Title of Invention

A STABILIZED SOLID COMPOSITION

Abstract 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, and the humectant is one or more compounds selected from ethylene glycol, propylene glycol, butylene glycol, glycerol, wherein the total amount of said humectant is 0.01-25% by weight relative to the 4-amino-3-substituted butanoic acid derivative.
Full Text FORM 2
THE PATENTS ACT, 1970
[39 OF 1970]
COMPLETE SPECIFICATION [See Section 10; Rule 13]
"A STABILIZED SOLID COMPOSITION"
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:-


The present invention relates to a stabilized solid composition.
This invention relates to a stabi.iied solid composition comprising a 4-amnino- 3-substitued ec-butanoic acid derivative and a process for the preparation cf the same.
Also, this invention relates to a solid pharmaceutical preparation of the 5-aminc-3-subtituied-butanoic acid derivative comprising the stabilize solid composition and a process for the preparation cf "the same.
More particularly, the invention is concerned with a stabilized solid pharmaceutical preparation of the 4-amino-3-substituced-butanoic acid derivative, including
gabapentin, pregabalin, baclofen, 3-amino-.ethyi-4-
pentanoic acid, 3-ammomethyl-4-phenyl-became acid or 3-
aminomethyl-3-phenyl-pentanoic acid, in .he dosage forms of
tablets, powders, granules and capsules, as -well as a process
for the preparation of the same.
BACKGROUND OF THE INVENTION 1-(Aminomethyi)cyclohexaneacetic acid, one of the 4-amino.no-3-substi tuted-butanoic acid derivatives, having the

WO 99/59572 PCT/US99/10I86
following structural formula 15 disclosed in U.5. Patent Nos> ■ 4,024,175 and 4,087.S44 and has been caliea " gabapen t ;r.", a generic name, aue to lis structural relation to Y-aminobutync acid (GABA) .

Gabapentm easily passes across the brain carrier. Owina to
this. the ccmpound is used as a meaicme fcr the treatment
of certain cerebral diseases such as certain icrros cf
■"
epilepsy, faint and hypokinesia as well es crenial traumas,
and also for improving the cerebral functions in senile
patients.
Moreover, U.S. PatenC No. S,084,47° discloses Chat
gabapentir. 15 used for Che treatment cf neuroaegenerative
disorders such es Alzneimer"s disease. Hur.::r.;:cr."s cr.orea
or Parkinson"s disease and amyotrophic lateral sclerosis.
U.S. Patent No. 5,025,035 discloses that gebacentin _s used
for the ireatisenc cf depression U.S. Patent No. 5,^10,381
discloses that cms compound is used for the treatment cf
mama and bipolar disorder. Furthermore, this compound,
having an analgesic act;vity, is expected to be used as
analgesics. Under these circumstances, there has been a
3

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PCT/US99/I0186






10
15
20

greatly increased utility of gabapentm as she therapeutic agents Cor those diseases or disorders or conditions as recited above, in addition to cerebral diseases such as epilepsy ana the like-As stared above, gabapentn is a very effective drug for cerebral diseases such as epilepsy and the like, and it has =n extremely low toxicity. However, in order to maintain the effect as expected, it has beer, 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 dieided 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 fluidity and that an extremely high dosage should be required for administration in the dosage torn-, ot powders.
Since gaoapantin is very difficult to fomulate because of instability, gabapentin capsules now available in the oversea markets are those manufactured by a simple ary blending of gabapent with necessary auxiliaries and subsequent 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-sized capsules; for example, Capsule No.
0 sould te applied to capsules having a content of 400 mg
per capsule Consequently, ingesting such capsules is
difficult aven for adults, much more for children. Although
gabapension capsules have already been markated, it is still
inaispsn5ao_e to attempt any improvement in compliance and
easy administrator.trat on of gabapentin, and a demand for a
smalier-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 fluidizmg of the drug having such powder propercies end the molding properties should be improved with the aid of pharmaceutical auxiliaries. However, many of the auxiliaries to be applied for compression molding tend to react wich caoapentir. with lapse cf time :c form 4-cyciohexylpyrroiiccne (the corresponding Lactam form) by accelerating the dehydration reaction between the amino group and trie carboxyl group within the T.c.ecuie of gahapentir. . This dehydration reaction would te far more accelerated as the gabapentin powder is oerng rr.ore tightly compressed. Moreover, tne reaction between gabapentin and
6






such auxiliaries with lapse of time would be further acceleratec by the use of water or an organic solvent in manufacturing a pharmaceutical preparation..
It has been standardized in ccrcmercially available gabapentin capsules that an allowable content cf 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 cf the .lactam by retarding the zehyaration reaction aetween the amino group and the carooxyl group within the molecule of gabapentm. On the other hand, there has been a demand for a small-sized dosage form for easier ingesting ;s 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 forni resulted due to alarge amount of the auxiliaries used cr because an increser amount of the lactam formed or both of them.
Such instability as encountered in manufacturing a gabaper.tir. preparation has been also observed in other 4-amino-3-SUBSUITUTED-butanoic acid derivatives which are structurally analogous to gabapentm and have a structurally
6






bulky subsequent at the 3-position there of sinilarlv to gabapentin.
For example, 4-amino-3-p-chlorocpnerny_ butanic acid, which 15 represented by the following structural formula and called "baclofen" m a generic r.ane.

and b-methyl- 3-eminomethyl-hexanoic acid, represented by the following structural formula and called "pregabalin" in a generic name,
CH:-CH{CHj)2 H,N-H,C-CH-CH,-COOH
are also a drug which has very poor compression.nolcability and fluidity like gabapentin. Compression molding or granulation used for small-sizing or fluiaizir.c ihe drug snould De improved with the aid cf pharmaceutical auxiliaries. However, many of the auxiliaries to be applied to compression molding tand to react with gaoapentin with lapse of rime to form 4-cyclohexylpyrrol idone (the
7

WO 99/59572 PCT/US99/I0186

corresponding lactam form) by accelerating the dehyaration reaction between the amino group and the carooxyl group within the molecule of the compound. This cerydration reaction would be far more accelerated as the compound is 5 oeirg /more tightly compressed and would he further
accelerated by the use of water or an organic solvent in manufacturing a pharmaceutical preparation, as is the case of gabapentin. It may be said that the mechanism of degradation. by the autocondensation is peculiar to the 4-
10 amino- 3- substituted-butanoic acid derivatives raving a
structurally bulky substituent at the 3-position there of.
Tc the contrary, in y-aminobutyric acid derivatives having no or a less bulky substituent at Che 3-position thereof, such as Y_aminobutyric acid or 4-amino-3-
15 hydroxy-butanoic acid, the dehydration reaction. is not
brought about, even when maintained in a driec state such as at a temperature of 105°c over 2-3 hours. and the formation of 4-cyclonexylpyrrolidone (the corresponcess lactam form) is not observed. In other words, in the 4-emino-3-
20 substicuied-butanoic acid derivative wherein the substituent at the 3-position -hereof has a bulky structure, the dehydration reaction could easily be brought about between the amino group and the carboxyl group within she molecule.
8

WO 99/59572 PCT/US99/I0186
In view of the aforesaid background, for drugs which are 4-amino-3-substltuted-butanoic acid derivatives, including gabapentin, having a structurally bulky substituent at the 3-position thereof, there have been desired a new pharmaceutical preparation containing said drugs which may be small-sized or fiuadized in a dosage form such as tablets or granules and may have a comparable storage stability to commercially available, pharmaceutical preparations including commercially availaole gabapentm 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 found that the degradation of 4-amino-3-suDstituted-butanoic acid derivatives including gabapentin owing to the lactam formation curing the formulation and .storage :an be prevented by blocking the evaporation and movement of a very small amout of residual water in a solid composition containing the A - amino-5-substituted-butanoic acid cerivative manufactured, irrespective of formulation methods employed, that it is effective to add a humectant es a stabilizer against decradation and that a solid composition containing


the 4 -amino-3-subtituted butanoic acid derivative stabilised by said humectant and a solid pharmaceutical preparation using said composition such 55 tablets, granules or the like have an excellent storage stability, en the 5 sasjs cl wnich this invention has been completed.
DETAILED DESCRIPTION OF THE ZNVTCNTION
The present invention relates tc a stabilized
solid composition containing a 4 - amino- 3- suJrst ituteo-
0 toutanoic acid derivative which comprises a. 4-3ramo-3-
substizutec-butanoic acid derivative havir.g the general
formula
NH.,CH,~C-CH2COOH / wherein,
P.. is B hydrogen ecom, a hydroxyl group, 3 aethyl group or an ethyi group;
R- is a monovalent group selected frcn
0 a straight or branched alkyl group of 3 - 3 carbon
atoms;
e straight or branched allcyiene group o: 3-6 carbon atoms,
Wo-

WO 99/59572 PCT/US99/10186
- tffe -
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 Elkoxy group, an alkylthio group, an amino group, a nitro group, an oxo group, e carboxyl group or a carboalkoxy ;rcu;
a cycloalkyl group of 3 - 8 carbon atoms;
a cycloalkyl group of 3 - 8 career. atoms which is mono-, di- or tri-substi tuted with a haloger. atom, a tnfluoromethyl group, a hydroxyl group, an a^xyl group, an alkoxy croup, an alkylthio 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 orthc-fusion of a phenyl ring with a cycloalkyl group of 4 - 8 carbon atoms wherein said phenyl ring is mono-, di- or tri-substituted "it a haloger. atom, a trifluoromethyl group, 2 hyaroxyl group, an alkyi group, an alkoxy group, an alkyl;h:o group, an ammo group, a nitro group, a carboxyl c;rcup cr a carboalkoxy group;
a condensed ring group formed by oxtho-fusion of a phenyl ring with a cycloaU.enyl group of 5 - 8 carbon atoms o a cycloaIkanedienyl group of 5 - 8 carbon atoms; "
-/(-

WO 99/59572 PCMJS99/10I86
- a condensed ring croup formed by crtho-fusion of a phenyl ring with a cycloal kenyl group of 5 - B carbon atoms or a cycloaikanedienyl group of S - 8 carbon atoras wherein said phenyl ring is mono-, di- or tri-substitutea with a halogen atom, a triflucromethy! group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an ammo group, 5 r.itro group, a carboxyl group or a carboalkoxy group,
en al kyl cycloal kyi group wherein saici cycloaikyl has 3-8 carbon atoms and is linked to an alkylene grouc having 1-4 carbon atoms optionally interrupted with -0-, -5- cr -SS-;
an alkylcycloaiky 1 group ^herein said cycloaikyl has 3-8 carbon atoms, is jinked to an alkylene group having i - a cycloaikyl group o f 5 - 9 carbon = coms wherein cne of the methylene groups (-CH2-1 is replaced oy -0-, -NH-, -S-, -SO- or -S(O);-;
4 1-

WO 99/59572
PCT7US99/10186 e cycloalkyl group of 5 - 8 carocn atoms "herein one of "he methylene groups (-CH7-i is replaced by -O-, -NH-. -S-, -SO- or -5(0),-, and one or two of the ur.substi tuted methylene groups (-CH?~) are mono- or ci-substituted with a halogen atoir., a tr 1 fluoromethyl group, a nyoroxyl group, an alkyl group, an alkoxy group, an alkylthic group, an amino group, a nitro group, an oxo group, a carboxyl group or a carbcalkoxy group;
a cycloalkenyl group cf 5 - 8 caroon atoms or a cycloalkanedlenyl group of 5-3 carbon atoms, one cf the methylene groups (-CH.,-) in said cycloalkenyl ring or cycloaikanedienyl ring being replaced by -O-, -NH-, =N-, -S-, -SO- or -5fO)2-;
a cycloalkenyl group.or 5-8 carbon atoms or a cycioalkanedienyl group of 5-3 carbon atoms, one of the methylene groups (-CH,-) in said cycloalkenyl ring cr cycioalkanedienyl ring being replaced cy -0-. "-NH-. *N-, -5-, -SC- or -5(052~, and one or ;wo of the unsuostituted methylene groups (-CH,-) being mono- or ci-substituted "ith a halogen atom, d trifluoromethyl group, a hydroxyl group, an alky", group, an alkoxy group, an alkyltriio group, an amino group, a nitro group, an oxo group, a carboxyi group or a carcoalkoxy group,

WO 99/59572 PCTAJS99/10I86
a condensed ring group formed by orthc-fusion of a phenyl ring with a cycloalkyl group of ~ - 9 carbon atoms wherein one of the methylene group;- i-CH--. is replaced by -0-, -NH-, -5-, -SO- or -5{0),-;
a condensed ring group formed by errno-fusion of a phenyl ring with a cycloalkyl group of 5 - 5 carbon atoms wherein one of the methylene groups is replaced by -0-. -NH-, -S-, -SO- or -5(0)?-. said phenyl group being mono- or ci -substitutea with a halogen atorr., a trifluoromethyl group, a hydroxy! group, an alkyl group, an alkoxy group, an alkylthio group, an ammo group, a nitro group, a carboxyl group or a carboalkoxy crcup;
c-
a condensed ring group formed by ortho-fusion of a phenyl ring with, a cycloalkenyl group or 5 - 8 carbon atoms or a cycloalkanedienyl group of 5 - 8 caraon atoms, one of the methylene groups (-CH.-) in said cyclcaikenyl ring or cycloalkar.eaienyl ring being replaced by -0-, -NH~, =N-, -50- or -5(0),-;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenyl group of - - 3 carbon atoms or a cycloai kanedienyl group of b ■ 8 carDor. acorns, one of the methylene groups {-CH,-) in said cyclcaikenyl ring or cycloalkanedienyl ring being replaced by -O-, -NH-, =N-, -5
(^

WO 99/59572

PCT/US99/10186

- ^jgs? -
-SO- or -S 10} 2-, said phenyl ring being rr.cr.o- 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 cerboalkoxy group;
an alkylcycloaJ Kyi group "herein said cycioalkyl has 5-3 carbon atoms and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted >-ith -O-, -5- or -5S-, one of the methylene groups (-CH,-) _n saia cycioalkyl ring being replaced by -0-, -NK-, -5-, -SO- cr -S(0),-,
an alkylcycloaiKyl group wherein 5310 cycioalkyl has S - 3 carbcn atoms and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -0-. -S- or -S5-, and one of the methylene groups (-CH.-) m said cycioalkyl ring being replaced by -0-, -NH-, -5-, -SO- cr -5(0)z- and one or two of the unsubstituted "ethylene groups t-CJi--: being mono-, ai- or tri-suostitur.ee -j.-r. e. halogen atom, e trifluororaethyl group, a hydroxyl group, 2n aikyl group, an alkoxy group, an aikylthio group, ;r. amino group, a nitro group, an oxo group, a carboxyl croup or a carboalkoxy group;
a phenyl or naphthyi group;

PCT/US99/10186
- -*-5 -
a phenyl group substituted wufi a nethylenedioxy group;
a pnenyl or naphthyl group which is rr.cno-, di - or tri-substi.uT.ed "ith a halogen atom, a tr;fiuororr.ethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a r.itro group, a carboxyl group, a phenoxy group- a pr.enylmethoxy group, a phenyimethoxy group wnerGin saic phQnyl ring is mono-substituted v-ith a halogen atom, tn f iuoromethyl group, an alkoxy group, an ammo group, a r.itro group, a carboxyl group or a csrooalkoxy group, a cycloalkyimethoxy group having 5-8 carbon atoms in the cyclcaikyl ring, a cycloalkenylmethoxy group having 5 - 8 carbon atoms in the cycloalkenyl ring, a cycloalkanedienylmethoxy group having 5-8 carbon atoms in the cycloalkancdienyl ring, a cycloalkylmetr.oxy group wherein one of the methylene groups i-CH,-: :r. ;aid cycloaikyl ring having 5-8 carbon atons is replacea by -0-. -NH-, -3-, -SO- or -5(05,-, a cycioalkenyimethoxy group wherein cr.e of the methylene groups (-CHJ-J m said cyclcalkenyl. ring having 5-9 carbon atari* is replaced by -O-, -NH-. =N- , -5-, -SO- or -5{0),-, a cycloalkanedienyl¬methoxy group wherein one of the methylene groups ;-CH,-5 in said cycloa i kranecienyl ring having 5-8 carbcn atoms :s
-~/6~

YVO 99/59572 PC17US99/I0186
- *6 -
replaced by -o-, -NH-, «N-, -5-, -SO- or -S(OJ:- group, a cycioalkylmethoxy group having 5-8 careen atoms in the cycioalkyl ring wherein said cycloalkyi ring 15 mono-substituted with & halogen atom, tnf luoromethyl group, 5 a hydroxy group, an alKyl group, an alkoxy group, an amino group, a n;;ro group, a carboxyl group or a carboalkoxy group and one of the methylene groups (-CH.-) m said cycioalkyl ring 15 replaced by -0-, -NK-", -S-, -50- or -5(C) -, e cycloalkenyimethoxy group r.avir.g 5-8 carbon
10 atoms in the cycloalkenyl ring wherein said cycloalkenyl ring is mono-substituted uith a halogen atom, a trifluoromethyl group, a hydroxy group, an alkyl group, an aikoxy group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group and one of the
15 methylene groups (-CH,-) in said cycloalkenyl ring is replaced by -O-, -NH-, =N-, -5-, -SO- or -5(0),-, or a cycioalkaneaienylmethoxy group having 5-8 carbon atoms 1.-. the cycloalkanedienyl ring wherein said cycloalkanedienyl ring 15 mor.o-subst 1 tuteci with 3 halogen atom, a
20 tnf luoromethyl group, a hydroxyl group, sn alkyl group, an aikoxy group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group and one cf the methylene groups (-CH?-) in said cycloalkanedienyl ring is
-f? -

PCTAJS99/I0I86
replaced by -O-, -NH-, = N-. -S-. -SO- or -5i0!,-;
an aikylphenyl group wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -0-, -S- or -55-;
an alkyl-O-, -5- or -SS-phenyl group -nerem said phenyl group is linked to an alkylene group having 1-4 carbon atoms via -O-, -S- or -55-;
an -O-, -S- or -5S-phenyl group;
a aiphenyiammo group.
an aikylphenyl group wherein said phenyl group is linked to an alkylene group having Z - 4 carbon atoms optionally interrupted with -O-, -5- or -55- and mono-, di-tn-substituted with a halogen atom, a tniluoromethyl group, a hydroxyl group, a alkyl group, an tlkoxy group, an amino group, a nitro group or a carboxyi group.
an alkyl-O-, -5- or -55-phenyl group -herein said phenyl group is l;.nked to an alkylene c:o-:; r. = ving 1-4 carbon atoms via -0-, -5- or -SS- and mono-, ci- or tri-substituted with a halogen atom, a triflucromethyl group, a hydroxyl group, an alkyl group, en
alkoxy group, an amino group, a nitro group or a carboxyi group;
-//-

WO 99/59572 PCT/US99/I0186
an -O-, -5- c: -55-phenyl group wherein saia phenyl group 15 mono-, di- or tri-substituted wi-.-i a nalogen atom,.
a tr i f i uororee Chyi group, a hydroxyl group. 5.7. alkyl group, an
alkoxy group, an amino group, a nitro group or a carboxy!
b group;
or
Ft. and R^, together with the carbon atcir to whicn they are attached, may form a divalent group selected from: a cycloaikylidene group of 5-8 careen atoms.
0 a cycloaikylidene group of 5-3 carcon atoms which
is mono-, di-, tri- or tetra-substituted -it,1-, e halogen atom, a trifluoromethy] group, a hydroxy! grcup, an alkyl group, an aikoxy group, an alkylthio group, a cycloalkyl group, a phenyl group, an amino group, a nitre group or a
5 carboxyl group;
£ cycloaikylidene group of 5-3 careen atoms wherein one of the methylene groups (-CK--) in se.L~ cyclcalkyl ring is replaced by -O-, -NH-, -S-, -SO- or -SiOi--;
a cycloalkylidene group of 5 - S carbon atoms wherein
0 one of the methylene groups i-CH?-) in ssic" cyclcalkyl ring is replaced by -O-, -NH~, -S-, -SO- or -S:0),- group and one or more of the ur.subst I tuted methylene groups ;-CH,-) m said cycloalkyl ring are mono-. di~, tri- or tetra-substizuted
^ff~

WO 99/59572
- JS9- -
with a halogen atom, a trifluoromethyl group, 3 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 cycloalkenylidene group of 5 - 8 carbon atoms cr 5 cycioalkanedienylidene group of 5 - 8 carbon atoms;
a cycloalkenylidene group of S - 8 caruon atoms or 6 cycioalkanedienylidene group of 5-8 carbon atoms which 15 mor.o-, di-, :ri- or tetra-substituted with 3 halogen atom, c crifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, a cycloalkyl group, a phenyl group, an ammo group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a cycloalkenylidene group of 5 - 0 carbon atoms or e cycioalkanedienylidene group of 5 - B carbon atoms wherein one of the methylene groups (-CHj-)" in said cycloalkenyl ring or cycioalksneaienyl ring is replaced by -O-, -NH-. =N-, -S-, -50- or -S!0);-;
a cycloalkenylidene group of 5-8 carbon atoms or a cycioalkanedienylidene group of 5-8 carbon atoms wherein one of the methylene groups (-CHZ~) in said cycloalkenyl ring or cycloaikanedienyl rang is replaced by -O-, -NH-, -N-, -5-. -50- or -3{C),- group and one or more of the unsubstituted
^.
Vp 99/59572 PCT/US99/10186
- ~2® -
methylene groups a condensed ring group formed by ortho-fusion of a phenyl rir.g with a cycloalkylidene group of 4 - 8 carbon atoms;
a condensed r:ng group formed by orthc-fusion of a phenyl ring with a cycloalkylidene group cf a condensed ring group formed by or~hc-fusion of a phenyl ring with a cycloalkenylidene grouF cf 5 - 8 carbon atc^s or a cycloalkanedienylidene group cf S - 8 carbon atoms
5 condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkenylidene group cf r "- 8 carbon atoms or a cycloalkanedienylidene group of 5 - 8 carbon atoms, saic phenyl ring being mono- or di-subsm tuted with e.
-1A

WO 99/59572

PCT/US99/10I86

- ^24--
halogen atom, a crifiuoromethyl group, a hydroxyl group, an alkyl group, an alkoxv group, an alkylthic group, an amino group, a r.itro group, a carboxyl group or a carbcaikoxy group; a numectant; and, if necessary, an auxiliary agent for manufacturing a pharmaceutical preparation.
The invention also relates tc a solid composition containing a 1-ammo-3-substituted-buiancic acid derivative which is a solid pharmaceutical preparation in the dosage form of taniets, powders, granules or capsules.
Also, the invention relates to a process for the preparation of a solid composition containing a 1-ajnmo-3-substituted-butanoic acid derivative which comprises combining a 4-ammo-3-substituted-butanoic acid derivative having the following formula
NH?CH,-OCH-C00H 7 \ R. R..
(wherein R, and R7 are as defined above) -ith a huraectant and, if necessary, an auxiliary agent *or ~.anufacturing a pharmaceutical preparation.
The invention further relats to a process for the preparation of a solid composition containing a 4-amino-3-substitutea-butanoic acid derivative which is a solid
^w

WO 99/59572 PCT/US99/10186
- -3« -
pharmaceutical prepration in the dosage fcrr c f cablets, powders, granules or capsules.
The invention furthermore relates ;c a stabilized solid composition containing a 4-aramo-3-suostituteo-butanoic acid derivative which further comprises 5 neutral amino acic.
The 4-amino-3-substituced-butar.cic acici derivatives which may be stabilized accorcing to the present invention mcluae those compounds es listea _r. zr.e following Tables 1 and 2:
^2,3-






25-

PCT/US99/10







WO 99/59572

PCT/US99/I0I86

.^9- -


WO 99/59572 I

PCT/US99/I0I86

- 2&~-






WO 99/59572

PCT/US99/I0186









,WO 99/59572

PCT/US99/I0I86







The present invention provides an extremely effective stabilizing means in manufacturing pharmaceutical preparation containing a emino sunstituted-butanoic acid derivative havir.o a bulky s"jbstituent at the 3-posicion thereof as explained above, and the means of the invention is extremely effective m preparing 5 pharmaceutical preparation of, for example, cabapentir., pregabalm, baclofen, j-aroinpinethyl-^-cyclchexy 1 - ou tanoic acid, j-aniinomethy] - S-cyclohexyi -pentanoic acid, 3-ammomethyl-4-pheny 1 -outancic acid, 3-aminomethyl-S-phenyl-pentanoic acid, etc
The humectant which may be employed in the invention m combination with a A-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 cf t"->o cr r.ore thereof.
Illustrative examples of the glycerol aliphatic acid esters may include glycerol lower aliphatic acid esters such as rr.cnoacetylglycer ide, di acetyl gl yceride, t riacet ylgl yceride (triacetin), middle chair, aliphatic acid mcnoglyceride such as monohexanoylglyceride, monooctanoy1glyceride, monodecar.oyi gl yceride. and middle
—41-

WO 99/59572 PCT/US99/10186
- 1fr>-
chain aliphatic 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 usual cosage form, cypical ly, in the dosage tarm ot ponders, granules, surface-coated granules, capsules, tablets or surface-coated tablets by conducting in turn the granulation step in which a humectant as a stabiliser and, if necessary, en auxiliary agent for manufacturing a pharmaceutical preparation are added to bulk powders of a 4 -amino-3-subs tir-Jted-butanoic acid derivative, such as gabapentin, pregabalin, baclofen and the like and the resulting mixture is granulated by means of a granulator. the encapsulation step in which the resulting granular powders are encapsulated under compression by means of a capsule filler or the tabletmq step ir. wr.ich the resulting granular powders ate compressed Dy 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 1-amino-2-substituted-butanoic acid derivative during the process for manufacturing pharmaceutical preparations as stated above
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- «gr -
such as canapentin may be conducted by any granulation method well-known per s_£, for example, a fluidized cranulaticn method, a high speed stirring granulation method, a melting granulation method and the like. In order 5 to effectively adhere a stabilizer to bulk powders of the 4-aroino-3-suostituted-butanoic acid derivative, there may be preferably employed a fluidized granulation method in which Dulk powders of the said compound are fluidized and then a stabilizer is sprayed onto the fluidized powders. Tn this
10 fluidized granulation step, a stabilizer is added in the form of its solution dissolved in water or an organic solvent such as alcohols or the like, whereby a small amount of the stabilizer may be sufficient for uniformly adhering to the surface of bulk powders of the 4-aiPino-3-subsituted
15 butanoic acid derivative.
In the granulation step using said fluidized granulation rxethod. granulation may be carried out by adding to bulk pc^ders of the 4-amino-3-substi-uted-butanoic acid derivative the stabilizer solution as described above and,
2C if necessary, a binder such as corn starch, a ceiluiose derivative (e.g., hydroxypropyicellulose), polyvinyl alcohol, a polyvinyl pyrrolidone (e.g., Kollidon-K30 or
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-•~&T -
Kollidon-K25) , a copolyvidonc (eg-, Ko J. lidon-VA64 I and the like in the form of a solution or suspension thereof.
The aforementioned stabiliser -solution may be applied to oulK powders of the 4-amino- 3-substituted-S 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
10 auxiliaries for manufacturing a pharmaceutical preparation.
The granular powders thus obtained may be used as a pharmaceutical preparation of the 15 4-amino-3-substituted~butanoic acid derivative. Also, they may be further compressed to tablets.
More sDecifically, the granular powders of the 4-dmino-3-suostltuted-butanotc acid derivative obtained as described above can be compression-molded to tablets by
20 means of a tablet machine It L3 essential 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
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lubricans employed in a compression-molding step for drugs m mfluence 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, "hich have hardly been used as a lubricant in compressing drugs, such as L-leucine, L-lsoleucine, L-valine, D-leucine, D-isoleucme, 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 nime and dissolution property provided by the present scab iluer.
Thus, in this compression-molding step, the resulting granules may be usually blended "ich {-Leucine, L-lsoleucine, L-valine, D-leucine, D-isoleucine. D-valme, DL-leucine, DL~ lsoleucme, 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
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disintegcotor 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 5 as a dry mixer, e.g., a v-blender or the like and then che resulting mixture is compression-molded to tablets by means of a suitable cablet machine.
The granular powders, granules or tablets thus obtained may be surface-coated, if necessary. The surface-
10 coating step for tablets is not essential and may be an
optional step. For example, in case of gabapentin having a strongly bitter taste, it may be desirable to surface-coat gabapentin tablets for easier ingestion. In the surface-coating step, there may be used as a film-forming material a
15 polymeric base ingredient such as a cellulose derivative, e.g., hydroxypropylcellulose (HPC), hydroxypropylmethyl-cellulose (HPMC), etc., a polyvinyl pyrrolidone, Kollidon-VA6 ?.0 To such a film-forming material, there may be
further added, if necessary, a humectant such as propylene glycol, glycerol, triacetm or the like and a neutral amino acid such as L-Leucine, L-isoleucine, I.-valine, L-alamns,
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D-leucme, D-isoieucine. D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine or glycine- Among those compounds, propylene glycol, glycerol and triacetin may exhibit not only an activity as a humectanc but also an 5 activity as a plasticizer for a coating film, while L-
leucme, L-isoleucine, L-valine, D-leucme, D-isoleucme, D-valme, DL-leucine, DL-isoleucine and DL-valine may exhibit an activity as a modifier for a coating film. Moreover, "hen the 4-amino-3-5ubstituted-but.anoic =.cid derivative 15
10 gabapentm, glycine, L-alanine, D-alanme and DL-alanine way exhibit an activity as a buffering agent against bitter taste of gabapentin. The surface-coating of the granular powders, granules cr tablets may be applied to the surface of the granular powders, granules or tablets according to a
15 "ell-Known method using a fluidired bed cr 3 rotary pan.
In a solid composition containing the 1-amino-3-3ubst1tutea-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 1-anino-3-substituted-
20 b"utanoi; 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 manuCacturtng a pharmaceutical preparation.
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The total amount to be used may be varied depending upon the sore of the humectant to be used, the specific dosage form of the solid composition containing the 4-amino-3-subst1tuted-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 che 4-amino-3-substituted-butanoic acid derivative by ensuring a water retention of the pharmaceutical preparation. And, in many cases, a total amount of the humectant may be preferably in the range of 0.02 - 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-substituced-butanoic acid derivative and an auxiliary agent when added cor manufacturing a pharmaceutical preparation. However, ~han sorbitol IS used together with other humectancs. che amount to be used is not limited to the ranges as mentioned above.
In preparing surface-coated tablets of the 4-amino-3-sucst1tuted-butanoic acid derivative, che amount of the humectant to be used in the surface-coating step may be
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usuaiLy in the range ot 0.1 - 50% by weight relative to the total amount of the coating materials.
Moreover, we have also found out chat in preparin a solid pharmaceutical preparation of the 4-ammo-3-S substituted-butanoic acid derivative, use of a certain
neutral amino acid including L-leucme, L-isoleucine, L-valine, L-aiamne, D-leucme, D-isoleucine, D-valine, D-alamne, DL-leucme, DL-isoleucine, DL-valine, DL-alanine and glycine, instead of the auxiliary agent commonly used
10 for manufacturing a pharmaceutical preparation, can bring about the desired pharmaceutical preparation without any prevention of the water retention effect of a humectant as stabilie"er of this invention. In other "ords, the said neutral amino acid may exhibit an activity as auxiliaries f
15 stabilization. The said neutral amino acid may be used
elone or :n combination of two or more thereof- The said neutral amino acid may be blended in any optional btep for che preparation of a pharmaceutical preparation of the 4-amino-3-subscituted-butanoic acid derivative irvcLudmq the
Z0 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 - 40t oy weight relativ to gabapentm.
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- -5TT-
The process for preparing a solid preparation of Che 4-amino-3-substltuted-butanoic acid derivative according to Che invention as explained above comprises, for example, the granulation step in which a humectant, that is, a 5 stabiliser, 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, t_he step for tableting in which additives 3Uch as a lubricant are added
10 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
15 the dosage form of powders or granules as a pharmaceutical preparation of the 20 Alternatively, :h2 granules us prepared by the granulation step may be admixed wLth 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
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solid preparation of the l-atnino-S-substituted-butanoic acid derivative thus prepared, for example, in case of the gabapentin preparation, gabapentin is m a compressed or fluidued state so that the solid preparation may be easily 5 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 10 1) Preparation of granular powders A of gabapentin
On 250 g of bulk powders of gabapentin was sprayed 72 g of wacer by means of a fluidized granulator (manufactured by FREUND CO., Ltd., SFC-Labo) and then dried to obtain gabapentin granular powders A. 15 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 6"7 g of water by
means of said fluidized granulator and then dried to obtain
gabapentin granular powders B.
20 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
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lactam content formed in each of the granular ponders was determined by means of HPLC-
The lactam concent in this example and examples hereinafter is expressed in term of % by weight based on gabapentin.
Table 3
Storage conditions Granular powders
A B
0.003 0 .003
0. 017 0. 011
0.020 0. 013
0. 003 0 . 003
When initiated
60"C/i week (sealed)
60°C/2 weeks (sealed)
SO°C/85« humidity/2 weeks (open) 0.003
50oC/85«> humidity/A weeks (open) 0.003 0.003
The above cable shows that the gabapentin bulk powders could be prevented from the degracation "ich lapse of rime ihe 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 waier by means of a fluidized granulator (manufactured by TREUND Co., Ltd., SFC-Labo) and
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subsequently a solution of 5 g of hydroxypropylcelLulose in 58 g of water was sprayed thereon, and then dried to obtain gabapentir. granular ponders C.
2) Preparation of granular powders D of gabapentm
5 On 250 g of bulk powders of gabapenCin was sprayed
a soLutior. of S g of propylene glycol in 67 g of water by means of a fluidized granulator (manufactured by FREUND Co., Ltd., SFOLabo) and subsequently a solution of 5 g of hydroxypropylcellulose in 58 g of water was sprayed thereon, 10 and then dried to obtain gabapentin granular powders D.
3) Preparation of granular powders E of gabapentin
On 250 g of bulk powders of gabapentin was sprayed a solution of S g of triacetin in 67 g of water by means of said fluic.iz.ed granulator and subsequently a solution of S g 15 of hydroxypropylcellulose in 58 g of water was sprayed thereon, =nd then dried to obtain gabapentin granular powders E
4) Preparation of granular powders F of gabapentin
On 250 g of bulk powders of gabapentir. was sprayed 20 a solution ct 2.5 g of propylene glycol and 2.5 g cf
triacetin ;.r. 67 g of water by means of the said fluidiz.ed granulator ana subsequently a solution of 5 g of hydroxypropylcellulose in 5B g of water was sprayed thereon,
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and then dried to obtain gabapentin granular powders F.
The gabapentin granular ponders C - F obtained as
described in the above 1) 4) were storea under the
conditions as defined in the following Table 4 and then a
5 lactam content formed in each of the granular powders was
determined by means of HPLC.
Tabl 4
Storage conditions Granular powders
C D E F
10 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) 0.210 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
IS
The above table shows that the gaoapentin bulk
powders could be prevented from the degradation with lapse
of tirae (the lactam formation) by the addition of either
propylene glycol or triacetm or both of them.
20 ExampLe 3
1) Preparation of gabapentin granules
On 700 g of bulk powders of gabapentin was sprayed
a solution o£ 15 g of copolyvidone and 11 g of propyLene
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10
lb

glycol in 252 g of water by means of a fluidized granulator (manufactured by FREUND Co., Ltd., SFC-Mmil 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 ram and a weight of 336 mg, by means of a rotary tablet machine (manufactured by KIKUSUI 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 ir. the above step 2) were film coated over the surface thereof ^ith a coating solution having the composition as defined in Che following Table S £>y means of a coater (manufactured by FREUND Co. , Ltd-, HI-COATOR. HCT-30).



20

Copolyvidone
L - Isolsucine Gl ycme
Propylene glycol Calcium stearate

labia 5

34 0 g
13 S g
13. 3 g
7.0 g
7.0 g

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- Water 432.0 g
The uncoaced cablets (I) and the film-coated
tablets (II) obtained according to the above seeps 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 0.01B
40°C/75£ humidity/2 months (sealed) 0.048 0.066 0.072 40°C/75% h.urj.idity/4 months (sealed) 0.123 0.119 0.129 40°C/7S% humidity/6 months (sealed) 0.229 0.172 0.219
(Note) *corr_-nercia 1 ly available gabapentin capsules prepared
according Co a dry blend method, eacr. capsule
containing 300 raq cf gabapentin
The above table shows that no significant increase in the lactam content -*as observed in Che film coated cablets and the film coated tablets had an excellent stability wich lapse of time, similar to that of the gabapentin capsules prepared by a dry,blend mechod.
-r*-

0
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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 l.
Table 1 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 gaoapentir. 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 af:er dissolution
Example 4 1) Preparation of baclofen powder sample G
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200 irig of baclofen crystals was wetted with 0.04 ml of water and the mixture was made to granular powders by means of a mortar and then dried to obtain baclofen powder sample G-
2) Preparation of baclofen powder sample H
200 mg of baclofen crystals was wetted with 0.04 ml of a 20% aqueous solution of propylene glycol and the mixture was made to granular powders by means of a mortar and then dried to obtain baclofen powder sample H.
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, tne content of the dehydrated condensates is expressed m terms of i by weight, based or. baclofen.
Storage conditions Samples
Untreated baclofen G H
when miniated 0.10 3.10 0.10
60°C/1 week (sealed) 0.36 0.95 0.42
60°C/2 weeks (sealed) 0.57 1.26 0.61
60°C/3 weexcs (sealed) 0.70 1 . 54 0.82
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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 S addition of propylene glycol as a humectant.
Example 5 1! Preparation of pregabalin powder sample I
1 g of pregabalin crystals was wetted with 0.1 ml of water anc the mixture was made to granular powders by means 10 of a mortsr and then dried to obtain pregabalin powder sample I.
2) Preparation of pregabalin powder sample J
1 g of pregabalin crystals was wetted with 0.1 ml cf a 1% aqueous solution of decaglyceryl monolaurate and the IS mixture was made to granular powders by means of a mortar and then dried to obtain pregabarrn powder sample J.
3) Preparation of pregabalin powder sample K
1 g of pregabalin crystals was wetted with 0.1 ml of a LOfc aqueous solution of butylene glycol and the mixture 20 was made to granular powders by means of a mortar and then dried to obtain pregabalin powder sample K.
The samples I. J and K obtained as described above and untreated pregabalin crystals were stored under the
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WO 99/59572 PCT/US99/I0I86
conditions as defined m the following Table 9 and then a
content aZ 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
5 dehydrated condensate is expressed in terms of I by weight.
based on pregabarin.
Table 9
Storage conditions Samples
Untreated I J K
10 pregabalm
When initiated 60"C/1 week (sealed) 0.001 0.009 0.001 0.001
60°C/2 weeks (sealed) 0.001 0.010 0.002 0.00Z
IS The above table shows that the granulated
pregabalm using water underwent an accelerated degradation with lapse of time (condensation "ith dehyeration) and that the degradation with lapse of time could be prevented by the addition of decagiyceryl rtionoiaurate or butylene glycol as a
20 humeccant .
Example 6 ll Preparation of pregabalm powder sample L
1 g of pregabalm crystals was wetted with 0.1 mi at a 10?; aqueous solution of hydroxypropylcei lulose and the
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mixture wa3 made Co granular powders by means of a mortar and chen dried to obtain pregabalin powder sample L. 2) Preparation of pregabalin powder sample M
1 g of pregabalin crystals was wetted with 0.1 ml or 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.
Tab1e 10
Storage conditions Samples
L M
When initiated 60°C/1 wee* (sealed; 0.005 0.001
60°C/Z weeks (sealed! 0.010 0.002
t
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
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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, tabletmg troubles or the like. It is the most significant feature of this invention that, unexpectedly, a stability of a solid preparation of the 4-amino-3-substituted-butanoic acid derivative can be remarkably improved by the addition of a humectant which has a water retention activity and has been considered to trigger unfavorable disturbances in the said preparation as stated above. Thus, the present invention has now provided a means for stabilizing pharmaceut ically unstable _6l-

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-&a-
Lfiventiori can be expected to greatly contribute to the developmer.c of a stabilized pharmaceutical composition containing the _ 64-

We Claim:
1. A stabilized solid composition containing a 4-amino-3- substituted-butanoic acid derivative which comprises a 4-amino-3-substitutes-butanoic acid derivative having the general formula:
NH2CH2 - C - CH2COOH
/Ri Rz
wherein,
Ri is a hydrogen atom, a hydroxyl group, a methyl group or an ethyl group; Rz 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 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 3-8 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 or a cycloalkanedienyl group of 5-8 carbon atoms;
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 wherein said phenyl ring is mono-, di-or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxy! group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group;
an alkylcycloalkyl group wherein said cycloalkyl has 3-8 carbon atoms and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -O-, -S- or -SS-;
an alkylcycloalkyl group wherein said cycloalkyl has 3-8 carbon atoms, is linked to an alkylene group having 1 -4 carbon atoms optionally interrupted with-0-,-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 cycloalkyl group of 5-8 carbon atoms wherein one of the methylene groups (-CH2 -) is replaced by-0-,-NH-, -S-,-SO - or-S(0)2-
a cycloalkyl group of 5-8 carbon atoms wherein one of the methylene groups (-CH2-) is replaced by-0-,-NH-, -S-, -SO- or -S (O) 2-and one or two of the unsubstituted methylene groups (-CH2-) are mono-or di-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, 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 (-CH2-) in said cycloalkenyl 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 -O-, -NH-, =N-,-S-, -SO-or-S(O) 2-, and one or two of the unsubstituted methylene groups (-CH2-) being mono-or di-substituted with a halogen atom, a trifluoromethyl group, a hydroxy! 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 5-8 carbon atoms wherein one of the methylene groups (-CH2-) is replaced by -0-,-NH-,-S-,-SO-or-S (O) 2- ;
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 (-CH2-) is replaced by -0-,-NH-,-S-,-SO-or-S (O) 2- said phenyl group being mono-or di-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group;
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-,-S-, -SO- or -S(O) 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 (-CH2-) in said cycloalkenyl ring or cycloalkanedienyl ring being replaced by-0-,-NH-,

=N-,-S-, -SO-or-S(O) 2-, said phenyl ring being mono-or di-substituted with a halogen atom, a tnfluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group;
an alkylcycloalkyl group wherein said cycloalkyl has 5-8 carbon atoms and is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with-0-,-S-, -OR-SS 2-, one of the methylene groups (-CH2-) in said cycloalkyl ring being replaced by-0-,-NH-, -S-, -SO-or-S(0)2-;
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-0-,-S-or -SS-, and one of the methylene groups in said cycloalkyl ring being replaced by-0-,-NH-, -S-, -SO-or-S(O) 2-, and one or two of the unsubstituted methylene groups (-CH2-) 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 naphthyl group;
a phenyl group substituted with a methylenedioxy group;
a phenyl or naphthyl group which is mono-, di-or trl-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 nitro group, a carboxyl group or a carboalkoxy group, a cycloalkylmethoxy group having 5-8 carbon atoms in the cycloalkyl ring,
a cycloalkenylmethoxy group having 5 -8 carbon atoms in the cycloalkenyl ring, a cycloalkylmethoxy group wherein one of the methylene groups (-CH2) in said cycloalkyl ring having 5-8 carbon atoms

is replaced by -0-,-NH-, -S-, -SO-or-S(O) 2-, a cycloalkenylmethoxy group wherein one of the methylene groups (-CH2-) in said cycloalkenyl ring having 5-8 carbon atoms is replaced by -0-,-NH-, =N-,-S-, -SO-or-S(O) 2-, a cycloalkanedienyl- methoxy group wherein one of the methylene groups (-CH2-) in said cycloalkanedienyl ring having 5-8 carbon atoms is replaced by -0-, -NH-, =N-,-S-,-SO-or-S(0)2 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 alkoxay 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-O-,-NH-,-S-,-SO-or -S(0)2-, a cycloalkenylmethoxy group having 5-8 carbon atoms in the cycloalkenyl ring wherein said cycloalkenyl ring is mono-substituted with a halogen atom, a trifluoromethyl group, a hydroxy group, an alkyl group, an alkoxy group, an amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group and one of the methylene groups (-CH2) in said cycloalkenyl ring is replaced by-0-,-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 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 cycloalkanedienyl ring is replaced by-0-,-NH-, =N-, -S-, -SO- or -S(0)2-;
an alkylphenyl group wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms optionally interrupted -O-, -S-or-SS-;
an alkyl-0-,-S-or-SS-; phenyl group wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms via-0-,-S-or-SS- ;
an-0-,-5-or-SS-phenyl group;
a diphenylamino group:

an alkylphenyl group wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms optionally interrupted with -O-, -S- or -SS- and mono-, di-or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, a alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyl group ;
an alkyl-0-,-S-or-SS- phenyl group wherein said phenyl group is linked to an alkylene group having 1-4 carbon atoms via-0-,-S-or-SS-and mono-, di-or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyi group, an alkoxy group, an amino group, a nitro group or a carboxyl group;
an-0-,-S-or-SS-phenyl group wherein said phenyl group is mono-, di-or tri-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, a nitro group or a carboxyl group; or
Ri and Rz, together with the carbon atom to which they are attached, may form a divalent group selected from:
a cycloalkylidene group of 5-8 carbon atoms;
a cycloalkylidene group of 5-8 carbon atoms which is mono-, di-, tri-or tetra-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, a cycloalkyl group, a phenyl group, an amino group, a nitro group or a carboxyl group;
a cycloalkylidene group of 5-8 carbon atoms wherein one of the methylene groups (-CH2-) in said cycloalkyl ring is replace -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 cycloalkyi ring is replaced by-0-,-NH-,-S-,-SO-or-S(0)2- group and one or more of the unsubstituted methylene groups (-CH2-) in said cycloalkyl 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 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;
a cycloalkenylidene group of 5-8 carbon atoms or a cycloalkanedienylidene group of 5-8 carbon atoms which is mono-, di-, tri-or tetra-substituted with a halogen atom, a 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 15 replaced by-0-,-NH-, =N-,-S-, -SO-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 (O),- 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 amino group, a nitro group, an oxo group, a carboxyl group or a carboalkoxy group;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkylidene group of 4-8 carbon atoms;
a condensed ring group formed by ortho-fusion of a phenyl ring with a cycloalkylidene group of 4-8 carbon atoms, said phenyl ring being mono-, di-, tri-or tetra-substituted with a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio

group, an amino group, a nitro group, a carboxyl group or a carboalkoxy group ;
a condensed ring group formed by 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 amino group, a nitro group, a carboxyl group or a carboalkoxy group;
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, glycerol, and a lower aliphatic acid ester of glycerol.
2. The stabilized solid composition as claimed in claim 1 wherein said humectant is ethylene glycol.
3. The stabilized solid composition as claimed in claim 1 wherein said humectant is propylene glycol.
4. The stabilized solid composition as claimed in claim 1 wherein said humectant is butylene glycol.
5. The stabilized solid composition as claimed in claim 1 wherein said humectant is glycerol or a lower aliphatic acid ester of glycerol.

6. The stabilized solid composition as claimed in claim 1 wherein a total amount of said humectant is 0.01-25 % by weight relative to the 4-amino-3-substituted butanoic acid derivative.
7. The stabilized solid composition as claimed in claim 1 wherein the stabilized solid composition is a pharmaceutical preparation in the form of tablets, granules or capsules.
8. A stabilized solid composition as claimed in claim 1 wherein it is optionally combined with a neutral amino acid.
9. The stabilized solid composition as claimed in claim 9 wherein the neutral amino acid is one or more of neutral amino acids selected from L-leucine, L-isoleucine, L-valine, L-alanine, D-Ieucine, D-isoleucine, D-valine, DL-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine and glycine.

Dated this 24th April, 2001.

[DEEPAK KUMAR] OF REMFRY 8B SAGAR ATTORNEY FOR THE APPLICANT^]

Documents:

in-pct-2001-00451-mum-abstract(2-1-2007).doc

in-pct-2001-00451-mum-abstract(2-1-2007).pdf

in-pct-2001-00451-mum-cancelled pages(2-1-2007).pdf

in-pct-2001-00451-mum-claims(granted)-(2-1-2007).doc

in-pct-2001-00451-mum-claims(granted)-(2-1-2007).pdf

in-pct-2001-00451-mum-correspondence(27-7-2007).pdf

in-pct-2001-00451-mum-correspondence(ipo)-(7-8-2006).pdf

in-pct-2001-00451-mum-form 1(24-4-2001).pdf

in-pct-2001-00451-mum-form 13(27-7-2007).pdf

in-pct-2001-00451-mum-form 18(28-2-2005).pdf

in-pct-2001-00451-mum-form 1a(8-5-2006).pdf

in-pct-2001-00451-mum-form 2(granted)-(2-1-2007).doc

in-pct-2001-00451-mum-form 2(granted)-(2-1-2007).pdf

in-pct-2001-00451-mum-form 3(22-4-2001).pdf

in-pct-2001-00451-mum-form 3(8-5-2006).pdf

in-pct-2001-00451-mum-form 5(8-5-2006).pdf

in-pct-2001-00451-mum-form-pct-ipea-409(26-4-2001).pdf

in-pct-2001-00451-mum-form-pct-isa-210(26-4-2001).pdf

in-pct-2001-00451-mum-petition under rule 137(9-5-2006).pdf

in-pct-2001-00451-mum-petition under rule 138(9-5-2006).pdf

in-pct-2001-00451-mum-power of attorney(2-5-2006).pdf

in-pct-2001-00451-mum-power of authority(15-5-2001).pdf

in-pct-2001-00451-mum-power of authority(8-5-2006).pdf


Patent Number 211681
Indian Patent Application Number IN/PCT/2001/00451/MUM
PG Journal Number 04/2008
Publication Date 25-Jan-2008
Grant Date 07-Nov-2007
Date of Filing 24-Apr-2001
Name of Patentee WARNER-LAMBERT COMPANY
Applicant Address DELAWARE CORPORATION 201 TABOR ROAD, MORRIS PLAINS, NEW JERSEY 07950 UAS
Inventors:
# Inventor's Name Inventor's Address
1 AKIRA AOMATSU 34-8-302 MATSUKA, HACIOJI-SHI, TOKYO 192-0362, JAPAN.
PCT International Classification Number FA61K 31/195
PCT International Application Number PCT/US99/10186
PCT International Filing date 1999-05-10
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10-133112 1998-05-15 Japan