in the cycloalicanedienyl ring wherein said cycloalkanedienyl ring is mono-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group, an oxo group, carboxyl group or a carboalkoxy group and one of the methylene groups (-CH2-) in said cycloalkanedienyl ring is
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PCT/US99/I0186
17 -
replaced by -o-, -Ml-, =N-, -S-, -SO- or -5 (O) ;
an alkylphenyl group wherain said phenyl group is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -0-/ -S- or -55-;
an alkyl-0-, -S- or -SS-phenyl group wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms via -O-, -S- or -SS-;
an -0-, -S- or -SS-phenyl group;
a diphenylamino group:
an alkylphenyl group wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -O-, -S- or -SS- and mono-, di-tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, a alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyl group;
an alkyl-0-, -5- or -SS-phenyl group ■wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms via -0-, -S- or -SS- and mono-, cii- or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyl group;
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an -O-, -s- or -SS-phenyl group wherein said phenyl group is mono-, di- or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyl 5 group;
or
Rj and K], together with the carbon atom to which they are attached, may form a divalent group selected from: a cycloalkylidene group of 5 - 8 carbon atoms; 10 a cycloalkylidene group of 5 - 3 carbon atoms which is mono-, di-, tri- or tetra-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, a cycloalkyl group, a phenyl group, an amino group, a r.itro group or a IS carboxyl group;
a cycloalkylidene group of 5 - 8 carbon atoms wherein one of the methylene groups (-CH.-) in said cycloalkyl ring is replaced by -O-, -NH-, -S-, -SO- or -5(05,-;
a cycloalkylidene group of 5 - 8 carbon atoms wherein Z0 one of the methylene groups (-CHZ-) in said cycloalkyl ring is replaced by -O-, -NH-, -S-, -SO- or —SCO) 2— group and One or more of the unaubstituted methylene groups !-CHz~) in said cycloalkyl ring are mono-, di-, tri- or tetra-substituted
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with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
S a cycloalkenylidene group of 5 - 8 carbon atoms or a cycloalkanedienylidene group of 5 - 8 carbon atoms;
a cycloalkenylidene group of 5 - 8 carbon atoms or a cycloalkanedienylidene group of 5 - 8 carbon atoms which is mono-, di-, tri- or tetra-substituted with a halogen atom, a 10 trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, a cycloalkyl group, a phenyl group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a cycloalkenylidene group of 5 - 8 carbon atoms or a 15 cycloalkanedienylidene group of 5 - 8 carbon atoms wherein one of the methylene groups (-CHZ-) in said cycloalkenyl ring or cycloalkanedienyl ring is replaced by -0-, -NH-, -N-, -S-, -SO- or -S(0)2-;
a cycloalkenylidene group of 5 - 8 carbon atoms or a 20 cycloalkanedienylidene group of 5 - 8 carbon atoms wherein one of the methylene groups (-CH2-) in said cycloalkenyl ring or cycloalkanedienyl ring is replaced by -0-, -NH-, -s-,
-50- or -5(0) 2- group and one or more of the unaubstituted
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methylene groups (-CHj-) in said cycloalkenyl ring or cycloalkanedienyl ring are mono -, di-r tri- or tetra-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkylidene group of 4 - 8 carbon atoms;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkylidene group of 4 - 8 carbon atoms, said phenyl ring being mono-, di-, tri- or tetra-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group;
a condensed ring group formed by orcho-fusion of a phenyl ring with a cycloalkenylidene group cf 5 - 8 carbon atoms or a cycloalkanedienylidene group cf 5 - 8 carbon atoms;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenylidene group of 5 - 8 carbon atoms or a cycloalkanedienylidene group of 5 - 8 carbon atoms, said phenyl ring being mono- or di-substituted with a
Printed from Mimosa 09/27/2000 11:16:41 page -22-
halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylth-c group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group a humectant'; and, if necessary, an auxiliary agent for manufacturing a pharmaceutical preparation.
The invention also relates to a solid composition containing a 4-amino-3-substituted-butanoic acid derivative which is a solid pharmaceutical preparation in the dosage form of tablets, powders, granules or capsules.
Also, the invention relates to a process for the preparation of a solid composition containing a 4-amino-3-substituted-butanoic acid derivative which comprises combining a 4-amino-3-substituted-butanoic acid derivative having the following formula
NHJCHJ-C-CH,C00H / \
Ri R,
(wherein Rt and Rz are as defined above) with a humectant and, if necessary, an auxiliary agent for manufacturing a pharmaceutical preparation.
The invention further relats to a process for the preparation of a solid composition containing a 4-amino-3-substituted-butanoic acid derivative which is a solid
Printed from Mimosa 09/27/2000 11:16:41 page -23-
pharmaceutical prepration in the dosage fcrtr. c; tablets, powders, granules or capsules.
The invention furthermore relates ro a stabilized solid composition containing a 4-amino-3-substituted-5 butanoic acid derivative which further comprises a neutral amino acid.
The 4-amino-3-substituted-butanoic acid derivatives which may be stabilized according to the present invention include those compounds as listed in the following 10 Tables 1 and 2:
Printed from Mimosa 09/27/2000 11:16:41 page -24-
23 -
Table 1
MUCHt-C-CHsCOOn
\
R z
-Ri
-8z
-Ri
-H
-CHi-CHj-CHs
-H
-H
-CH(CHs)»
-H
-CHI-CHl-CHl-CH,
-H
-H
-CH«-CH(CHa)i
-H
-C(CH,)»
-H
-H
-<CHi)«-CH,
-H
-CCH»)J-CH-(CHj)I
-H
-H
-CHCCH,-CH3)(CH,)
-H
-CHi-CHt-CfliNHi
-H
-H
-CHi-CHj-CIIj-CHj-NHj
-H
-CH»-CH»-CHiCl
-H
-H
-CHj-CHI-CHIOH
-H
-CHi-CHi-CH,-CH,-Cl
-H
-H
-CH2-CH»-CH»Br
-H
-CHj-CHi-CHtl
-H
-H
-Cn,-CH(CH,)-CHC1
-H
-CHa-CO-CHs
-H
-H
-CHt-CHi-CO-CHi
-H
-CHJ-CHi-CHJ-CHOH
-H
-Ri
-o
-O
O
-0-"*e
-0-°H
—HE.
<5°
-cf
^C1
-co
-4 1-
CI
Printed from Mimosa 09/27/2000 11:16:41 page -25-
-Ri
-II
-H
-H
-H
-H
-H
Table 1 (Cont'd)
NHiCMi-C-CH jCOOH Ri ^2
-R i -Ri
OHe nCQ "CO
"8
-H
CO"
-a.^1
OH
CI
OHe
-H
-H
-H
-II
-H
-Ri
-H -CHj
-H
-n
-ra.-O
✓OH
<5
-CH2-^^-OMe -au-Q-ci
Printed from Mimosa 09/27/2000 11:16:41 page -26-
Table 1 (Cont'd) NRtCHi-C-CHiCOOI!
-R. -Rz -Hi -Bj
-H "»
-H —-H
-H
-H
-o - -ft
-o " ~tft
-H —-H
"0
-a
-H -""V. -H
""OH
H N-
-H
-H
H
M
•r^
~o
-O-- -« -ftr
Printed from Mimosa 09/27/2000 11:16:41 page -27-
- 28
-8,
-H
-H
-H
-H
-H
-H
-H
-H
Table I (Cont'd)
NHiCH*^CHiC00H R i Rz
-Ri
-tY* -AT
-fh le/
T±r -cY
A
^rBr
-£f\
Nn_
-H
-H
-H
-H
-H
-H
-H
-II
-R»
Br'
HO
A.
T^O
Printed from Mimosa 09/27/2000 11:16:41 page -28-
Table 1 (Cont'd)
NH
iCHr^CHsCOOH
K| Kl
-RI 'Hi
■CO -ci:>
-t^O"
OHe
-H -t^v^pfc
-H
-CI H
—-H
-t-xy
OHe _
-H
-i±Ci
-i±xy - -^c
-co.
H
CI
CI
^^sci fT
CI
-irXf1
from Mimosa 09/27/2000 11:16:41 page -29-
Table 1 (Cont'd)
NH,CH^CH»C00«.
Ri Ri
-Ri "Ri "R i -Ri
-H
''nPro
CI
-H -II
-H
T^O
-H
-H ~T\ if ^1 -H
MX
H
T?a"
- -ticC -
- -&y" - -cgc
H OHe
-^Xl -1 "tYS
L^snPra ^
OH OH
OHe OHe
OHe
-H
CI ^x0ke
CI
-H -rrv'S
U I
Printed from Mimosa 09/27/2000 11:16:41 page -30-
-H
-H
-H
-H
-H
Table 1 (Cont'd)
NHtCHi^CHsCOOH Ri S,
-Ri
-£0"
CI
CI
CI
CI
He
He
He
-tier"-
-H
-H
-H
-H
-H
-H
-H
-H
Et
II I
Et
Et
-txx nPro
^6
iPro
I I
iPro
-m""
/Et ch NUe
Printed from Mimosa 09/27/2000 11:16:41 page -31-
-
Table l (Cont'd) nhjCH,-CM:H,cooh Rl R*
~Ri -8a -R i -Ri
-H
-H
-AOC - A?
OEt
"tVj
-H
OEt
COiH
Me
- -cc
- ■"
-H -H
vOnBu
CI
-H —CH, —CHa-^°^[
A?" "
AX "A
~fl <f^N ~H -CHa-Q-CHt-j"^
HLjQ("e
Printed from Mimosa 09/27/2000 11:16:41 page -32-
WO 99/59572 PCT/US99/I0186
Table 1 (Cont'd)
NH.CHi^C-CHJCOOH Si Kt
~81 -81 -Bi -R»
-H — CHt-CHi—f^Vj -H
-H
-A
0
-ou-r^]
-H — CHg—
-H -CK2—-H
'He
H
-CH
-c\
Nil
"Me
* -"-""-O -
/""I
-H -H -Q
-H -CH»-CHi-£^j -H a
H —CH z -0-CII t—-H —^ ^-CI
CI
Civ
I ^
N:i ci'
Printed from Mimosa 09/27/2000 11:16:41 page -33-
WO 99/59572 PCT/US99/10186
Table 1 (Cont'd)
NH«CH»H^CHtC00H K. Rt
-R i -Ht ~8t
"H "H
-H ~Ci "H
V /A_I "H
/Br
-H —< CI -H
Me
-H ) -H
,He
-H —^ CF3 -H —°"e
OMb^
V./-01 "H —V^~ OHe
CI OHe
_H —v_r~0M® "H /)
"He
"H -^^~Me "H —G>-oh
Mev /OH
-o - 3->
Printed from Mimosa 09/27/2000 11:16:41 page -34-
WO 99/59572 PCT/US99/10I86
Table 1 (Cont'd)
-H
-ii
NH»CH,^C-CH»COOH Ri Ri
-Ri -Ri -Ri iL
-<£« -» ^X>
-h -h -ch ,-y
X. y) -« -i )
OHe
-h —
CHa-^^
-H —C^-0"e -H -^0M,"CH,"^y1 ^OMe
-H —OiPro ~H -CHj-0-CHt-^~^
-H —^ ^-—OMe -H -CHi-CHt~S-CHr\ ff
HeO OHe
-H —£ V—OtBu "H -CHj-CHi—6
-H °G° "H -CHi-S—4
Printed from Mimosa 09/27/2000 11:16:41 page -35-
WO 99/59572 PCT/US99/10186
Table 1 (Cont'd)
NH iCH zpjC-CH iCOOH R. Rz
-R i -81 ~81 ~8»
^ -H -CH1-0-^ tBu
-H -CH
-H — Nf__ -H -CHz-5-^~^-Br
/CI
-H -CHa-S-CHr^^-Cl
-H -CH»-S-CH,-^_y-Me -H CI
-H -CHz-S-CHz-CHj-^Vci -H
-H -CH z -S-CH i -CH r^^-Cl -H -H -CHz-CHj-O-CHr^^-NHz -H -H -CHz-CHi-S-CH -H -CH t -CH i -S-CH r^^-Br
-H
■H -CHj-O-CHj-^ /-CI -H -CHs-ChVS-^_y-CF,
/CI
V/
0
•CI JL
NHz t3>
vHe
Printed from Mimosa 09/27/2000 11:16:41 page -36-
WO 99/59S72
PCT/US99/I0186
- 35
Table 1 (Cont'd) NHzCHz-C-CIl tC00H Ri Ri
-R«i -Ri
-OH -CHj-C(CHJ)j -CH,
-OH -CHi-CHi-CH, -CH,
-OH -CHi-CHi-CHj-CHi -CH, -OH -CH|-CH(CH))»
-CH, -CH,
1 -CH,
-OH -Oil
-OH
-OH —^ /—CI
-OH
0H
OH -CH,-0-^^
H
-OH
-O-Cl
H
-6
"db
"TljI
-OH -OH
-CHi -CH2-CH,-CH,
-CH,
-CH,-CHS -CH,
-CHi-CH, -CHi-CH, -CHi-CH, -CH,-CHj -CHa-CH, -CHi-CHj
-CH(CHj)j
-CH,-CHCCHi)t
-CHj-CHi-CHt-CHj
-o
Cl
-CFi-Q -CH,-CHCCH»)i
-o
-CIWH0
—1d)~C1
-CHr-O-Cl
"tb
-o
Printed from Mimosa 09/27/2000 11:16:41 page -37-
Table 1 (Cont'd)
NH zCH t-C-CHiCOOH
irfNia
-Ri -Ri -Ri ~Ri
-H -CH=CH-CHj -H -CH-CH-CHj-CHj-CHj
-H -CH=CH-CHi-CHj -H -CH-CH-CH(CHS) j
-H -CCCH,)=CH-CHS -H -CH-C(CHj)»
Printed from Mimosa 09/27/2000 11:16:41 page -38-
WO 99/59572 PCT/US99/10186
Table 2 NHiCHt — C - CH»COOH
lOii
>c<r! X:
SMe
CI
>o >Cr oO
^ >CrO
xir x^r""' xy"
X~TC1 ^
>cc S
xy"■ 1?
xy ^
*** x>
^ X3
Br
Me Me
Me
Printed from Mimosa 09/27/2000 11:16:41 page -39-
WO 99/59572 PCT/US99/10186
Table 2 (Cont'd) NH,CH|—C — CHiCOOH Ri R»
X: ><:
n Pro n Pro i Pro
X> >t>
M® / i Pro v /—f-w® Nyr?
X>
i Pro i Pro
Me
>c£:
Me
M Pro
E t n Bu
>t> >o n Bu x3 >c5
X>-
n Pro ' 8u
>o >o
' n Pro , i B u
X3 X5
x>— Bu
, t Bu
Printed from Mimosa 09/27/2000 11:16:41 page -40-
WO 99/59572 PCT/US99/10186
Table 2 (Cont'd) NH.CH.—C-CH.COOH
>< ><;
,OMe a u _
xy >onh'
OMe
>0 X>
>C> X>
X>oM. XD!
H
XT >0
OM e x>G> >0
>o e
X3*»
Me >&
>Q„
Me
)
Me
Printed from Mimosa 09/27/2000 11:16:41 page -41-
40 -
Table 2 (Cont'd) NHjCHI-C-CHJCOOK
><:
>aCI >o
>0
>o» >o
>co ci
M e
ci
>cO
>cP
>
>cP
>cP"cl
>Cp"CF'
xy"'
XX
.Me -M e
Printed from Mimosa 09/27/2000 11:16:41 page -42-
The present invention provides an extremely effective stabilizing means in manufacturing a pharmaceutical preparation containing a 4-amino-3-substituted-butanoic acid derivative having a bulky 5 substituent at the 3-position thereof as explained above,
and the means of the invention is extremely effective in preparing a pharmaceutical preparation of, for example, gabapentin, pregabalin, baclofen, 3-aminomethyl-4-cyclohexyl-butsnoic acid, 3-aminomethyl-5-cyclohexyl-10 pentanoic acid, 3-aminomethyl-4-phenyl-butanoic acid, 3-
aminomethyl-S-phenyl-pentanoic acid, etc.
The humectant which may be employed in the invention in combination with a 4-amino-3-substituted-butanoic acid derivative is selected from ethylene glycol, 15 propylene glycol, butylene glycol, sorbitol and glycerol and an aliphatic acid ester thereof, alone or in any combination of two or more thereof.
Illustrative examples of the glycerol aliphatic acid esters may include glycerol lower aliphatic acid esters 20 such as monoacetylglyceride, diacetylglycerz.de,
triacetylglyceride (triacetin) , middle chain aliphatic ac'id monoglyceride such as monohexanoylglyceride, monooctanoylglyceride, monodecanoylglycende, and middle
Printed from Mimosa 09/27/2000 11:16:41 page -43-
chain aliphatic acid polyglycerol ester such as monolauric acid polyglyceride or monomyristxc acid polyglyceride and the like-
The solid pharmaceutical preparation of the present invention can be obtained in a usual dosage form, typically, in the dosage form of powders, granules, surface-coated granules, capsules, tablets or surface-coated tablets by conducting in turn the granulation step in which a humectant as a stabilizer and, if necessary, an auxiliary agent for manufacturing a pharmaceutical preparation are added to bulk powders of a 4-amino-3-substituted-butanoic acid derivative, such as gabapentin, pregabalin, baclofen and the like and the resulting mixture is granulated by means of a granulator, the encapsulation step in which the resulting granular powders are encapsulated under compression by means of a capsule filler or the tableting step in which the resulting granular powders arc compressed by means or a tablet machine and, if necessary, the coating step in which the granular powders, tablets or granules obtained in the preceding steps are surface-coated.
The granulation of the 4-amino-3-substituted-butanoic acid derivative during the process for manufacturing pharmaceutical preparations as stated above
Printed from Mimosa 09/27/2000 11:16:41 page -44-
such as gabapentin may be conducted by any granulation method well-known per ££« Cor example, a fluidized granulation method/ a high speed stirring granulation method, a melting granulation method and the like. In order to effectively adhere a stabilizer to bulk powders of the 4-amino-3-substituted-butanoic acid derivative, there may be preferably employed a fluidized granulation method in which bulk powders of the said compound are fluidized and then a stabilizer is sprayed onto the fluidized powders- Tn this fluidized granulation step, a stabilizer is added in the form of its solution dissolved in water or an organic solvent such as alcohols or the like, whereby a small amount of the stabilizer may be sufficient for uniformly adhering to the surface of bulk powders of the 4-amino-3-subsituted butanoic acid derivative.
In the granulation step using said fluidized granulation method, granulation may be carried out by adding to bulk powders of the 4-amino-3-substituted-butanoic acid derivative the stabilizer solution as described above and, if necessary, a binder such as corn starch, a cellulose derivative (e.g., hydroxypropylcellulose), polyvinyl alcohol, a polyvinyl pyrrolidone (e.g., Kollidon-K30 or
Printed from Mimosa 09/27/2000 11:16:41 page -45-
Kollidon-K25) , a copolyvidone (e.g., Kollidon-VA64) and the like in the form of a solution or suspension thereof.
The aforementioned stabiliser solution may be applied to bulk powders of the 4-amino-3-substituted-butanoic acid derivative prior to the granulation using the binder or other auxiliaries for manufacturing a pharmaceutical preparation. In this granulation step, there may be also incorporated/ if necessary, a sweetening agent such as mannitol, sorbitol, xylitol or the like and other auxiliaries for manufacturing a pharmaceutical preparation.
The granular powders thus obtained may be used as a pharmaceutical preparation of the 4-amino-3-substituted-butanoic acid derivative as such, or they may be also encapsulated under compression for capsules containing the 4-amino-3-substituted-butanoic acid derivative. Also, they may be further comprcssed to tablets.
More specifically, the granular powders of the 4-amino-3-substituted-butanoic acid derivative obtained as described above can be compression-molded to tablets by means of a tablet machine. It is essential in this compression-molding step to use a lubricant as ordinarily done for the manufacture of a pharmaceutical preparation-However, it has been discovered that some conventional
Printed from Mimosa 09/27/2000 11:16:41 page -46-
lubricans employed in a compression-molding step for drugs may influence on a stability with lapse of time of the pharmaceutical preparations of the 4-amino-3-substituted-butanoic acid derivative and further bring about a delayed 5 dissolution of the drugs, so that these lubricants are not preferable in some cases..
However, we have also found out that a certain neutral amino acid, which have hardly been used as a lubricant in compressing drugs, such as L-leueine, L-10 isoleucine, L-valine, D-leucine, D-isoleucine, D-valine, DL-
leucine, DL-isoleucine or DL-valine or a mixture thereof can exert a remarkable effect as a lubricant for compression-molding into tablets of the present derivative such as gabapentin and t.hat in the tablets thus prepared, there has 15 ' been no adverse influence on both the stability with lapse of time and dissolution property provided by the present stabilizer.
Thus, in this compression-molding step, the resulting granules may be usually blended with l.-leucine, L-20 isoleucine, L-valine, D-leucine, D-isoleucine, D-valine, DL-
leucine, DL-isoleucine, D£>-valine or a mixture thereof as a lubricant and, if necessary, an auxiliary for manufacturing a pharmaceutical preparation, for example, a binder or a
Printed from Mimosa 09/27/2000 11:16:41 page -47-
disintegrator such as a cellulose derivative (e.g., hydroxypropylcellulose), crystalline cellulose, com starch, partially gelatinized stareh, lactose or the like or other conventional auxiliaries by means of a suitable mixer such as a dry mixer, e.g., a v-blender or the like and then the resulting mixture is compression-molded to tablets by means of a suitable tablet machine.
The granular powders, granules or tablets thus obtained may be surface-coated/ if necessary. The surface-coating step for tablets is not essential and may be an optional step. For example, in case of gabapentin having a strongly bitter taste, it may be desirable to surface-coat gabapentin tablets for easier ingestion. In the surface-coating step, there may be used as a film-forming material a polymeric base ingredient such as a cellulose derivative, e.g., hydroxypropylcellulose (HPC) , hydroxypropylmethyl-cellulose (HFMC), etc., a polyvinyl pyrrolidone, Kollidon-VA64, Eudragits, etc., and as a sweetening agent mannitol, sorbitol, xylitol, aspartame and the like.
To such a film-forming material, there may be further added, if necessary, a humectant such as propylene glycol, glycerol/ triacetin or the like and a neutral amino acid such as L-leucine, L-isoleucine, I,-valine, L-alanine,
Printed from Mimosa 09/27/2000 11:16:41 page -48-
WO 99/59572 PCT/US99/10186
D-leucine, D-isoleucine, D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine or glycine. Among those compounds, propylene glycol/ glycerol and triacetin may exhibit not only an activity as a humectant but also an activity as a plasticizer for a coating film, while L-leueine, L-isoleucine, L-valine, D-leucine, D-isoleucine, D-valme, DL-leucine, DL-isoleucine and DL-valine may exhibit an activity as a modifier for a coating film. Moreover/
when the 4-amino-3-substituted-butanoic acid derivative is gabapentin, glycine, L-alanine, D-alanine and DL-alanine may exhibit an activity as a buffering agent against bitter taste of gabapentin. The surface-coating of the granular powders, granules or tablets may be applied to the surface of the granular powders, granules or tablets according to a wen-Known method using a fluidized bed or a rotary pan.
In a solid composition containing the 4-amino-3-substituted-butanoic acid derivative according to this invention, the humectant may be used in a total amount of 0.01 - 25% by weight relative to the 4-amino-3-substituted-butanoic acid derivative, or in an amount of 0.01 - 25% by weight relative to the total amount of the 4-amino-3-substituted-butanoic acid derivative and the auxiliary agent when added for manufacturing a pharmaceutical preparation.
Printed from Mimosa 09/27/2000 11:16:41 page -49-
The total amount to be used may be varied depending upon the sort of the humectant to be used, the specific dosage form of the solid composition containing the 4-amino-3-substituted-butanoic acid derivative, in other words,
tablets, powders, granules or capsules, and also the sort and amount of an auxiliary to be added. The humectant should be used/ in any case, in an effective amount to stabilize the 4-amino-3-substituted-butanoic acid derivative by ensuring a water retention of the pharmaceutical preparation. And, in many cases, a total amount of the humectant may be preferably in the range of 0.0Z - 20% by weight relative to the 4-amino-3-substituted-butanoic acid derivative, or it may preferably be in the range of 0.02 -20% by weight relative to the total amount of the 4-amino-3-substituted-butanoic acid derivative and an auxiliary agent when added for manufacturing a pharmaceutical preparation. However, when sorbitol is used together with other humectants, the amount to be used is not limited to the ranges as mentioned above.
In preparing surface-coated tablets of the 4-Bmino-3-substicuted-butanoic acid derivative, the amount of the humectant to be used in the surface-coating step may be
Printed from Mimosa 09/27/2000 11:16:41 page -50-
PCT/US99/I0186
usually in the range of 0.1 - 50% by weight relative to the total amount of the coating materials.
Moreover, we have also found out that in preparing a solid pharmaceutical preparation of the 4-amino-3-substituted-butanoic acid derivative, use of a certain neutral amino acid including L-leucine, L-isoleucine, L-valine, L-alanine, D-leucine, D-isoleucine, D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine and glycine, instead of the auxiliary agent commonly used for manufacturing a pharmaceutical preparation, can bring about the desired pharmaceutical preparation without any prevention of the water retention effect of a humectant as a stabilizer of this invention, in other words, the said neutral amino aqid may exhibit an activity as auxiliaries for stabilization. The said neutral amino acid may be used alone or in combination of two or more thereof. The said neutral amino acid may be blended in any optional step for the preparation of a pharmaceutical preparation of the 4-amino-3-substituted-butanoic acid derivative including the granulation step. A total amount of the said neutral amino acid to be used, for example, in a gabapentin solid preparation is in the range of 0.0S - 40% by weight relative to gabapentin.
Printed from Mimosa 09/27/2000 11:16:41 page -51-
The process for preparing a solid preparation of the 4-amino-3-substituted-butanoic acid derivative according to the invention as explained above comprises/ for example, the granulation step in which a humectant, that is, a stabilizer, a binder and an auxiliary agent for manufacturing a pharmaceutical preparation are added to bulk powders of the said compound and then the resulting mixture is granulated by means of a granulator, the step for tableting in which additives such as a lubricant are added to the resulting granular powders and then the granules are compressed by means of a tableting machine and, if necessary, the coating step in which the surface of tablets obtained is coated. However, the granular powders as prepared by the granulation step may be applied as such in the dosage form of powders or granules as a pharmaceutical preparation of the 4-amino-3-substituted-butanoic acid derivative without conducting the tableting step, or the granules as prepared by the granulation step may be further subjected to the surface-coating step as described above. Alternatively, the granules as prepared by the granulation step may be admixed with a lubricant or the like and the ' resulting mixture may be filled into gelatin hard capsules by means of a capsule filler to prepare capsules, in the
Printed from Mimosa 09/27/2000 11:16:41 page -52-
51
solid preparation of the 4-amino-3-substituted-butanoic acid derivative thus prepared, for example, in case of the gabapentin preparation, gabapentin is in a compressed or fluidized state so that the solid preparation may be easily taken when orally administered to human.
Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising" and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of "including, but not limited to".
This invention will be more fully explained by way of the following examples, but it should not be construed that these examples limit the scope of this invention.
1) Preparation of granular powders A of gabapentin
On 250 g of bulk powders of gabapentin was sprayed 72 g of water by means of a fluidized granulator (manufactured by FREUND Co., Ltd., SFC-Labo) and then dried to obtain gabapentin granular powders A.
2) Preparation of granular powders B of gabapentin
On 250 g of bulk powders of gabapentin was sprayed a solution of 5 g of propylene glycol in 67 g of water by means of said fluidized granulator and then dried to obtain gabapentin granular powders B.
The gabapentin granular powders A and B obtained as described in the above 1) and 2) were stored under the conditions as defined in the following Table 3 and then a
Example 1
Intellectual Property Office of NZ
18 SEP 2003
WO 99/59572 PCT/US99/10186
- 52
lactam content formed in each of the granular powders was determined by means of HPLC.
The lactam content in this example and examples hereinafter is expressed in term of * by weight based on 5 gabapentin.
Table 3
Storage conditions Granular powders
A B
When initiated 0.003 0.003
60"C/1 week (sealed) 0.017 0.011
60"C/2 weeks (sealed) 0.020 0.013
50°C/85% humidity/2 weeks (open) 0.003 0.003 50°c/85% humidity/4 weeks (open) 0.003 0.003
The above table shows that the gabapentin bulk powders could be prevented from the degradation with lapse of time (the lactam formation) by the addition of propylene glycol.
Example 2
1) Preparation of granular powders C of gabapentin
On 250 g of bulk powders of gabapentin was sprayed 72 g of water by means of a fluidized granulator (manufactured by FREUND Co., Ltd./ SFC-Labo) and
Printed from Mimosa 09/27/2000 11:16:41 page -54-
subsequently a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon, and then dried to obtain gabapentin granular powders C.
2) preparation of granular powders D of gabapentin on 250 g of bulk powders of gabapentin was sprayed a solution of 5 g of propylene glycol in 67 g of water by means of a fluidized granulator (manufactured by FREUND Co., Ltd., SFC-Labo) and subsequently a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon, and then dried to obtain gabapentin granular powders D.
3) Preparation of granular powders E of gabapentin
On 250 g of bulk powders of gabapentin was sprayed a solution of 5 g of triacetin in 67 g of water by means of said fluidized granulator and subsequently a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon, and then dried to obtain gabapentin granular powders E.
4) Preparation of granular powders F of gabapentin
On 250 g of bulk powders of gabapentin was sprayed a solution of 2.5 g of propylene glycol and 2.5 g of triacetin in 67 g of water by Beans of the said fluidized granulator and subsequently a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon.
Printed from Mimosa 09/27/2000 11:16:41 page -55-
54 -
and then dried to obtain gabapentin granular powders F.
The gabapentin granular powders C - F obtained as described in the above 1) - 4) were stored under the conditions as defined in the following Table 4 and then a lactam content formed in each of the granular powders was determined by means of HPLC.
Table 4
Granular powders
C D E F
0.004 0.003 0.003 0.003 0.131 0.076 0.044 0.072 0.214 0.130 0.118 0.124 50"C/85% humidity/2 weeks (open) 0.011 0.008 0.006 0.007 50°C/85% humidity/4 weeks (open) 0.012 0.013 0.010 0.011
Storage conditions
When initiated 60°C/1 week (sealed) 60°C/2 weeks (sealed)
The above table shows that the gabapentin bulk powders could be prevented from the degradation with lapse of time (the lactam formation) by the addition of either propylene glycol or triacetin or both of them.
Example 3
1) Preparation of gabapentin granules
On 700 g of bulk powders of gabapentin was sprayed a solution of 14 g of copolyvidone and 14 g of propylene
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glycol in 252 g of water by means of a fluidized granulator (manufactured by FREUND Co., Ltd., SFC-Mini) and then dried to obtain gabapentin granular powders.
2) Compression to tablets
The dry granules obtained according to the above step 1) were admixed with L-valine at 7% by weight based on the granules and then compressed to tablets, each tablet having a diameter of 9 mm and a weight of 336 mg, by means of a rotary tablet machine (manufactured by KIKUSUI 5EXSAKUSHO K.K.). Each tablet contained 300 mg of gabapentin and had a hardness of 6 - 10 kg.
3) Surface coating of tablets
Tablets obtained in the above step 2) were film coated over the surface thereof with a coating solution having the composition as defined in the following Table 5 by means of a coater (manufactured by FREUND Co., Ltd., HI-COATOR HCT-30J.
TaMe 5
Copolyvidone
34.0
g
L-Isoleucine
13.5
g
Glycine
13.5
g
Propylene glycol
7.0
g
Calcium stearate
7.0
g
Printed from Mimosa 09/27/2000 11:16:41 page -57-
WO 99/59572 PCT/US99/10186
- 56
Water 432.0 g
The uncoated tablets (I) and the film-coated tablets (II) obtained according to the above steps 2) and 3) 5 and the commercially available gabapentin capsules (III)
were stored under the conditions as defined in the following Table 6 and thereafter a content of the lactam as formed in each of the said tablets and capsules were determined.
Table 6
Storage conditions Lactam content (%)•
Gabapentin preparations (I) (II) (III)*
When initiated 0.005 0.004 0.018
40°C/75S humidity/2 months (sealed) 0.048 0.066 0.072 IS 40°C/75% humidity/4 months (sealed) 0.123 0.119 0.129
40*C/75% humidity/6 months (sealed) 0.229 0.172 0.219
[Note] '"commercially available gabapentin capsules prepared according to a dry blend method, each capsule containing 300 mg of gabapentin
The above table shows that no significant increase in the lactam content was observed in the film coated tablets and the film coated tablets had an excellent stability with lapse of time, similar to that of the 25 gabapentin capsules prepared by a dry blend method.
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WO 99/59572 PCT/US99/10I86
Moreover, the film coated tablets obtained as described above were subjected to the dissolution test according to the dissolution test procedure as prescribed in the Japanese Pharmacopoeia XIII (using 900 ml of water and a 5 puddle method at 50 rpm) ■ The test conditions and test results are shown in the following Table 7 wherein the numerical value means to represent the dissolution amount expressed in terms of t.
Table 7
Dissolution time (min.) Storage conditions
When initiated 60#c/4 hrs (sealed) 15 90.3 91.5
103.1 103.3
60 103.2 103.3
The above test results have proved that the film coated gabapentin tablets prepared according to the process of this invention can exhibit a good dissolution in the dissolution test and also have a good stability with lapse
of time after dissolution.
Example 4
1) Preparation of baclofen powder sample G
Printed from Mimosa 09/27/2000 11:16:41 page -59-
WO 99/59572 PCT/US99/10186
- 58
200 mg of baclofen crystals was wetted with 0.04 ml of water and the mixture was made to granular powders by means of a mortar and then dried to obtain baclofen powder sample G.
2} Preparation of baclofen powder sample H
200 mg of baclofen crystals was wetted with 0.04 ml of a 20% aqueous solution of propylene glycol and the mixture was made to granular powders by means of a mortar and then dried to obtain baclofen powder sample H. 10 The baclofen powder samples G and H obtained as described above and untreated baclofen crystals were stored under the conditions as defined in the following Table 8 and then a content of dehydrated condensates formed in each of the samples was determined by means of HPLC. In this 15 Example, the content of the dehydrated condensates is expressed in terms of % by weight, baaed on baclofen.
Tnhln 8
Storage conditions Samples
Untreated baclofen
G
H
when initiated o «
o
0.10
o
H O
60*C/1 week (sealed)
0.36
0.95
0.42
60°C/2 weeks (sealed)
0.57
1.26
0.61
60°C/3 weeks (sealed)
0.70
1.54
o
CD
IS)
Printed from Mimosa 09/27/2000 11:16:41 page -60-
The above table shows that the granulated baclofen using water underwent an accelerated degradation with lapse of time (condensation with dehydration), and that the degradation' with lapse of time could be prevented by the 5 addition of propylene glycol as a humectant.
Example 5
1) Preparation of pregabalin powder sample I
1 g of pregabalin crystals was wetted with 0.1 ml of water and the mixture was made to granular powders by means 10 of a mortar and then dried to obtain pregabalin powder sample I.
2) Preparation of pregabalin powder sample J
1 g of pregabalin crystals was wetted with 0.1 ml of a 1% aqueous solution of decaglyceryl monolaurate and the 15 mixture was made to granular powders by means of a mortar and then dried to obtain pregabarin powder sample J.
3) Preparation of pregabalin powder sample K
1 g of pregabalin crystals was wetted with 0.1 ml of a 10% aqueous solution of butylene glycol and the mixture 20 was made to granular powders by means of a mortar and then dried to obtain pregabalin powder sample K.
The samples I, J and K obtained as described above and untreated pregabalin crystals were stored under the
Printed from Mimosa 09/2*7/2000 11:16:41 page -61-
WO 99/59572 PCT/US99/10186
conditions as defined in the following Table 9 and then a content of the dehydrated condensate formed in each of the samples was determined by means of HPLC. In the present Example and the following Example 6, a content of the 5 dehydrated condensate is expressed in terms of I by weight,
based on pregabarin.
Table 9
Storage conditions Samples
Untreated I J K
pregabalin
When initiated <0.001 <0.001 <0.001 <0.001
60"C/1 week (sealed) 0.001 0.009 0.001 0.001
60*C/2 weeks (sealed) 0.001 0.010 0.002 0.002
The above table shows that the granulated pregabalin using water underwent an accelerated degradation with lapse of time (condensation with dehydration) and that the degradation with lapse of time could be prevented by the addition of decaglyceryl monolaurate or butylene glycol as a 20 humectant-
Example 6
1) Preparation of pregabalin powder sample L
1 g of pregabalin crystals was wetted with 0.1 ml of a 10% aqueous solution of hydroxypropylcellulose and the
Printed from Mimosa 09/27/2000 11:16:41 page -62-
WO 99/59572 PCT/US99/I0186
mixture was made Co granular powders by means of a mortar and then dried to obtain pregabalin powder sample L. 2) Preparation or pregabalin powder sample M
1 g of pregabalin crystals was wetted with 0.1 ml of 5 an aqueous solution containing 10% hydroxypropylcellulose and 10% propylene glycol,, and the mixture was made to granular powders by means of a mortar and then dried to obtain pregabalin powder sample M.
The samples L and M obtained as described above 10 were stored under the conditions as defined in the following
Table 10 and then a content of the dehydrated condensate formed in each of the samples was determined by means of HPLC.
io
Storage conditions Samples
L M
when initiated <0.001 <0.001
60°C/1 week (sealed) 0.005 0.001
60°C/2 weeks (sealed) 0.010 0.002
60°C/4 weeks (sealed) 0.014 0.004
The above table shows that the degradation with lapse of time (condensation with dehydration) of the pregabalin could be prevented by the addition of
Printed from Mimosa 09/27/2000 11:16:41 page -63-
hydroxypropylcellulose and propylene glycol as a humectant.
It has been believed that an excess water remaining generally in solid preparations including a preparation'of the 4-amino-3-substituted-butanoic acid derivative would be undesirable since it may cause discoloration, degradation, tableting troubles or the like. It is the most significant feature of this invention that, unexpectedly, a stability of a solid preparation of the 4-amino-3-substituted-butanoic acid derivative can be remarkably improved by the addition of a humectant which has a water retention activity and has been considered to trigger unfavorable disturbances in the said preparation as stated above. Thus, the present invention has now provided a means for stabilizing pharmaceutically unstable 4-amino-3-substituted-butanoic acid derivatives including gabapentin/ and further elucidated the principle of this stabilization, which have been regarded as the problems to be solved in the art over many years. A significant effect of this invention is that the wet granulation method using water, which has been widely utilized for a small-sized pharmaceutical preparation to be easily taken by patients, can be applied to gabapentin having an extremely poor moldability without causing any degradation of gabapentin. The present
Printed from Mimosa 09/27/2000 11:16:41 page -64-
Claims (18)
1. A stabilized solid composition comprising: a 4-amino-3-substituted butanoic acid derivative, a humectant, and an optional auxiliary agent for manufacturing a pharmaceutical preparation, wherein the 4-amino-3-substituted butanoic acid derivative is gabapentin or pregabalin, or a combination thereof) and the humectant is one or more compounds selected from ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerol, aid a lower aliphatic acid ester of glycerol, provided that when the 4-amino-3-substituted butanoic acid derivative is gabapentin, the humectant is not sorbitol.
2. The stabilized solid composition of claim 1, wherein the humectant is ethylene glycol.
3. The stabilized solid composition of claim 1, wherein the humectant is propylene glycol.
4. The stabilized solid composition of claim 1, wherein the humectant is butylene glycol.
5. The stabilized solid composition of claim 1, wherein the humectant is "glycerol or a lower aliphatic acid ester of glycerol.
6. The stablized solid composition of any one of claims 1 to 5, wherein a total amount of the humectant is 0.01 — 25% by weight relative to the 4-amino-3-substituted-butanoic acid derivative.
7. The stabilized solid composition of any one of claims 1 to 6, wherein a total amount of the humectant is 0.01 - 25% by weight relative to a total amount of the 4-amino-3-substituted-butanoic acid derivative and an auxiliary agent for manufacturing a pharmaceutical preparation.
8. The stabilized solid composition of any one of claims 1 to 7, wherein the stabilized solid composition is a pharmaceutical dosage form of tablets, powders, granules, or capsules.
9. The stabilized solid composition of any one of claims 1 to 8, further comprising one or more neutral amino acids.
10. The stabilized solid composition of claim 9, wherein the neutral amino acids is one or more of L-leucine, L-isoleucine, L-valine, L-alanine, D-leucine, D-isoleucine, D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine, and glycine. Intellectual Property Office of NZ 18 SEP 2003 akiw cn 65
11. A process for stabilizing a solid composition containing a 4-amino-3-substituted butanoic acid derivative, the process comprising combining the 4-amino-3-substituted butanoic acid derivative with a humectant and an optional auxiliary agent for manufacturing a pharmaceutical preparation, wherein the 4-amino-3-substituted butanoic acid derivative is gabapentin or pregabalin, or a combination thereof, and the humectant is one or more compounds selected from ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerol, and a lower aliphatic acid ester of glycerol, provided that when the 4-amino-3-substituted butanoic acid derivative is gabapentin, the humectant is not sorbitol.
12. The process of claim 11, wherein the solid composition is a pharmaceutical dosage form of tablets, powders, granules, or capsules.
13. Use of a humectant for stabilizing a 4-amino-3-substituted butanoic acid derivative in a solid pharmaceutical composition, wherein the 4-amino-3-substituted butanoic acid derivative is gabapentin or pregabalin, or a combination thereof, and the humectant is effective against degradation of the 4-amino-3-substituted-butanoic acid derivative due to lactam formation.
14. The use of claim 13, wherein the humectant is one or more compounds selected from ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerol, and a lower aliphatic acid ester of glycerol, provided that when the 4-amino-3-substituted butanoic acid derivative is gabapentin, the humectant is not sorbitol.
15. The use of claim 13 or claim 14, wherein the solid pharmaceutical composition is a dosage form of tablets, powders, granules, or capsules.
16. A stabilized solid composition of claim 1, substantially as herein described with reference to any one of Examples 1,2,3,5 or 6.
17. The process of claim 11, substantially as herein described with reference to any one of Examples 1,2,3,5 or 6.
18. The use of claim 13, substantially as herein described with reference to any one of Examples 1,2, 3,5 or 6. Intellectual Property Office of NZ 18 SEP 2003 RECEIVED
Applications Claiming Priority (2)
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JP13312298A JP3761324B2 (en) | 1998-05-15 | 1998-05-15 | Passenger rice transplanter |
PCT/US1999/010186 WO1999059572A1 (en) | 1998-05-15 | 1999-05-10 | Gamma-aminobutyric acid derivatives containing, solid compositions and process for preparing the same |
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JP (1) | JP3761324B2 (en) |
CN (1) | CN1171587C (en) |
AT (1) | ATE407668T1 (en) |
CA (1) | CA2325045C (en) |
CY (1) | CY1108488T1 (en) |
DE (1) | DE69939532D1 (en) |
DK (1) | DK1077691T3 (en) |
EA (1) | EA006553B1 (en) |
EE (1) | EE05530B1 (en) |
EG (1) | EG26287A (en) |
ES (1) | ES2312208T3 (en) |
GE (1) | GEP20032987B (en) |
IL (2) | IL139202A0 (en) |
NZ (1) | NZ507162A (en) |
PT (1) | PT1077691E (en) |
UA (1) | UA76398C2 (en) |
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PT1077691E (en) | 2008-11-04 |
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EA006553B1 (en) | 2006-02-24 |
JPH11318133A (en) | 1999-11-24 |
CN1171587C (en) | 2004-10-20 |
EE05530B1 (en) | 2012-04-16 |
EG26287A (en) | 2013-06-12 |
CY1108488T1 (en) | 2014-04-09 |
IL139202A0 (en) | 2001-11-25 |
DK1077691T3 (en) | 2008-10-27 |
CA2325045A1 (en) | 1999-11-25 |
ATE407668T1 (en) | 2008-09-15 |
ES2312208T3 (en) | 2009-02-16 |
UA76398C2 (en) | 2006-08-15 |
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IL139202A (en) | 2014-12-31 |
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