CA2325045C - Gamma-aminobutyric acid derivatives containing, solid compositions and process for preparing the same - Google Patents

Abstract

The present invention provides a stabilized solid composition containing a 4-amino-3-substituted-butanoic acid derivative which can be obtained by incorporating a humectant as a stabilizer.

Description

2 PCT/1.lS99/10186 -GAMMA-AMINOBUTYRIC ACID DERIVATIVES CONTAINING, SOLID COMPOSITIONS AND
PROCESS FOR PREPARING THE SAME
FIELD OF THE INVENTION
This invention relates to a stab:.l_zed solid composition comprising a 4-amino-3-substitu~ec-butanoic acid derivative and a process for the preparat.cn ef the same.
Also, this invention relates to a solid pharmaceutical preparation of the 4-amine-3-substituted-butanoic acid derivative comprising the stabi'_ize solid composition and a process for the preparaticn o~ the same.
More particularly, the inventio:: is concerned with a stabilized solid pharmaceutical preparation of the 9-amino-3-substituted-butanoic acid derivative, _..~.cluding gabapentin, pregabalin, haclofen, 3-aminv-ethyi-4-cyclohexyi-butanoic acid. 3-aminomethyl-5-cyc'_ohexyl pentanoic acid. 3-am~.nomethyl-4-phenyl-buta::aic acid or 3-aminomethyl-~-phenyl-pentanoic acid, in ~he dosage Lorms of tablets, powders, granules and capsules. ~s well as a process for the preparation of the same.
BACKGROUND OF TFiL IN'~~NTION
1-(Aminvmethyl)cyclohexaneacetic aci~, one of the 4-amine-3-substituted-butanoic acid derivatives, havzng the _z_ rollowing structural formula is disclosed .n U.S. Patent Nos. 4,024,175 and 9,087,544 and has been called "gabapentin", a generic name, due to its structural relation to Y-aminobutyric acid (GABA).
HEN-CHz CHZ-COOH
Gabapentin easily passes across the brain barrier. owing to this, the compound is used as a medicine 'or t~e treatment of certain cerebral diseases such as certa:.-~ f;.rms ef epilepsy, faint and hypokinesia as well as ~~aniaJ. t-aumas, and also for improving the cerebral funct-cns =:z senile patients.
15 Moreover. U.S. Paterit No. 5,084,479 discloses that gabapentir. is used for the treatment of neurodegenerative disorders such as Alzheimer's disease, Hur_~_ngron 's cores or Parkinso:~'s disease and amyotrophiC locera: sclerosis.
U.S. Patent No. 5,025.035 discloses that gabapenLin is used ?0 for the treatment of depression. U.S. Paten' Vo. 5,10,381 discloses that this compound is used for the =~eatment of mania and bipolar disorder. Furthermore, .his compound, having an analgesic activity, is expected to be used as analgesics. Under these circumstances, there has been a greatly increased utility of gabapentin as ~he therapeutic agents for those diseases or disorders yr conditions as recited above, in addition to cerebral diseases such as epilepsy ana the like.
~.s stated above, gabapentin is a very effective drug for cerebral d~.seases such as epilepsy and the like, and it has an extremely low toxicity. However, in order to maintain the effect as expected, ~t has been administered to adults usuGlly at a single daily dose of 900 - 1800 mg or in some cases a daily dose of up to 2400 mg =n twee 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 f.luidi~ty and that an extremely high dosage should be required for administration in the dosage corm of powders.
Since gabapentin is very difficult to fornula~e because of instability, gabapentin capsules now available in the oversea markets are these manufactured by a simple dry ZO blending of gabapentin with necessary auxiliaries and subaeQuent encapsulating into hard capsules.
-owever, a single dose is as high as 300 - 600 mg or in some cases up to 800 mg as stated above, which necessitates large-sized capsules: for example, Capsule No.
0 should be applied to capsules having a ccntent of 400 mg per capsule. Consequently, ingesting such capsules is difficult aven for adults, much more for children. Although S gabapentin capsules have already been marketed, it is 5ti11 indispensable to attempt any improvement '_n compliance and easy admlistration of gabapentin, and a cemand far a smaller-sized pharmaceutical preparation of gabapentin exists in the clinical field.
Gabapentin itself is a powdery ~:aterial 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 px'operties and the molding properties should be improved with 1.5 the aid of pharmaceutical auxiliaries. However. many of the auxl_.iarica to be applied for compression molding tend to react with gabapenti.~. with lapse of time -_c °orm 4-cyclohexylpyrrolicone (the corresponding _acta:l form? by acceleratinc the dehydration reaction between the amino group and the carbo:cyl group within the melecuie of gabapenta.r.. This dehydration reaction wou'_d be far more acccleratec: as the gabapentin powder is being pore tightly compressed. Moreover, the reaction between gabapentin and such auxiliaries with lapse of time would be f;:rther accelerated by the use of water or an organic solvent in manufacturing a pharmaceutical preparation.
It has been standardi2ed in commercially available gabapentin capsules that an allowable content of the lactam up tv the beyond-use date should be nv more tzars J..O$ in view of safety. Accordingly, it is necessary .n manufacturing a pharmaceutical preparation of gabapentin to prevent the formation of the lactam by retarding the ~ehydration 1C 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 ever years var._ous methods.
However, none of these attempts has succeeded either because a large-sized dosage form resulted due ~c ~ :.urge amount of the auxiiiam es used or because an increased ariount of the lactam fcrmed or both of them.
Such instability as encountered .n manufacturing a gabaperitin preparation has been also observed _n ether 4-amino-3-substituted-butanoi.G acid derivatives which are structurally analogous to gabapentin and have a structuzally - v -bulky subst~tuent at the 3-position thereo' 5_~riiarly to gabapentin.
ror axample, 4-amino-3-p-chlorophe::yi?~utanoic acid, which is represented by the following structural .. formula and caJ.led "baclofen" in a generic name, cl I
HZN-HZC-CH-CHZ-COOH
and 5-methyl-3-aminvmethyl-hexanoic acid, which .s represented by the following structural 'ornula and called "pregabalin" in a generic name.
1 S CH_-CH ( CHI 3 Z
HZN-H;C-CH-CH,-COOH
are also a drug which has Very poor compression-:~oldability and fluidity like gabapentin. Compression :no_ding or granulation used for small-suing or fluidiai~g .he drug should be '_mproved with the aid of pharmaceutCal auxiliaries. However, many of the auxil.aries to be applied to compression molding tend to react with gabapentin with lapse of time to form Q-cyclohexylpyrrolidone tthe WO 99/595?2 PCTNS99/10186 cvrrespond~ng 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 be far more accelerated as the compound is being more tightly compressed and would be further accelerated by the use of water or an organic solvent in manufactu-ing a pharmaceutical preparation, as is the case of gabapentin. It may be said that the mechanism of degradatio:: by the autocondensation is peculiar tv the 4-amino-3-substituted-butanoic acid derivatives '.-.awing a structurally bulky substituent at the 3-posz~ion thereof.
To the contrary, in Y-aminobutyric acid derivatives having no or a less bulky substituent at the 3-position Thereof, such as Y-aminvbutyric acid or 4-amino-3-hydro;~y-butanoic acid, the dehydration react=o:~ is not brought ab ut even when maintained in a dried state such as at a temperature or 105°C: over 2 - 3 hours, and the formation of 9-cyclohexylpyrrol~.done lthe corresponding iactam form) is not cbserved. Zn other words, in the 4-am_nv-3-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 she molecule.

In view of the aforesaid background. for drugs which are 4-amino-3-substituted-butanoic acid derivatives, including gabapentin, having a structurally bulky substituent at the 3-position thereof, there have been desired a new pharmaceutical preparation containi::g 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, phar:aaceutical preparat~.ons including commercially available gabapentin capsules, and a procESS for_ manufacturing ~he same.
SUN~iARY 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. 9-amino-3-substituted-butanoic acid derivatives ~.ncluding gabapentin owi.~.g to the lactam formatio~ during the formulation and storage can be prevented by blocking the evaporation and movement of a very small amout of residual water in a solid compvs_tion 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 decradation and that a solid composition 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.
In a preferred embodiment the invention comprises 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-substituted 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 NHZCH2~ -;HZCOOH

wherein, R1 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;

a straight or branched alkyl group vi 3 - a carbon atoms which is mono- or di-substituted with a halogen atom, a trifluvromethyl group, a hydroxyl grouF. an alkoxy group.
an alkylthio group. an amine group, a vitro group. an oxo 3 group, a carboxyl group or a carboalkoxy 7rcup;
a cycloalkyl group of 3 - 8 carbon atoms;
a cycloalkyl group of 3 - 8 carbon. a=oms which is mono-, di- or tri-substituted with a haloge.~. atom, a trifluoromethyl group, a hydroxyl group, a:~ aiKyl group. an :.0 alkoxy group. an alkylthio group, an amine group, a vitro group, an oxo group, a carboxyl group yr ~ carbvalkoxy group;
a condensed ring group formed by orti:o-!'union of a phenyl ring with a cycloalkyl group of 4 - A carbon atoms;
a condensed ring group formed by ort'~c-fusion of a 15 phenyl ring with a cycloalkyl group of 4 - a carbon atoms wherein said phenyl ring is mono-, di- or ~ri-substituted with a haloge.~. atom, a trifluoromethyl group, a aydroY.y.i. group, an alkyl group. an alkvxy group. ari alky:.~hio group, an amino group, a vitro group. a carboxyl grcup cr a carboalkoxy ZO group;
a condensed ring group formed by c=t:~c-fusion of a phenyl ring with a cycloalkenyl group of S - 8 carbon atoms or a cycloalkan8dienyl group of 5 - 8 carbon atoms;

- li -a condensed ring croup formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - B carbon atoms or a cycloaikanedienyl group of S - B 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 .~.=tro group. a carboxyl group or a carboalkoxy group;
an alkylcycloalkyl group wherein said cycloalkyl has 3 - a carbon atoms and is linked to an alkylene group having 1 - 4 carbon atoms optionally interrupted with -O-, -S- or -SS-;
an alkylcycloalkyl group where~.n said cycloalkyl has 3 - a carbon atoms, is 7.inked to an alkylene group having 1 - 4 carbon atoms optionally interrupted with -O-, -S- or -i5 -SS- and is mono-, di- or tri-substituted with a halogen atom, a t=ifluoromethyl group. a hydroxyl group, an alkyl group, ~n ~lkoxy group, an alkylthio group, an a~niro group, a vitro group, an o:co group, a carbonyl gro~,:p or a carboalkoxy group;
a cycloalkyl group of 5 - 8 carbon ~LOms wherein one of the metylene groups i-CHZ-) is replaced by -O-, -NH-, --5-, -SO- yr -S (O) Z-;

_ 12 a cycloalkyl group of 5 - B carbon atoms wherein one of .he methylene groups (-CHZ-) is replaced by -O-, -NH-, -5-, -SO- or -S(O)2-, and one or two of the u:aubstituted methylene groups (-CHz-) are mono- or d.i-substituted with a haicgen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group. an alkoxy group, an alkylthic group, an amino group, a vitro group, an oxo group, a carboxyl group or a carb;,alkvxy group;
a cycloalkenyl group of 5 - a carbon atoms or a cyc:~oalkanedieriyl group of S - B carbon atoms, one of the methyiene groups (-CHZ-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by -O-, -NH-, ~N-, -5-, -SO- or -S (O) 2-;
a cycloa,lkenyl group of 5 - 8 carbon atoms or a ;5 cycloalkanedieny). group of 5 - 8 carbon atoms, one of the methylene groups (-CH,-) ~.n said cycloalkenyl r_ng er cycioa~kanedienyl ring being replaced by -O-, -NH-, =N-, -S-, -5C- or -.~(O)Z-, and one or tWo of the unsubstituted methylene groups f-CH2-) being mono- or di-substituted pith a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkyltr.io group, an amino group, a ni:.ro group, an oxo group, a carboxyl group or a carboalkoxy group;

a condensed ring group formed by o~the-fusion of a phenyl ring with a cyclvalkyl group of 5 - 3 carbon atoms Nherein one of the methylene groups (-C'.-.'.'~-i .s replaced by -O-, -NH-, -S-, -SO- or -S (O) 7-, a condensed ring group formed by ertro-fusion of a phenyl ring with a cycloalkyl group of 5 - 8 carbon atoms wherein one of the methylene groups (-CH.-) is replaced by -O-, -NH-, -S-, -SO- yr -5(O)z-, said phenyl group being mono- or ci-substituted with a halogen ator:, a -3 trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a vitro group, a carboxyl group or a carboalko:cy grcup;
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 - A carbon atoms, one of the methyiene groups S-CHi-) in said cyclcalkenyl ring or cycloalkaredienyl ring being rep).aced by -4-, -NH-, mN-, -S-, -SO- or -S (O) z-;
a condensed zing group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of 5 - B carbon atoms or a cycloalkanedienyl group of 5 - 8 Carbon aLOms, one of the methylene groups (-CHI-? in said cyclcalkenyl ring or cycloalkanedienyl ring being replaced by -O-, -NH-, ~N-, -5-, -SO- or -S(Oi2-, said phenyl ring being mvro- or di-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy g=oup, an alkylthio group, an amino group, a vitro group, a carboxyl group or a carboalkoxy group;
an alkylcycloalkyl group wherein said cycloalkyl has 5 - B carbon atoms and is linked to an alkylene group having 1 - 9 carbon atoms optionally interrupted with -O-, -S- or -SS-, one ef the methylene groups (-CHZ-) _Z said cycloalkyl ring being replaced by -O-, -NH-, -S-, -SO- cr -S(O)Z-;
an alkylcycloalkyl group wherein said cycloalkyl has S - 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~-) in said cycloalkyl ring being replaced by -0-, -NH-, -S-, -SO- or -S (O) 2- and one or two of the unsubstit;:ted :"e;.hylene groups (-C ..-; being mono-, di- or tri-substituted w7.~1: ~, halogen atom, a trifluorvmethyl group, a hydroxyl grcLp, an alkyl group, an alkoxy group, an alkylthi.o group, an amino group.
c0 a vitro group, an oxo group, a carboxyl. group or a carboalkoxy group;
a phenyl or naphthyl group;

a phenyl group substituted with a r~e~hylenedioxy group;
a phenyl or naphthyl group which is mcno-, di- yr tra.-substituted with a halogen atom, a tri~luoromethyl group, a ydroxyl group, an alkyl group, an elkoxy group, an amino group, a nitro group. a carboxyl group, a phenoxy group, a p:~enylmethoxy group, a phenylmpthvxy group wherein said phenyl ring is mono-substituted kith a halogen atom, trifluoromethyl group, an alkoxy group, an amino lg group, a r.~.tro group, a carboxyl group or a ca=boalkoxy group, a cycloalkylmethoxy group having 5 - 8 carbon atoms in the cycloaikyl ring, a cycloalkenyJ.methoxy group having 5 - a carbon atoms in the cycloalkenyl ring, a cycloalkanedienylmethvxy group having 5 - H carbon atoms in .5 the cycloalkanedienyl zing. a cycloalkylmethoxy group where~.n one of the methylene groups (-CHz-! ; r. said cycloal)cyl _-::g having 5 - 8 carbon atons is replaced by -O-, -NH-, -S-, -50- or -S(O)Z-, a cycloalkenyimethoxy group wherein c..~.$ of the methylene groups (-CHI-) in said 20 cyclcalkeny_ ring having 5 - 8 carbon atoms is replaced by -O-, -NH-, =N-, -S-, -SO- off' -S (O) Z-, a cyclvalkanedienyl-methoxy group wherein one or the methylene groups (-CHz-) in said cycloa~kanedienyl ring having 5 - 8 carbon atoms is replaced by -O-, -NH-, =N-, -S-, -SO- or -5(0)1- group, a cycloalkylmethoxy group having 5 - 8 carbon atoms in the cycloalkyl ring wherein said cycloalkyl ring is mono-substituted with a halogen atom, tri:luoromethyl group, a hydroxy group, an alkyl group, an alkoxy group, an amino group, a n:~rv group, a carboxyl group or a carboalkoxy group and one of the methy>.ene groups (-CHI-) in said cycloalkyl ring is replaced by -O-, -NH-, -S-, -SO- or -s(c),-, ~ cycloalkenylmethoxy group having 5 - 8 carbon atoms -~n 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 vitro group, an oxo group, a carboxyl group or a carboalkoxy group and one of the methylene g=oups l-CHZ-) in said cycloalkeryl =ing is replaced by -O-, -NH-, =N-, -S-, -SO- or -S(O),-, or a cycioalkanedienylmethoxy group having 5 -- 8 carbon atoms in the cycJ.oalkanedienyl ring wherein said cycloalkanedienyl ring is mono-substituted with a halogen atom, a ZO trifluoromethyl group, a hydroxyl group, an alkyl group. an alkoxy gro;:p, an amino group, a vitro group. an oxo group, a carboxyl group or a carboalkvxy group and one cf the methylene groups f-CHZ-) in said cycloalkanedienyl ring is replaced by -O-, -NH-, =N-, -S-, -SO- or -~(O?2-:
an aikylphenyl group wherein said Fhenyl group is linked to an alkylene group having 1 - 4 carbon atoms optionally znterrupted with -O-, -S- or -S~-:
S an alkyl-O-, -5- or -SS-phenyl group wzerein 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 diphenyJ.amino group IO ari alkylphenyl group wherein saic phenyl group is linked to an alkylene group hawing I - 4 carbon atoms optionally interrupted with -O-, -5- or -55- and mono-, di-- or tri-substituted with a halogen atom, a tri~luoromethyl group, a hydroxyl group, a alkyl group, an alkoxy group, an 15 amino group, a vitro group or a carboxyl group:
an alkyl-O-, -S- or -SS-phenyl arc~:c ~.:herezr, said phenyl group is l~.nked to an alkylene group :~amng 1 - 4 carbon atoms via -O-, -5- or -SS- and mono-, di- or tri-substituted with a halogen atom, a t=i~lLC=cmethyl ZO group, a hydroxyl group, an alkyl group, an alkoxy group. an amino group, a vitro group o_- a carboxyl group:

an -O-, -5- or -SS-phenyl group wne=ezn said phenyl group is mono-, di- or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, a:. alk 1 y group, an alkoxy group. an amino group. a vitro gro;:p or a carboxyl S group:
or and hz, together with the carbon atom ~c which. they are attached, may form a divalent group selec~ed from:
a cyclvalkylidene group of 5 - 8 carbon atoms;
a cyclvalkylidene group of 5 - 3 carbon atoms which is mono-~ di-, tri- or tetra-substituted wit: a halogen atom, a trirJ_uoromethyl group, a hydroxyl grcup, an alkyl group, an alkoxy group, an alkylthio group, a cycloalkyl group, a phenyl group, an amino group, a ::itro group or a carboxyl group;
a cycloalkylidene group of 5 - 8 carbe:~ atoms wherein one of the methyiene groups (-CHI-) in save cyc'_oalkyl ring is replaced by -O-, -NH-, -S-, -50- or -5((J;,-, a cycloalkylidene group of 5 - 8 carbon atoms wherein z0 one of the methylene groups (-CHZ-) in sa'd cycloalkyl ring is replaced by -O-, -NH-, -S-, -SO~ or -S ;0) Z- group and ~bne or more of the unsubstituted methylene groups ;-CHI-1 in said cycloalkyl ring are mono-, di-, tri- or tetra-substituted with a halogen atom, a tritluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a vitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a cycloalkenylidene group or 5 - 8 carbon atoms or a cycloalkanedienylidene group of 5 - 8 carbon atoms;
a cyclvalkenylidene group of 5 - 8 carbon atoms or a.
cycloalkanedienylidene group of 5 - 8 carbon atoms which is mono-, di-, ~ri- or tetra-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, a cycloalkyi group, a phenyl group, an amine group, a vitro group, an oxo group, a carboxyl group or a carboalkoxy group:
a cycloalkenylidene group of 5 - A carbon atoms or a i5 cycloalkanedienylidene group of 5 - B carbon atoms wherein one of the methylene groups (~CHz-) in said cycloalkenyl ring or cycloa~kanedienyl ring is replaced by -O-, -NH-, ~N-, -S-, -SO- or -S(O11-;
a ~ycloalkenylidene group of 5 - 8 carbon atoms or a ZO cycloalkan2dienylidene group of 5 - 8 carbon atoms Wherein one of the r,.ethylene groups (-GHZ-1 in said cycloalkenyl ring or cycloaikanedienyl ring is replaced by -o-, -NH-, ~N-, -5-, -50- yr -S(O1z- group and one or more of the unsubstituted methylene groups f-cH2-? in said cycloalke~yl _ng or cycloalkanedienyl ring are mono-. di-, tri- or tetra-substituted with a halogen atom, a trif;.uoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthi.o group, an amino group, a vitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a condensed ring group formed by vrtho-fusion of a phenyl ri:.g with a cycloalkylidene group o. 4 - 8 carbon atoms;
a condensed ring group formed by orthc-fusion of a phenyl ring with a cycloalkylidene group ef 4 - 8 carbon atoms, said phenyl ring being mono-. di-. t.ri- or tetra-substituted with a halogen atom, a trifluoromethyi group, a hydroxyl group, an alkyl group, ~n alkoxy group, an alkylthio group, an amino group, a. vitro group, a carboxyl gro::p or 3 carboal.'~coxy group;
a condensed ring group formed by ortro-fusion of a phenyl =ing with a cycloalkenylidene group cf ' - 8 carbon ato:~s or a cycloalkanedienylidene group cf 5 - 8 carbon atoms:
70 a ccndensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenylidene group of 5 - 8 carbon atoms yr a cycloalkanedienylidene group o' S - a carbon atoms, said phenyl ring being mono- ar d'_-substituted with a halogen atom, a trifluoromethyl group. a !:ydroxyl group, an alkyl group, an alkoxy group, an alkylth:.c group, an amino group, a ~i.tro 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 preparat:.en in the dosage form of tablets, powders, granules or capsules.
1Q Also, the invention relates to a process zor the preparation of a solid composition containyng a 9-amino-3-substituted-butanoic acid derivative whit: comprises combining a 4-amino-3-substituted-butanoic acid derivative having the 'ollowing formula ;. 5 NHZCHZ-G-CHzCOOH
/ \

20 (wherein R: and RZ are as defined above) with a humectant and, if necessary, an auxiliary agent 'o~ _:.anufacturing a pharmaceu~~cal preparation.
The invention further relats to a process for the preparation of a solid composition containing a 4-amino-3-25 substituted-butanoic acid derivative which is a solid pharmaceutical prepration in the dosage fort. e' tablets, powders, granules or capsules.
The invention furthermore relates ~o a stabilized solid composition containing a 4-amino-3-supstituted-butanoic acid derivative which further c~:npri5es a neutral amino acid.
The 9-amino-~-substituted-butar_oic acid derivatives which may be stabilized accorcing to the present invention include those compounds as listed ~.=~ the following :~ Tables 1 and Z:

Table 1 NHxCHz~ ~ HzC00(1 Ev Rz _Rt _Rz _R~ _Rz -H CHz Cfia-CHg H

-H -CHCCHs)a -H -CHz-Cllz-CHz-CHs -H

-H -CHz-CHCCHa)z -H -CCCHz)a -H

-H -CCHz)I-CH3 -H -CCHa)a-CH-CCHa)z -fI ---~~4e -H -CHCCH=-CH3)CCHs) -H -CtIi-CHz-CHzNHz -H ~aH

-H -CHa-CHs-CIIz-CHz-NHz -H -CHz-CHz-CH2C1 -H -~--NHz -H -CHa-CHz-CHzOH
H

-H -CHz-CHz-CHz-CHz-C1 --H -CH z-CH z-CH zf3r C1 -H -CHz-CHz-CHzI -H -CI
-H -Cllz-CHCCHs)-CHC1 -H -CHa-CO-CHs -H
i -H -Cflz-CHs-CO-CHs -H -CHz-CHz-CHz-CHOH -H

-H -H yY
i Table 1 (Cont'd?

NHzCH ~ -CHZCOOH
~
ft z , -R, -RZ -R~ -Rz ...~ \ OH
11 ~ H CH2 i OMe H ~ i H ~CH 2 -H ~ ~ ~ -H -CH=-CNa i H ~ H CHp 0 CHZ-i / \ -lI -CHz-~~--OH

H OH
\ ~ -H -CHz OH
-H ~ I -H -CHZ-~--Oh6e -H ~ ~ ~ -H -Cltz--~ I
i Ol~e -H \ ~ ~ -H -CHz-0-CH=-O-OH

_H -. Cll Z -fl - ZS -Table 1 tCont'dl NHzCH ~= CHzC00H
R~ ~z _R~ _Rz _ _Ri _Rz H
_ H _ N _ H --~\Y~-0 H
H
N
_H ~ -H ~S
N
H
-H H
H
H - H ' H H
N
-H
-H ~~ i 0' H
-H ~~~ _H _._ ~' 1 'OH
H - EI
N--H
OH ' -H ~N~
H
N _ ~ CH, -H H H I I

Table :. l Cont' d ) NHxCHz~CHxC00H
R, Rz -gl -Rz - -R, -Rz 0~ Ode -H -.~1 -~ - I I
9r~
ate ~N
-H I I -H '' AO
~N
-H I I -H
~!e OH
Ft -H I I -H I
-H I I C1 -H a i H
,N
_H I aI '_H -rl I .i~

-H I I -H ~ N I i Br -Ii I I -H
-H I f Br Table 1 t Cont' d ) NH,CH=~CHzC00H
R~ RZ
-R~ -RZ -R, -Rs ~N~ ~ H
N
_g ---i w N
06~e _H I ~ _g ( ~ Me / i OMe Me _H 0 I ~ _H I
i _H ,0 ~ .Ohle __~~ I
i ~
~H 0 I ' -H ' C1 ~Y
OMe Cl.
-H ,0 ,. Rt ..H , v I
i ~1 -H 0, ~ C1 _H I ~/Br H CI
_H 0 I w _H ..~N i w.
J
H H
_H N~ ~ OMe -H N .~ C1 Table 1 tCont'd) NH zCH z~ ~CH zC00fI _ R, R z 'Rz 'R~ _._._ 'Rz A ~ OH
_H ~ I ~ C1 H I H I ~ OH

I~
N ~ nPro ~ OMe -A I I -~
~ O~e H OMe N
-H I 1 H ~ I, nPro C1 0lde -H I I ~ _iI I - I
i N
H
_ H ~0 1 w ~OMe I N I i p \ F
H -H I
F
II ~ ~ H I I
N ~ C1 ~~ F
H
~0 -H 'i Ee N ~ J~0 H -H 'I
i Zg Table 7. ( Cont' d ) NHZCHz~~ HzCpOH
R1 Rz -R= -~ -Rs Et -H I I -~~ I I
i 0 Et -H I I \ -H I I

-H p~ '~ -H I
I I ~ ~ Et C1 nPro Br CI p -H _ 0 w ~H I
I i nPrv Id a iPro Me -H p 'I
,0 ~ ' -H I I

-H p w I ~ iPrv M~
iPro 0 ~ -H I I
-H - I I
Me -jI 0, ,.~ Me -H y.
I I -~ I I ~ CHE t ~Me Table 1 (Cont'd) NHaCHz~ ~ Hzc00H
R, xx _R, _Ra _R, _Rz Me -H I I -H y Me C02H
0Et -H I 0 I ~ _H ~Y ' ~ Me i ~ i ~N ~ C1 _ 0 ft I ! i H ~ I ~ C3.
OEt -H ~ -H -CAa V 'OnBu -H ~ -H -CH,-CHx~
I UI
H I I I ~ Cl -H __ Cg i ~0 J
-H ~ I ~ -H -CHz-~' I I ' H - CH z-0-CH z-i-Me H
H I I ~ ~ ~E -H -CHZ--~~
1~e Tabla 1 (Cont'd) HHtCH=%C\ HxC00H
R, Rz -Rz -H~ -RZ
H
H CHz CHz~ H \ /
NHZ
-H -CHZ~ -H \ /
_H _ CHz_CHa~ _H \ / NHa ..H -CHz-0_CIIz~ _H \ / CI
1~J0 Cl.
H -CHz~ -H \ /
C
-R - CH z-,i0 ~,/~\~
_ H ~\ . /' CI. CIt.

-H - CH a ~ -H \ / CI
bie -H - CH z N -H \ / C1 Me -H -CHz-0-CHz~N~ -H \ / F
J

Table 1 (Cont'd) rr~~cH~c~ HtcoaH
R, Rz _R~ _Rz _R~ _Ha F Me _ -FI \ / -H \ / Ide Me F _ -H \ / -H \ ~ Et F
-H \ / I -H \ / nPro Br _ H \ / ~1 -H \ / iPrv -H - \ / F~ -H \ / OMe Me OM
II \ / ~1 H \ / OMe C1 OMe -H ~ 0Me 'H \ /
Me H \ / Me -H \ ~ OH
Me OH
-H ~ / -H ~ /
Me H _ -H ~ / -H \ /

Table 1 (Cvnt'd) NHzCFIz/~ H=COON
R, Rz _R~ _Kz _R~ _Rz OMe ~ 0 -H .... ~ / -OH -H
OMe --H \ / -H \ /
OMe -II \ _ O H -'~0 \
-II \ / 0Me -A \ / -CHa \ /
O~te I
-H \ / ~e -H \ / ~Ha~
Oble -H \./ OiPro -H -CHi-0-CHs \ /
OMe _ _H ~. ~ / 0hfe -H -CAZ-CHZ-S-CHz \ /
Me0 O~te -H \ / -H -CH a -'~~ /
OMe O~e _ H \ / 0t Bu -H -CH z-CH z - \ /
_H 0~0 -H -CHZ..S \ /
\ /

Table 1 (Cont'd) NN=CHz/ ~CHZCOOH

Rz _R~ -Hz _R. _Rz --H -CHz-NH \ / -H -CHi-'~ \ / tBu \ /

-H --N -H -CHz-~ \ / Br \ /

-H -CHa-0-CHz \ / C1 -H -tea;,-L;iZ-S
\ / CF3 CI _ -H -CHz-S-CHz \ ~ C1 -H -0 \ / CI

-H -CHz-S-CHz \ / 6te -H \ / CFa -H -CHz-S-CH=-CH= ~-/ -H -SS \ / C1 I

,Cl -H -Ctlz-S-Cffz-CHn~l -H -~~ C1 H CHz CHz-0-CHz \ / NHz -H -S'-'~ CI

-H -CHz-CHz-S-CH \~/ I -H
~/'NH Z
-H -CHZ-CH1-5-CH \ / Br 0 _H _~~ 0 ~Me :able 1 (Cvnt'd) NH=CHz/ ~Ci1 iC00ff R, Rz -R~ . -Rz -R~ -Ra -OH -CHz-C(CH,)~ -CH3 -CHCCHs)Z
-OH -CHz-CHz-CH, -CH3 -CHZ-CHCCH3)Z
-OH -CHZ-CH2'CH~-CH, -CH3 -CHZ-CH~-CAz-CHs -OH -CHp-CHCCNs) s -CHs \ /
-OH ~ /
-CH s --~\~/ --C1 -OH \ ~ -C1 -CHs -MHz \ /
-OH
-CHs -~CA=---OH \ / Me -CHz-CH, -CHZ-CHCCHs)z -OH -CH Z -0- ~ /
-CH, -OH
-CHz-CHa -CHZ \ /
-OfI ~C~, ~H -CHz-CHa \ / C1 -OH
-CHZ-CH, -CHZ \ / C1 -OH
-CH=-CH3 -OH
I I ~0 -CHz-CHs -OH ,N
wI
-CH z-CEi s -CHI -CHZ-CHs-CH, Table 1 (Cont'd) I~HzCHx-C-CH=COOH
R~~a _R. _Rs -R~ -Rx -H -CH=CH-CHI -H -CIi=CH-CHx-CHx~CHs -H -CH=CH-CHt-CH3 -H -CIi-CH-CH(CH9)x -H -CCCHy)=CH-CH9 -H -CH6C(CHa)z Table NH=CHZ-C -CHzC00H
/\
R, R=
~R ~
\R= C Ra %~.~-S Me i ~ /

C1 NHz Br COON

~~C1 F3r ~Br Br C F , Me O H Me Me ~~~ M a O Me Me Table 2 (Cont'd) NHsCH= ~~ CHsCOOH
R, RZ
/C\R> > .~R~
C
_ i Pro a ) U
Me i Pro a ~,..
M a ,,~ '--' i Pro M a ''-' i Prv ~Me Me i Pro Et n Bu Et n $u E t ~ ~; i- n F3 a nPr~o / i F3u ,, n Pro i $ a ~~~ n Pro ~~~~ i H a n Pro ~t Bu n Pr ~/o Table 2 (Cant'd) NHeCHt~C-CHcCOOH
/\
R, R=
C R, /C\Rx ~R z t Bu ~~NH=
O M a ~ ~/
/~~N H
O M \\~~//e /~
~;~0 ~~ O M a ~i~ S
OMe .. .
OMe _ \ /
\ /
M a N Ii 1~I a ~~~~~ O H O
O Fi M a O
OH ~Me y0 ~OH . ~C1 'Table Z ( Cont' d ) NH~CHr ~~ CHaCOOH
R, R=
/C\Rs lC\Rs Me \5 /

C 1 1.
Me \ /
S
O ~ O
%/~S \ /

~,~'~ N H
j -C F , J
%~ M a C1 %~Ma ~(~~..M a Ma '~~/
/ \

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 in preparing a pharmaceutical preparation of, for example, gabapentia, pregabalin, baclofen, 3-aminomethyl-4-cyclohexyl-butanoic acid, 3-aminomethyl-5-cyclohexyl-pentanoic acid. 3-amin,omethyl-9-phenyl-butanoic acid. 3-aminomethyl-5-phenyl-pentanoic acid, etc.
The humectant which may be employed in the invention in combination with a 9-amino-3-substituted-butanoic acid derivative is selected from ethylene glycol.
propyJ.ene glycol, butylene glycol, sorbital and glycerol and an aliphatic acid ester thereof. alone or :a any combination of two o~ 'vre thereof.
illustrative examples of the glycerol aliphatic acid esters may include glycerol lower aliphatic acid esters such as monoacetylglyceride, diacetylglyeer~de, triacetylglyceride (triacetin), middle chal_~. aliphatic acid mvnoglyce-ide such as monohexanoylglyceride, monooctanoylglyceride, monodecanoylglycer~de, and rnzddle chain aliphatic acid polyglycervl ester such as monolauric acid polyglyeeride or monomyristic acid poiyglyceride 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 aux~l~ary agent for manufacturing a pharmaceutical preparation are added to bulk powders of a 4-amino-3-subst'~uted-butanoi.c 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 tabletinq step _:. whic:~ the resulting gx'anulaz~ powders at-e compressed by means of a tableC machine and, if necessary, the coating step in which the granular powders, tablets or granules ZO 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 WO 99/59572 PC'T/US99/10186 such as ga5apentin may be conducted by any granulation :aethod wel_-known gg~ fig, For example, a fluidized granulation method, a high speed stirring granulation method, a melting granulation method and the like. In order to effect-vely adhere a stabilizer to bulk powders of the 4-amino-3-substituted-butanoic acid derivative, there may be preferably employed a flui,di.zed granulation method xn which bulk powders of the said compound are fluidized and then a stabilizer is sprayed unto the fluidized powders. In this fluidized granulation step, a stabilizer is added in the form of its solution dissolved in water yr an organic solvent such as alcohols or the like, whereby a small. amount of the stabilizer may be sufficient for uniformly adhering to the surfar_e of buJ.k powders of the 9-amino-3-subsituted butanoic acid derivative.
~~n the granulation step using said °luidized granuJ.atio~ method, granulation may be carried out by adding to bulk powders of the 4-amino-3-substituted-butanoic acid derivative ;.hP stabilizer solution as described above and.
if necessary, a binder such as corn starch, a ceiluiose derivative (e. g., hydroxypropylcellulose), polyvinyl alcohol, a polyvinyl pyrrolidone (e.g., Kollidon-K30 or Kollidon-K25), a copolyvidone (e.g., Ko7_lidon-VA64) and the like in the form of a solution or suspension thereof.
The aforementioned stabiliaez solut~.on 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 prepaxation_ The granular powders thus obtained may be used as a pharmaceutical preparation of the Q-amino-3-substituted-butanoic acid derivative as such, or they may be also encapsulated under compression for capsules containing the 4-ammo-3-substituted-butanoic acid derivative. Also, they may be further compressEd to tablets.
More specifically, the granular powders of the 4-amine-3-substituted-butanoac acid derivative obtained as described above can be compression-molded to tablets by means of a tablet machine. It i5 2ssenti.a7. in this compression-molding step to use a lubricant as ordinarily done for the manufacture of a pharmaceutical preparation.
However, ;;. has been discovered that some conventional - 45 _ lubricans employed in a compression-melding 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 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-leucine, L-isvleucine, 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 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 stabiliser.
Thus, in this cvmpressien-molting step, the resulting granules may be usually blended with t.-leucine, L-isvleucine, L-valine, D-leucine, D-isoleucine, D-valine, DL-leucine, DL-isoleucine, DL-valine or a mixture thereof as a lubricant and, i.~ necessary, an au.ciliary for manufacturing a pharmaceutical preparation, fvr example, a binder or a dis~ntegrator 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, 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 exalaple, in case oL 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 (HPMC), etc., a polyvinyl pyrrolidone. Kollidon-VA64, Eudragits, etc.. and as a sweetening agent mannitol.
sorbitol. xylitol, aspartame and the like.
?0 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, T,-valine. L-alan~ne.

D-leucine, D-isoleucine. D-valine, D-alanine, DL-leuc~ne, 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 plastieizer for a coating film, while L-leucine. L-isoleucine. L=valine, 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 ac:.d derivative is gabapentin, glycine. L-aianine, D-alanine and DL-alanine may exhibit a:. activity as a buffering agent against bitter taste of gabapentin. The surface-coating of the granular powders, granules or tablets may be appJ.ied to the surface of the granular powders, granules or tablets according to a well-knowr, method using a fluidized bed cr 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 q-amino-3-substituted-butanoic acid derivative, or in an amount of 0.01 - 25$ by weight relative to the total amount of the 9-amine-3-substituted-butanoic acid derivative and the auxiliary agent when added for manuLacturing a pharmaceutical preparation.

- ~48 -The total amount to be used may be varied depending upon the sort of the humectant tv be used, the specific dosage form of the solid composition containing the 4-amine-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 9-amino-3-substituted-butanoic acid derivative by ensuring a water retention of the pharmaceutical preparation. Anal, in many cases, a total amount of the humectant may be preferably in the range of 0.02 - ZO$ by weight relative to the 4-amino-3-substituted-butanoic acid derivative, or it may preferably be in the range of 0.0Z -20$ by weight relative to the total amount of the 9-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-amino-3-substituted-butanoic acid derivative, the amount of the humectant to be used in the surface-coating step may be 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 acrd derivative, use of a certain neutral amino acid including L-leucine, L-isoleueine, L-valine, L-alanine, D-leucine, D-isoleucine, D-valine, D-alanine, DL-leurine, DL-~soleucine. DL-valine, DL-alanine and glycine, instead of the au:ciliary agent commonly used for manufacturing a pharmaceutical preparation, can bring about the desired pharmaceuticz~l preparation without any prevention of_ the water retention effect of a humectant as a stabiliser of this invention. In other words, the said neutral amino acid 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-butanoi.c acid derivative including the ZO 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 0.05 - 40~ by weight relative to gabapentin.

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 9-amino-3-substituted-butanoic acid derivative without conducting the tableting step, or the granules as prepared by the granulation step may be further subjected ~o the surface-coating step as descra.bed 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 fiJ.led mto gelatin hard capsules by means o~ a capsule filler to prepare capsules. In the solid preparation of the 4-amino-3-substituted-butanoic acid derivative thus prepared. for e~cample, in case of the gabapentin preparation. gabapentin is in a compressed or fluidized state so that the solid preparation may be easily S taken whet 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 buJ.k powders of gabapentiri was sprayed ~2 g of water by means of a fluidized granulator (manufactured by FREUNJ~ Co., Ltd., 5FC-Labo) and then dried to obtain gabapentin granular powders A.
2) Prepara~ion of granular powders B of gabapentin On 250 g of bulk powders of gabapentin was sprayed a solution of S g of propylene glycol in 67 g of water by means of said fluidized granulator and then dried to obtain gabapentin granular powders 8.
The gabapentin granulaz 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 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 gabapentin.
Storage conditions Granular powders A H
When initiated 0.003 0_003 60°C/1 week (sealed) 0.011 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 degr3cation 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 subsequently a solution of 5 g of hydroxypropylcellulose in 58 g or water was sprayed thereon, and then dried to obtain gabapentin granulax 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 imanufactured by FREUND Co., Ltd., 5FC-Labo) and subsequently a solution of 5 g of hydroxypropylcellulvse in 58 g of water was sprayed thereon, and then dried to obtain gabapentin granular powders D.
3) Prepara~ivn of granular powdezs E of gabapentin On z50 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 S g of hydroxypropylcellulose in 5B g of water was sprayed thereon, and then dried tv obtain gabapentin granular powders E.
4) Preparation of granular powders F of gabapentin On 250 g of bulk powders of gabapentin was sprayed a solutior_ of 2.5 g of propylene glycol and 2.5 g of triacetin in 67 g of water by means of the said fluidized granulatvr and subsequently a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon, and then dried tv obtain gabapentin granular powders F_ The gabapentin granular powders C - k~ obtained as described in the above 11 - 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 E F

When initiated 0.004 0.0030.003 0.003 60C/1 week (sealed) 0.131 0.0760.044 0.072 60C/2 weeks (sealed) 0.214 0.1300.118 0.124 50C/8S$ humidity/2 weeks (open) 0.011 0.0080.006 0.007 50C/85~ humidity/4 weeks (open) 0.012 0.0130_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 triacetin yr both of them.
z0 Example 3 1) Preparation of gabapentin granules On 700 g of bulk powders of gabapentin was sprayed a solution of 14 g of copvlyvidone and 14 g of propylene glycol in Z52 g of water by means of a f=uidized granulator (manufactured by PREUND Co., Ltd., SFC-Minx) 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 7v 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
SEISAKUSHO 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 seep 2) were film coated over the surface thereof with a coating solution having the composition as defined in the following Table 5 by means o~ a coater (manufactured by FREUND Co., Ltd., HI-COAfOR HCT-30) .
Copvlyvidone 34.0 g L-Isoieucine 13.5 g Glycine x,3.5 g Propylene glycol 7,0 q Calcium stearate 7.0 g 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 coma~nercially 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 ($)~
Gabapentin preparations (I) (II) (III)*
when initiated 0.005 0.009 0.018 90~C/75~ humidity/2 months (sealed) 0.048 0.066 0.072 40°C/75$ humidity/4 months (sealed) 0.123 0.119 0.129 40°C/75$ humidity/6 months (sealed) 0.229 0.172 0.219 [Note) *'com~ercially available gabapentin capsules prepared according tv a dry blend method, eac~ 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 gabapent~.n capsules prepared by a dry blend method.

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 S 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 oP ~.
Table 7 IO Dissolution time (min.) Storage conditions when initiated GO°C/9 hrs (sealed) 1S 90. 3 97, .5 30 103.1 103.3 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

200 mg of baclv~en 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.
2l Preparation of baclofen powder sampJ.e H
200 mg of baclofen crystals was wetted with 0.04 ml of a 20~ aqueous solution of propylene glycol and the mi:cture was made to granular powders by means of a mortar and then d.tied tv obtain baclofen powder sample H.
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 condensatea formed in each of the samples was determined by means of HPhC. In this Example, the content of the dehydrated condensates is expressed in terms of ~ by weight, based on baclofen.
Tahle 8 Storage conditions Samples Untreated baclofen G H
when initiated 0.10 0.10 0.10 60°C/1 week (sealed) 0.36 0_95 0.92 60°C/2 weeks (sealed? 0.57 1.26 0.61 60°C/3 weeks (sealedl 0.70 1.54 0.82 The above table shows that the granulated baclvfen 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 of watez and, the mixture was made to granular powders by means of a mortar and then dried to obtain pregabalin powdex sample I.
2) Preparation of pxegabali.n powder sample J
1 g of pregabalin crystals was wetted with O.l ml of a 1~ aqueous svl,ution 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 pxegabalin 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 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 conditions as defined in the following Table 9 and then a content of the dehydrated evndensate formed in each of the samples was determined by means of HPLG. In the present Example and the following Example 6, a content of the dehydrated cvndensate is expressed in terms of L by weight, based on pregabarin.
Storage conditions Samples Untreated I J K

l0 pregabalin When initiated <0.001 <0.001 <O.OOI <0.001 60C/1 week (sealed) 0.001 0.009 0.001 0.001 60C/2 weeks (sealed) 0.001 0.010 O.OOZ 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 o~ tune could be prevented by the addition of decaglyceryl monolaurate yr 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 of a lOv aqueous solution of hydroxypropylcellulose and the mixture was made to granular powders by means of a mortar and then dried to obtain pregabalin powder sample L.
Z) Preparation of pregabalin powder sample M
1 g of pregabalin crystals was wetted with O.X ml of an aqueous solution containing 10~ hydro:cypropylcellulose 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.
~he 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.
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 O.OOZ
60°C/4 weeks (sealed) 0.014 0.004 ZO
The above table shows that the degradation with lapse of time (condensation with dehydration) of the pregabalin could be prevented by the addition of 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 9-amine-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 prov~_ded a means for stabilising pharmaceutically unstable 4-amino-3-IS 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 z0 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 invention can be expected to greatly contribute to the development of a stabilized pharmaceutical composition containin,; the 4-amino-3-substituted-butanoic acid derivative.

Claims (15)

What is claimed is:

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, 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.

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 stabilized solid composition of claim 1, 2, 3, 4, or 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 claim 1, 2,3,4, or 5, wherein a total amount of the humectant is 0.01-25% by weight relative to the 4-amino-3-substituted butanoic acid derivative and the optional auxiliary agent.

8. The stabilized solid composition of claim 1, 2, 3, 4, or 5, further comprising one or more neutral amino acids.

9. The stabilized solid composition of claim 8, wherein the one or more neutral amino acids are L-leucine, L-isoleucine, L-valine, L-alanine, D-leucine, D-isoleucine, D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine or glycine.

10. The stabilized solid composition of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the stabilized solid composition is a pharmaceutical preparation in the form of tablets, granules or capsules.

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 solid 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 a compound selected from ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerol, or an aliphatic acid ester of glycerol.

15. The use of claim 13 or 14, wherein the solid pharmaceutical composition is in the form of tablets, powders, granules or capsules.