Title of Invention

GAMMA-AMINOBUTYRIC ACID DERIVATIVES CONTAINING, SOLID COMPOSITIONS AND PROCESS FOR PREPARING THE SAME

Abstract

A process for the preparation of a solid composition containing a 4-amino-3-substituted-butanoic acid derivative having the general formula NH,CH2-C-CH2COOH / \ R, R3 wherein, R, is a hydrogen atom, a hydroxyl group, a methyl group or an ethyl group; R? 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 atoros; 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 alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group; a cycloalkyl group of 3 - 8 carbon atoms; a cycloalkyl group of 3-9 carbon atoms which 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, 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 - 8 carbon atoms; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkyl group of 4 ~ 8 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, a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - 8 carbon atoms cr a cycioaikanedienyl group of 5 - 8 carbon a Corns; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - 8 carbon atoms or a cycioaikanedienyl group of 5-0 carbon atoms wherein said phenyl ring is mono-, di- or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10] "GAMMA-AMINOBUTYRIC ACID DERIVATIVES CONTAINING, SOLID COMPOSITIONS AND PROCESS FOR PREPARING THE SAME" WARNER-LAMBERT COMPANY, a Delaware Corporation, of 201 Tabor Road, Morris Plains, New Jersey 07950, United States of America The following specification particularly describes the nature of the invention and the. manner in which it is to be performed:- GAMMA-AMINOBUTYRIC ACID DERIVATIVES CONTAINING, SOLID COMPOSITIONS AND PROCESS FOR PREPARING THE SAME FIELD OF THE INVENTION This invention relates to a stabilised solid composition comprising a 4-ainino-3-substitutec-butanoic acid derivative and a process for the preparation cf the same. Also, this invention relates to a solid pharmaceutical preparation of the 4-aminc-3-surstituced-butanoic acid derivative comprising the stabilize soiid 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-ammo-3-substituted-butanoic acid derivative, including gabapentin, pregabelm, baclofen, 3-aminc-ethyi-4-cyciohexyl-butar.oic acid, 3-aminomethyI-S-cycichexyi pentanoic tela, 2 - aminomethyl - 4 -phenyl-but = r.oic dCio or 3-aminomechy 1 - 5-phenyi-pentancic acid/ in tne dosage forms of tablets, powders, granules and capsules, c.5 well as a process for the preparation of Che same. BACKGROUND 0f THE INVENTION I - (Aminomethyl) cyclohexaneacenc acid, one of the 4-amino-3-substituted-butanoic acid, derivatives, having the rollowmg structural formula is disclosed in U.S. Patent Nos. 1,024,175 and 4,087,544 and has been called "gabapent^n", a generic name, due to its structural relation to y-aminobutyric acid (GABA)- H.N-CH, CH2-C00H Gabapentin easily passes across the brain carrier. Owing to this, ths compound is used as a medicine for the 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 pat:ents . Moreover, U.S. Patent No. 5,084,47° discloses that qabapentm is ubed for the treatment of neuroasgenerative disorders sue.- es Al zr.eimer ' 5 disease, Hur. - :r. ;:cr.' s c.-.orea or Parkinson's disease ana amyotrophic iacera_ sclerosis. 'J. S Patent No. 5,025,035 discloses that gabapencin _s used for the treatment of depression. U.S. Patent No. 5,tl0,38l discloses that trus compound is used for ine treatment of mania and bipolar disorder Furthermore, this compound, having an analgesic activity, is expected zo be used as analgesics. Under these circumstances, there has been a - 3 - greatly increased utility of gabapentm as the cherapeutic agents Cor chose diseases or disorders or conditions as recited above, m addition to cerebral diseases such as epilepsy ana the like. As staced above, gabapentin is a very effeccive drug for cerebral diseases such as epilepsy and the like, and it has an extremely low toxicity. However, in order to maintain Che effect as expected, it has been administered to adults usually at a single daily dose of 900 - 1800 ng or in some cases a daily dose of up to 2400 rag 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. Farther, gabapentin has difficulties m that it is a drug having a scrongly bitter taste and also a very poor fluidity ar.d that an extremely high dosage should be required for administration in the dosage corrr. of powders. Since gaoaosncin is very difficult to formulate because or it instability, gabapentin capsules now available m the oversea markets are those manufactured by a simple dry blending of gaDapantin with necessary auxiliaries and 5ut)5equenr. encapsulating into hard capsules. However, a single dose is as high as 300 - 600 mc or in some cases up to 800 mg as stated above, which - 4 - necessitates large-sited capsuies; for example, Capsule No. 0 snould be applied to capsules having a content of 400 mg par capsule. Consequently, ingesting such capsules is difficult =ven for adults, much more for children. Although gabapentm capsules have already been marketed, it is still mai spensao.e 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 wit the aid of pharmaceutical auxiliaries. However, many of the auxiliaries to be applied for compression noldmg tend to react Jiir. raoapentir. witn lapse cf time t = form -5-cyciohaxylpyrroiiccne (the corresponding lactam, form) by accelerating the dehydration reaction between the amino group and tne zarboxyl group within the rr.clacule of gabapentir. . This dehydration reaction would be :ar more accelerated as the gabapentin powder is oemg rr.ore tightly compressed. Moreover, tne reaction oetween gabapentin and - 5 - such auxiliaries with lapse of time would be further accelerarec by the use of water or ^n organic solvent in manufacturing a pharmaceutical preparation. It has been standardized in commercially available gabapervtin capsules that an dllowable 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 gabapentm to prevent the formation of the lactam by retarding the Rehydration reaction oerween the amino group and the carboxyl group within the molecule of gabapentin. On the other hand, there has been a demand for a small-sired dosage form for easier ingesting is 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 zz = Urge amount of the auxiliaries used ur because an increased amount of the lactam formed or both of them. Such instability as encountered m manufacturing a gabapentir. preparation has been also observed in other 4-amino-3-suostituted-butanoic acid derivatives which are structurally analogous to gabapentm and have a structurally o bulky substituent at: the 3-position thereof similarly 10 gabapentin. For example, 4-amino- 3-p-chloropnenyl) butanoic acid, which is represented by the following structural formula and called "baclofen" in a generic nane, CI I H?N-H,C-CH-CK2-COOH and 5-methyl-3-aminoroethyl-hexanoic acid, which is represented by the following structural formula and called "pregabalm" in a generic name, CH,-CH(CH.) 3 I " H,N-H,C-CH-CH,-COOH are also a drug which has very poor compress ion-nolcability and fluidity like gabapentm. Compression molding or granulation used for small-sizing or fluidizir.g -he crug snouid oe improved with the aid cf pharmaceutical auxiliaries. However, many of the auxiliaries to be applied to compression molding tend to react with gaoapentm with lapse of time to form 4-cyclohexylpyrrolidone (the corresponding lactam form) by accelerating the dehydration reaction between the amino group and the carooxyl group within the molecule of the compound. This dehydration reaction would be far more accelerated as the compound 15 beir.g more tiqhtly compressed and would be further accelerazea 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 autocondensation is peculiar to the 4-ammo-3-suDStltuted-butanoic acid derivatives having a structurally bulky substituent at the 3-position thereof. To the contrary, in Y-aminobutyric =cid derivatives having no or a less bulky substituent at the 3-position thereof, such as v-aminobutyric acid or 4-amino-3-hydroxy-butanoic acid, the dehydration reaction is not brought about even when maintained in a driec state such as at a temperature of 105°C over 2-3 hours, and the rormaticn of 1-cyclohexylpyrrol J done (the corresponcir.g lactam form) 15 not observed^ In other words, in the 4-ammo-2-subst ltuted-butanoic acid derivative wherein tne sucst::uent at the 3-posicion -hereof has a bulky structure, the dehydration reaction could easily be brought about between the amino group and the carboxyl group within the molecule. - 8 - In view of the aforesaid background, for drugs which are 4-amino-3-substituted-butanoic acid derivatives, including gabapentin, having a structurally bulky subatituent at the 3-position thereof, there have been desired 5 a new pharmaceutical preparation containing said drugs which may be small-sized or fluidiz.ed 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 10 capsules, and a process for manufacturing the same. SUMMARY OF THE INVENTION we have made earnest studies to solve the prior art problems as stated above and, as a result, have now 15 found that the degradation of 4-amino-3-suDstituted-butanoic acid derivatives including gabapentin owing to the lactam formation ouring the formulation anc storage can be prevented by blocking the evaporation and movement of a very small amout of residual water in a solid composition containing 20 the 4-amino-3-suos ti tuted-butanoi-c acid cerivative manufactured, irrespective of formulation methods employed, that it is effective to add a humectant as a stabilizer against degradation and that a solid composition containing - 9 - the 4-amir.o-3-substituted-butanoic acid derivative stabilized by said humectant and a solid pharmaceutical preparation using said composition such as tablets, granules or tne like have an excellent storage stability, en the basis cf wnich this invention has been completed. DETAILED DESCRIPTION OF THE INVENTION The present invention relates tc a stabilized solid composition containing a 4-am.ino- 3-substituted-butanoic acjd. derivative which comprises a 4-araino-3-substitutec-butanoic acid derivative having the general formula NH,CH,-C-CH,COOH i. i. i. R1/ \R2 wherein, R. is a hydrogen atom, a hydraxyl group, a raethyl group o nn ethyi group; R- is a Mnovaier.t group selected from. a straight or branched alkyl group of 3 - 8 carbon atoms ; a straight or branchea alkyiene group of 3-6 carbon. atoms. - 10 - a straight or branched alkyl group of 3 - 8 carbon atoms which is mono- or d1-substituted with a halogen atom, 3 trifluoromethyl group, a hydroxyl group, an alkoxy group, an aikylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group, a cycloalkyl group of 3 - 8 carbon atoms; a cycloalkyl group of 3 - 8 carbon atoms which is mono-, d1- or tri-substituted with a haloger. atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy croup, an aikylthio group, an amine 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 - 8 carbon atoms; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkyl group of C - 8 carbon atoms wherein said phenyl ring 15 mono-, di- or tri-substituted with a haloger- atom, a trifluoromethyl group, 2 nyaroxyl group, an alkyl group, an alkoxy group, an alkythio group, an amino group, a nitro group, a carboxyl group cr a carboalkoxy group; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - 8 carbon atoms o a cycloa I kanedieny 1 group of 5 - 8 carbon atoms; a condensed ring group formed by ortho-fusion of a phenyl, ring with a cycloaikenyl group of 5 - 8 carbon atoms or a cycloalkanedienyl group of 5 - 8 carbon atoas wherein said phenyl ring is mono-, di- or tri-substitutea with a halogen atom, a trifluoromethyl group, a hydroxy! group, an alkyl group, an alkoxy group, an alkyithio group, an amino group, a r.itro group, a carboxyl group or a carboalkoxy group; an alkylcycloalkyi group wherein said cycloalkyl has 3-8 carbcn atoms and is linked to an alkylene grouo having 1-4 carbon atoms optionally interrupted with -0-, -S- or -SS-; an alkylcycloalkyl group wherein said cycloalkyl has 3-8 carbon atoms, is linked to an alkylene group having i - 4, carbon atoms optionally interrupted with -0-, -3- or -55- and is mono-, d1- or tri-substituted with a halogen atom, a t:;riucromethyl group, a hydroxyl group, an alkyl group, an =lxoxy group, an alkyithio group, an amino group. a tro group, an oxo group, a carboxyl group or a carboalkoxy group; a cycloalkyl group of 5 - S carbon atoms wherein one of the methylene groups (-CH2- is replaced by -O-, -NH-. -S-, -SO- or -S (O) 2-; - L2 - a cycloalkyl group of 5 - 8 caroon atoms wherein cne of the methylene groups (-CH:-) is replaced by -O-, -NH-, -5-, -SO- or -5(0),-, and one or two of the ur.substituted methylene groups (-CH2-) are mono- or di-substituted with a haicgen atom, a trifluoromeUhyi group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthic group, an ammo group, a nitro group, an oxo group, a carboxyl group or a carbcalkoxy group; a cycloalkenyl group cf 5 - 8 carbon atoms or a cycoalkanedienyl group of 5 - 3 carbon atoms, one of the methylene groups (-CH2-) in said cycloalkenyl ring or cycloalkanedrenyl ring being replaced by -0-, -NH-, -N-, -S-, -SO- or -5(0)2-; a cycloalkenyl group of 5 - 8 carbon atoms or a cycioalkanedienyl group of 5 - 3 carbon atoms, one of the methylene groups (-CK,-) in said cycloalkenyl ring cr cyc:oaikanecienyl ring being replaced by -0-, -NH-. =N-, -5-, -5C- or -S(O)2-, and one or c«o of the unsuostluted methylene groups (-CH,-) being mono- or ai-substituted with a ha-ogen atom, a trifiuoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkyltr.io group, an amino group, a miro group, an oxo group, a carboxyl group or a carcoalkoxy group; - 13 - a condensed ring group formed by orthc-fusion of a phenyl ring with a cycloalkyl group of 5 - 9 carbon atoms wherein one of the methylene groups (-CH2 - is replaced by -O-, -NH-, -S-, -SO- or -5(O)7-; a condensed ring group formed by oretho-fusion of a phenyl ring with a cycloalkyl group of 5 - S carbon atoms wherein one of the methylene groups (-CH2-1 is replaced by -0-, -NH-, -S-, -SO- or -5(0),-, said phenyl group being mono- or d1-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an sikyi group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy croup; a condensed ring group formed by ortho-fusion of a phenyl ring with, a cycloalkenyl group of ~ - 8 carbon atoms or a cycloalkanedienyl group of 5 - 0 carrion atoms, one of the methylene groups (-CHt-> in said cyclcalfcenyi ring or cycioal kar.eaienyl ring being replaced by -0-, -NH-, =N-, -S-. -50- or -5(0),-; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - 3 carbon atoms or a cycloa i kanedier.yl group of 5-8 caroon atoms, one of the methylene groups (-CH2,-) in said cycicalkenyl ring or cycloalkanedienyl ring being replaced by -O-, -NH-, =N-, -5-, - is - -SO- or -5(O)2-, 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 aikylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group; an slkylcycloalkyl group wherein saia cycioalicyi has 5-3 carbon atoms and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted an alkylcycloaikyl group wherein saia cycloalkyl has 5-3 carbon atoms and is linked to an alkyiene group having 1-4 carbon atoms optionally interrupted with -0-, -5- or -55-, and one of the methylene groups (-CH2-) in said cycioalkyi ring being replaced by -0-, -NH-, -5-, -SO- cr -5(0!:- and one cr two of the unsubstit'Jted "ethylene groups : -Ch--; oeir.g mono-, ai - or Lr:-5UD5txtute: with a. halogen atom, a trifluoromethyl group, a hydroxyl group, en dikyl group, an alkoxy group, an alkylthlo group, an amino group, a nitro group, an oxo group, a carboxyl croup or a carooalkoxy group; a phenyl or naphthyl group; - 15 - a phenyl group substituted with a nethylenedioxy group; a pnenyl or naphthyl group which 15 rccno-, dx- or tri-substituzed with a halogen atom, a trifluoromethyi 5 group, a r.ydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group, a carboxyl group, 3 phenoxy group, a prenylmethoxy group, a phenylmsthoxy group wherein said phenyl ring is mono-substituted with a halogen atom, trifluoromethyl group, an alkoxy group, an amino 10 group, a nitro group, a carboxyl group or a carboalkoxy group, a cycloalkyimethoxy group having 5-8 carbon atoms in the cyclcalkyl ring, a cycloalkenylmethoxy group having 5 - 8 carbon atoms in the cycloalkenyl ring, a cycloalKanedienylmethoxy group having 5-8 carbon atoms in 15 the cycloalkanedienyl ring, a cycloalkylmetr.oxy group wherein one of the methylene groups i-CH2-1 in said cycloalkyl ring having 5-8 carbon a tons is replaced by -0-, -NH-, -i.-, -SO- or -5(0),-, a cycloalkenyl methoxy group wherein cr.e of the methylene groups (-CH2-) in said 20 cycloalkenyl ring having 5-3 carbon atom is repiacea by -O-, -NH-, = N-, -5-, -50- or -5(0),-. a cycloaikanedieny 1 -methoxy group wherein one of the methylene groups ;-CH2-1 in said cycloa1kaneoienyl ring having 5-3 carbon atoms is - '„ b - replaced by -O-, -NH-, -N-, -5-, -50- or -5(0).- group, a cycioalkylmethoxy group having 5-8 carbon atoms in the cycloalkyl ring wherein said cycloalkyl ring is mono-substituted with a halogen atom, trifluoromethyl group, 5 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 (-CH2-) in said cycloalkyl ring is replaced by -0-, -NH-, -S-, -SO- or -S(C):-, a cycloalkenyimethoxy group having 5-8 carbon 10 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, a carboxyl group or a carboalkoxy group and one of the 15 methylene groups (-CH2~! in said cycloaikenyl ring is replaced by -0-, -NH-, =N-, -5-, -SO- or -S(O).-, or a cycloalkaneaienylmethoxy group having 5-9 carbon atoms the cycloalkanedienyl ring wherein said cycloalkanedienyl ring is mono-substituted with a halogen atom, a 2O trii" luoromethyl group, a hydroxyl group, an alkyl group, in alkoxy group, an amino group, a nitro group, an oxo group, a carooxyl group or a carboalkoxy group and one cf the methylene groups (-CH2-) in said cycloaikanedienyl ring is replaced by -0-, -NH-, =N-, -S-, -SO- or -S(O),-; an aikylphenyl group wherein said phenyl group 15 linked to an aikylene group having 1-4 carbon atoms optionally incerrupted with -0-, -5- or -55-; an alkyl-O-, -5- or -SS-phenyl group wnerein said pnenyi group is linked to an aikylene group having 1-4 carbon acorns via -O-, -S- or -55-; an -0-, -S- or -SS-phenyl group; a diphenyiamino group. an aikylphenyl group wherein said phenyl group is linked Co an aikylene group having 1-4 carbon atoms optionally incerrupted with -0-, -S- or -55- and mono-, d tra-substituted with a halogen atom, a trifluoromethyl group, a hyaroxyl group, a alkyl group, an eikoxy group, amino group, a nitro group or a carboxyi qroup, an alkyl-O-, -5- or -55-phenyl group --.-herein said phenyl group is l;.nked to an alkylene group - having 1 - 4 carbon atoms via -O-, -S- or -SS- and mono-, ci- or tra-substituted with a halogen atom, a traflucromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro grouo or a carboxyi group; - 13 - an -O-, -5- c: -SS-phenyl group wherein said phenyl group 15 mono-, di- or tri-substituted with a nalogen atom, a trifluoromechyi group, a hydroxyl group, an alkyl group, an alkoxy qroup, an amino group, a nitro group or a carboxyl group; or R1 and R2, together with the carbon atcrr. to which they are attached, may form a divalent group selected from: a cycloaikylidene group of 5 - 8 carson atoms; a cycloaikylidene group of 5 - 3 carcon atoms which is mono-, di-, tri- or tetra-substituted with a halogen atom, a trifluoromethyi group, a hydroxyl group, an alkyl group, an aikoxy group, an alkylthio group, a cycloaikyl group, a phenyl group, an ammo group, a nitre group or a cycloaikylidene group of 5-8 Carbon atoms wherein one of the methyxene grcups (-CH.-) in cyclocaikyi : ting is replaced by -0-, -NH-, -5-, -SO- or -5i0.,-; a cycloaikylidene group of £ - 9 carbon aeons wherein one of the methylene groups (-Ch2-) in said cycloalicyl rir.g is replaced by -G-, -NH-, -5-, -SO- or -S(O),- group and one or more of the unsubstltuted methylene groups i-CH2-i in said cycloaikyl ring are mono-, di-, tri- or tetra-subst:ruted - 19 - with a. halogen atom, a trifluoromethyl group, a hydroxyi group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, a carboxyi group or a carboalkoxy group; a cycloalkenylidene group of 5 - 8 carbon atoms cr a cycioalkanedienylidene group of 5 - 8 carbon atoms; a cycloalkenylidene group of 5 - 8 caroon atoms or a cycioalkanedienylidene group of 5 - 8 carbon atoms which is mono-, di-, ~ri- or tetra-substituted with 3 halogen scon, a trifluororaethyl group, a hydroxyl group, an alkyi group, an alkoxy group, an aikylthio group, a cycloalkyl group, a pheny] group, an amino group, a nitro group, an oxo group, a carboxyi group or a carboalkoxy group; a cycloalkenylidene group of 5 - 8 carbon atoms or a cycioalkanedienylidene group of 5 - B carbon atoms wherein one of the methylene groups t-CH?-) in said cycloalkenyl ring or cycioalkanedienyl ring is replaced by -0-. -NH-, -N-, -s-, -50- or -S(O)r; a cycloalkenylidene group of 5 - 8 carbon atoms or a cycioalkanedienylidene group of 5 - 8 carbon atoms whereir. one of the rr.ethyiene groups (-CH2~) in said cycloalkenyl ring or cycloaikanedienyl ring is replaced by -0-, -NH-, -N-, -5-, -SO- or -3 (O) ,- group and one or more of the unsubstituteci - 20 - methylene groups (-CH2-) in said cycloai.kenyl ring or cycloalkanedienyl ring are mono-, di-, m- 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 orthc-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, a.n alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group; a condensed ring group formed by orrhc-fusion of a phenyl ring with a cycloalkenylidene group cf 5 - 8 carbon atoms or a cycioalkanedienylidene group cf 5 - 8 carbon atoms; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenylidene group cf 5 - 8 carbon atoms or a cycioalkanedienylidene group of 5 - 8 carbon atoms, said phenyl ring being mono- or di-substituted with 4 - 2 1 - halogen atom, a trifiuoromethyl group, a hydroxy! group, an alkyl group, an alkoxy group, an alkylthic group, an amino group, a r.itro group, a carboxyl group or a carboaikoxy group; a numectant; and, if necessary, an auxiliary agent for manufacturing a pharmaceutical preparation. The invention also relates tc a solid composition containing a 4-amino-3-5ubsti tuted-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-ammo-3-substltuted-butanoic acid derivative which comprises combining a 4-amino-3-substituted-butanoic acid derivative having the following formula NH,CH,-C-CH.COOH / R, R.. (wherein R. and Kz are as defined above) with a humectant and, if necessary, an auxiliary agent .or "r.anu f acturing a pharmaceutical preparation. The invention further relats to a process for the preparation of a solid composition containing a 4~amino-3-substituted-butanolc acid derivative which is a solid - 22 - pharmaceutical prepration in the dosage form of tablets, powders, granules or capsules. The invention furthermore reiatas to a stabilized solid compositxon containing a 4-amino-3-suostituted-butanoic acid derivative which further comprises a neutral amino acid. The 4-amino- 3-substituted-butar.oi:: acid derivatives which may be stabilized accorcmg to the present invention include those compounds as listed in. the following Tables 1 and 2: - 24 - - 25 - 6 - - 11 - - 28 - Z9 - - 30 - 3 1 - 32 - J 3 - - 34 J D - 37 - W - 38 - 39 - 40 - - 41 - 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 substituent at the 3-position thereof as explained above, and the means of the invention is extremely effective m preparing a pharmaceutical preparation of, for example, gabapentin, pregabalin, baclofen, 3-arainoinethyl-4-cyclohexy 1-outanoic acid, 3-arainomethyl-S-cyclohexyl-pentanoic acid, 3-aminojnethyl-4-phenyl-butanoic acid, 3-aromomethyl-5-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, propylene glycol, butylene glycol, sorbitol and glycerol and an aliphatic acid ester thereof, alone or :.-. any combination of two or r.or? thereof. Illustrative examples of the glycerol aliphatic acid esters may include glycerol lower aliphatic acid esters sucn as rr.onoacetylg1yceride, diacety 1 gl ycende, tr lacetylql yceride (triacetin), middle chair, aliphatic ac:c nonoglyceride such as monohexanoylglycende, monooctanoy1g1yceride, monodecanoyiglyceride, and middle - 42 - chain aliphacic acid polyglycerol ester such as monolauric acid polygiyceride or monomyristic acid poiygiyceride and the like. The solid pharmaceutical preparation of the present invention can be obtained in a 'JSual cosaqe form, typically, in the dosage form of powders, granules, surface-coated granules, capsules, tablets or surface-coated tablecs 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-araino-3-substituted-butsnoic 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 cabletinq step ;r. wr.ich the resulting granular powders arc compressed by means of 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-araino-3-substituted-butanoic acid derivative during the process for manufacturing pharmaceutical preparations as stated above - 43 - such as gaoapentin may be conducted by any granulation method well-known per se, for 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-ammo-3-suostituted-butanoic acid derivative, there may be preferably employed a fluidized granulation method an which bulk powders of the said compound are fluidized and then a stabilizer is sprayed onto the fluidized powders. In 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 or the 4-aiPino-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-substiuted-butanoic acid derivative -he 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 - 44 - Kollidon-K25) , a copolyvidone (e.g., Kollidon-VA64) and the like in the form of a solution or suspension thereof. The aforementioned stabilizer solution may be applied to bulk powders of "he 4-amino-3-substituced-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-3-5ub5tituted-butanoic acid derivative as such, or they may be also encapsulated under compression for capsules containing the 4-amino-3-5ubstituted-butanoic acid derivative. Also, they may be further compressed to tablets - More specifically, the granular powders of the 4-amino-3-suostituted-butanoic acid derivative obtained as described above can be compression-molded to tablets by means of a tablet machine. It is essentia.) in this compress ion-molding step to use a lubricant as ordinarily done for the manufacture of a pharmaceutical preparation. However, it has been discovered that some conventional - 45 - lubricans employed in a compression-molding step for drugs ma influence on a stability with lapse of time of the pharmaceutical preparations of the 4-ammo-3-substituted-butanoic acid derivative and further bring about a delayed 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, uhich have hardly been used as a lubricant in compressing drugs, such as L-leucine, L-isoleucine, L-valme, D-leucme/ D-isoleucine, D-valine, DL-leucine, DL-isoleucme 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 that in the tablets thus prepared, there has 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 I.-leucine, L-lsoleucme, L-valine, D-leucine, D-isoleucine, D-valme, DL-leucine, DL-isoleucine, DL-valine or a mixture thereof as a lubricant and, if necessary, an auxiliary for manufacturing a pharmaceutical preparation, for example, a binder or a - 46 - disintegrator such as a cellulose derivative (e.g.. hydroxypropylcellulose) , crystalline cellulose, corn starch, partially gelatinized starch, lactose or the like or other conventional auxiliaries by means of a suitable mixer such as a dry mixer, eg-, 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 or 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), bydroxypropylmethyl-cellulose (HPMC), 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 huroectant such as propylene glycol, glycerol, triacetin or the like and a neutral amino acid such as L-leucine, L-isoleucine, I,-valine, L-alanine, - 47 - D-leucine, D-isoieucine, D-valine, D-alanme, DL-leucine, DL-isoleucine, DL-valine, DL-alanine or glycine. Among thos compounds, propylene glycol, glycerol and triacetin may exhibit not only an activity as a humectant but also an activity es a plasticizer for a coating film, while L-leucine, L-isoleucine, L-valnine, D-leucine, D-isoleucine, D-valine, 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-alaruns and DL-alanine may exhibit ar. 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 well-known method using a fluidized bed cr a rotary pan. In a solid composition containing the 1-araino-3-substituted-butanoic acid derivative according to this invention, the humectant may be used in a total amount of 0.01 - 256 by weight relative to the 4-anino-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. - 48 - The tocal amount Co be used may be varied depending upon th sort of the humectant to be used, the specific dosage form of the solid composition containing Che 4-amino-3-substituted-butanoic acid derivative, in other words, tablets, ponders, 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 derivativ 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 0.02 - 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-ammo-3 substituted-butanoic acid derivative and an auxiliary agent when added for manufacturing a pharmaceutical preparation. However, whan sorbitol is used together with other humectancs, the amount to be used is not limited to the ran as mentioned above. In preparing surface-coated tablets of Che 4-amino-3-sufcstituted-bucanoic acid derivative, the amount of the humeccant to be used in the surface-coating step may be - 49 - 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-ammo-3-substituted-butanoic acid derivative, use of a certain neutral amino acid including L-leucme, 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 Tor 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 acid may exhibit an activity as auxiliaries fo stabilization. The said neutral amino acid may be used alone or m 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-ammo-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 gabapentm solid preparation is in the range of 0.05 - 40% by weight relative tc gabapentin. - 50 - The process for preparing 2 solid preparation of t 4-amino-3-substltuted-butanoic acid derivative according to the invention as explained above comprises, for example, the granulation step in which a humectant, that 15, a stabilise:, 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 tableing 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 o: a capsule filler to prepare capsules. In the - 51 - solid preparation of the 4-amino-3-substituted-butanoic acid derivative thus prepared, for example, in case of the gabapentin preparation, gabapentin 15 in 3 compressed or fluidized state so that the solid preparation may be easily taken when orally administered to human 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. Example 1 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./ 5FC-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 fluidiz.ed granulator and then dried to obtain gabapentin granular powders B. The gabapentin granular powders .a. and 3 obtained as described in the above 1) and 2) were stored under the conditions as defined in the following Table 3 and then a - 52 - lactam content fornied in each of the granular powders was determined by means of HPLC. The lactam content in this exanpie and examples hereinafter is expressed in term of a by weight based on gabapentin. A B 0 . 003 C . 003 0. 017 o. 011 0. 020 0. .013 0. ,003 0 . .003 Table 3 Storage conditions Granular powders When initiated 60°C/1 week, (sealed) 6C0C/2 weeks (sealed) 500C/85% huraidity/2 weeks (open) 0.003 500C/85% humidity/4 weeks (open) 0.003 0.003 The above table shows that the gabapentin bulk powders could be prevented from the degracation 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., 5FC-Labo) and - 53 - subsequently a solution of 5 g of hydroxypropylcellulose in 58 g or water was sprayed thereon, and then dried to obtain gabapentin granular ponders 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 FRZUND Co., Ltd., SFC-Labo) and subsequently - a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon, and then cried 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 cf triacetin lr. 67 g of water by means of the said fluidized granulator and subsequently a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon. - 54 - and then dried to obtain gabapentin granular powders F. The gabapentin granular powders C - F obtained a 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 Storage conditions Granular powders C D Z F When initiated 0.004 0.003 0.003 0.003 60°C/1 week (sealed) 0.131 0.076 0.044 0.072 60°C/2 weeks (sealed) 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 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 triacetm or both of "hem. Example 3 1) Preparation of gabapentin granules On 700 g of bulk powders of gabapentin was spray a solution of 1 4 g of copolyvidone and 14 g of propylene - 55 - glycol in 252 g of water by means of a fluidized granulator (manufactured by FREUND Co., Ltd., SFC-Mini) and then dried to obtain gabapentm granular powders. 2) Compression to tablets The dry granules obtained according to the above step 1) were admixed with L-valine at 75 by weight based on the granules and then compressed to tablets, each tablet having a diameter of 9 nun and a weight of 336 mg, by means of a rotary tablet machine (manufactured by KIKUSU2 5EISAKUSKC 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-30). Table 5 Copolyvidone 34.0 g L-Isoleucine 13.5 g Glycine 13.5 g Propylene glycol 7.0 g Calcium stearate 7.0 g - 56 - Water 432.0 g The uncoated tablets (I) and the film-coated tablets (II) obtained according to the above steps 2) and 3) 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/75% humidity/2 months (sealed) 0.048 0.066 0.072 40°C/75% hunidity/4 months (sealed) 0.123 0.119 0.129 40°C/7S% humidity/6 months (sealed) 0.229 0.172 0.219 (Note) *coir.tiercially available gabapentin capsules prepared according to a dry blend method, eacr. 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 gabapentin capsules prepared by a dry blend method. - 57 - 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 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 (mm.) Storage conditions when initiated 60°C/4 hrs (sealed) 15 90.3 91.5 30 103.1 103.3 60 103.2 103.3 The above test results have proved that the film coated gabapentm 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 - 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 "as wetted with 0.0 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 Example, the content of the dehydrated condensates is expressed ir. terms of ° by weight, based on baclofen. TABLE 8 Storage conditions Samples Untreated baclofen G H When initiated 0.10 0.10 0.10 60°C/1 week (sealed) 0.36 0.9S 0.42 60°C/2 weeks (sealed) 0.57 1.26 0.61 60°C/3 weeks (sealed) 0.70 1-54 0.82 - 59 - 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 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 o water anc the mixture was made to granular powders by means of a mortar and then dried to obtain pregabalin powder sample I. Z) Preparation of pregabalin powder sample J 1 g of pregabalin crystals was wetted with 0.1 ml o a 1% aqueous solution of decaglyceryl monolaurate and the 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 o a 10% aqueous solution of butylene glycol and the mixture 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 - 60 - 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 consent of the dehydrated condensate is expressed in terms of ?. by weight, based on pregabarin. Table 9 Storage conditions Samples Untreated I J K pregabalin When initiated 60"C/1 week (sealed) 0.001 0.009 0.001 0.001 606C/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 humectant. Example 6 1) Preparation of pregabalin powder sample L 1 g of pregabalin crystals was wetted with 0.1 ml a 108 aqueous solution of hydroxypropylcellulose and the - 61 - mixture was made to granular powders by means of a mortar and then dried to obtain pregabalin powder sample L. 2) Preparation of pregabalin powder sample M 1 g of pregabalin crystals was wetted with 01 ml of 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 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. Table 10 Storage conditions Samples L M When initiated 60°C/1 week (sealed) 0.005 0.001 60°C/2 weeks (sealed) 0.010 0.00Z 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 - 62 - 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-ammo-3-substituted-butancic acid derivative can be remarkably improved by the addition of a humectant which has a water retention activity and has been considered to trigge unfavorable disturbances in the said preparation as stated above. Thus, the present invention has now provided a means for stabilizing pharmaceutical^ 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 WE CLAIM : 1. A process for the preparation of a solid composition containing a 4-amino-3-substituted-butanoic acid derivative having the general formula NH,CH2-C-CH2COOH / \ R, R3 wherein, R, is a hydrogen atom, a hydroxyl group, a methyl group or an ethyl group; R? 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 atoros; 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 alkylthio group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group; a cycloalkyl group of 3 - 8 carbon atoms; a cycloalkyl group of 3-9 carbon atoms which 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, 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 - 8 carbon atoms; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkyl group of 4 ~ 8 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, a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - 8 carbon atoms cr a cycioaikanedienyl group of 5 - 8 carbon a Corns; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - 8 carbon atoms or a cycioaikanedienyl group of 5-0 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 aLkylcycloalkyi group wherein said cycloaikyl has 3-8 carbon atoms and is linked to an alkyiene group having 1-4 carbon atoms optionally interrupted with -0-, -S- or -S5-; an alkylcycloalkyl group wherein said cycloaikyl has 3-8 carbon atoms, is linked to an alkyiene group having 1 - 4 carbon etoras optionally interrupted with -O-, -S- or -SS- and 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, an oxo group, a carboxyl group or a carboalkoxy group; a cycloaikyl group of 5 - 8 carbon atoms wherein one of the methylene groups (-CH2-) is replaced by -0-, -NH-, -5-. -50- or -5(O)2~; a cycloaikyl group of 5 - 8 carbon atoms wherein one of the methylene groups (-CHZ-) is replaced by -0-, -NH-, -5-, -SO- or -S(-0)j-, and one or two of the unsubstituted methylene groups (-CH2-1 are mono- or di-substituted with a halogen atom, a trifluororoethyl 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 cycloalkanedienyl group of 5 - 8 carbon atoms, one of the methylene groups (-CHj-) in said cycloalJcenyl ring or cycloalkanedienyl ring being replaced by -0-, -NH-, =N-, -S-, -SO- or -S(O)2; a cycloalkenyl group of 5 - 8 carbon atoms or a cycloalkanedienyl group of 5 - 8 carbon atoms, one of the methylene groups (-CH2-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by -0-, -NH-, =N-, -S-, -SO- or -S{0)7-, and one or two of the unsubstituted methylene groups (-CH2-) being mono- or di-substituted with a halogen atom, a trifluororaethyl group, a hydroxyl group, an alky! group, an aikoxy 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 5 - 8 carbon atoms wherein one of the methylene groups (-CHj-) is replaced by -O-, -NH-, -5-, -30- or -S(O),-; a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkyl group of S - 8 carbon atoms wherexn one of the methylene groups (-CH2-) is replaced by -0-, -NH-, -S-, -SO- or -S(0)7-, said phenyl group being mono- or di-substituted with & halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthxo group, an amino group, a nitco 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 5-8 carbon atoms or a cycloalkanedienyl group of 5 - 8 carbon atoms, one of the methylene groups {-CH2-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by -0-, -NH-, =N-, -5-, -SO- or -S(0)2-, a condensed ring group formed by ortho-fusion of a 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 {-CHi-) in said cycloalkenyl ring or cycloalkanedienyl ting being replaced by -O-. -NH-, -N-. -S-, -SO- or -5(0)2-, said phenyl ring being mono- or di-substituted with a halogen atom, a trifluoromethyi group, a hydroxy! group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyi group or a carboalkoxy group; 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-, -5- or -SS-, one of the methylene groups (-CH,-) in said cycloalkyl ring being replaced by -Q-, -NH-, -S-, -SO- or -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 (-CH,-J in said cycloalkyl ring being replaced by -O-, -NH-, -S-, -SO- or -SIO),- and one or two of the unsubstituted methylene groups (-CHa-) being 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, an oxo group, a carboxyl group or a carboalkoxy group; a phenyl or n-aphthyl group; a phenyl group substituted with a methylenedioxy 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 phenylmethoxy group, a phenylmethoxy group wherein said phenyl ring is mono-substituted with a halogen atom, trifluoromethyl group, an alkoxy group, an amino group, a mtro group, a carboxyl group or a carboalkoxy group, a cycloalkylraethoxy group having 5-8 carbon atoms in the cycioallcyl ring, a cycloalkenylmethoxy group having 5 - 8 carbon atoms in the cycloalkenyl ring, a cycloalkanedienylraethoxy group having 5-8 carbon atoms in the cycloalkanedienyl ring, a cycloaDcylmethoxy group wherein one of the methylene groups (-CH2-I in said cycloalkyl ring having 5-8 carbon atoms is replaced by -O-, -NH-, -S-, -SO- or -5(O} 2-, a cycloalkenylmethoxy group wherein one of the methylene groups (-CH?-) in said cycloalkenyl ring having 5-8 carbon atoms is replaced by -O-, -NH-, =N-, -S-, -SO- or -5(0)2-, a cycioalkanedienyl-methbxy group wherein one of the methylene'groups (-CH2-) in said cycloalkanedienyl ring having 5-3 carbon atoms is replaced by -O-, -NH-, =N-, -S-, -SO- or -SCO),- group, a cycloalkylmethoxy group having 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 mtro group, a carboxyl group or a carboaikoxy group and one of Che methylene groups (-CH,-) in said cycloailcyl ring is replaced by -O-, -NH-, -S-. -SO- or -S(6)?-, a cycloalkenylmethoxy group having 5-8 carbon atoms in the cycloalkenyi 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, a carboxyl group or a carboalkoxy group and one of the methylene groups {-CH2) in said cycloalkenyl ring is replaced by -O-, -NH-, =N~, -S-, -SO- or -S(0)2-, or a cycloalkanedienylmethoxy group having 5 - 8 carbon atoms in the cycloalkanedienyl 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, a carboxyl group or a carboalkoxy group and one of the methylene groups (-CH.-1 in said cycloalkanedienyl ring is replaced by -O-, -NH-, -N-, -5-, -SO- or -S(O)2-; 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-; an alkyl-O-, -5- 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 -O-, -S- or -SS-phenyl group; a diphenylamino group: an alkylphenyl group wherein said phenyl group is linked to an aikylene group having 1-4 carbon atoms optionally interrupted with -0-, -S- or -SS- and mono-, di- or tri-substicuted with a halogen atom, a trifluoromethyi group, a hydroxyl group, a alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyi group; an alkyl-O-, -S- or -SS-phenyl group wherein said phenyl group is linked to an aikylene group having 1-4 carbon atoms via -O-, -s- or -SS- and mono-, di-,or tri-substituted with a halogen atom, a trifluoromethyi group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyi group; an -0-, -5- or -SS-phenyl group wherein said phenyl group is mono-, di- or tri-substituted with a halogen atom, a trifluoromethyi group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyi group; or Rl and R,, together with the carbon atom to which they are attached, may form a divalent group selected from: a cycloaikylidene group of 5 - 8 carbon atoms; a cycloalkylidene group of 5 - 8 carbon atoms which is mono-, di-, tri- or tetra-substituted with a halogen atom, a trifluororaethyl group, a hydroxyl group, an alkyl group, an alkoxy group/ an alkylthio group, a cycloaikyl group, a phenyl group, an amino group, a nitro group or a carboxyi group; a cycloalkylidene group of 5 - 8 carbon atoms wherein one of the methylene groups (-CHZ-) in said cycloaikyl ring is replaced by -O-, -NH-, -S-, -SO- or -S(0)2~; a cycloalkylidene group of 5-8 carbon atoms wherein one of the methylene groups (-CH2-) in said cycloaikyl ring is replaced by -O-. -NH-, -S-, -SO- or -S(0)j- group and one or more of the unsubstituted. methylene groups 1-CH2-) in saxd cycloaikyl ring are mono-, di-, tri- or tetra-substituted wxth a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthxo group, an amino group, a nxtro group, an oxo group, a carboxyi group or a carboalkoxy group; a cycloalkenylidene group of 5 - B 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 wich 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 nitro group, an oxo group, a carboxyl group or a carboalkoxy group; a cycloalkenylidene group of 5 - 8 carbon atoms or a cycloalkanedienylidene group of 5 - 8 carbon atoms wherein one of the methylene groups (-CH2-) in said cycloalkenyl ring or cycloalkanedienyl ring is replaced by -O-, -NH-, =N-, -S-, -50- or -S(0)2-; a cycloalkenylidene group of 5 - 8 carbon atoms or a 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-, -N-, -S-, -SO- or -S(0) 2- group and one or more of the unsubstituted methylene groups (-CH2-) in said cycloalkenyl ring or cycloalkanedienyl ring are 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 ammo 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 ortho-fusion of a phenyl ring with a cycloalkenylidene group of 5 - 8 carbon atoms or a cycloalkanedienylidene group of 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 halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an ammo group, a nitro group, a carboxyl group or a carboalkoxy group, which comprises combining the 4~amino-3-substituted- Dated this 29th day of September, 2000. 3. The process as claimed in claim 2 wherein said composition is a solid preparation of gabapentin, pregabalin, baclofen, 3-aminomethyl-4-cyclohexyl-butanoic acid, 3-aminomethyl-5-cyclohexyl pentanoic acid, 3-aminomethyl-4-phenyl-butanoic acid or 3-aminomethyl-5-phenyl-pentanoic acid. {NALINI KRISHNAMURTI) OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

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