Note: Descriptions are shown in the official language in which they were submitted.
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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
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_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
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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
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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
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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
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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
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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.
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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
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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
R1 R2
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;
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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;
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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-;
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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;
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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-,
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-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;
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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
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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
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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:
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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
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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
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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
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WO 99/59572 PCT/US99/10186
- 21 -
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
/ \
R1 A
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
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WO 99/59572 PCT/US99/10186
- 2Z -
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:
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WO 99/59572 PCT/US99/10186
- 23 -
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
C1
-H -H yY
i
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WO 99/59572 PCT/US99/10186
- 24 -
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
C1
-H ~ ~ ~ -H -Cltz--~ I
i
Ol~e
-H \ ~ ~ -H -CHz-0-CH=-O-OH
_H -. Cll Z -fl
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WO 99/59572 PCT/US99/10186
- 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
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WO 99/59572 PCT/US99/10186
- 26 -
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~
C1
-H I I -H ~ N I i
C1 H
Br
-Ii I I -H
-H I f
Br
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WO 99/59572 PCTNS99/10186
- 27 -
Table 1 t Cont' d )
NH,CH=~CHzC00H
R~ RZ
-R~ -RZ -R, -Rs
~N~ ~ H
N
_g ---i w
N
06~e
0
_H I ~ _g ( ~ Me
/ i
OMe Me
_H 0 I ~ _H I
i
C1
_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
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WO 99/59572 PCT/US99/10186
- 28 -
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
C1 H
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
C1
I N I i p \ F
H -H I
F
II ~ ~ H I I
N ~ C1 ~~ F
H
~0
-H 'i
Ee
-H I I C1
N ~ J~0
H -H 'I
i
CA 02325045 2000-09-20
WO 99/59572 PCT/US99/10186
Zg
Table 7. ( Cont' d )
NHZCHz~~ HzCpOH
R1 Rz
-R= -~ -Rs
Et
C1
-H I I -~~ I I
i
0 Et
-H I I \ -H I I
C1
C1
-H p~ '~ -H I
I I ~ ~ Et
C1 nPro
H 1 I H L
Br
CI p
-H _ 0 w ~H I
I i nPrv
Id a
iPro
Me -H p
'I
,0 ~ '
-H I I
C1
-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
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WO 99/59572 PCTNS99110186
- 30 -
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
C1 0
-H ~ -H -CH,-CHx~
I UI
H I I I ~ Cl -H __ Cg i ~0
J
-H ~ I ~ -H -CHz-~'
C1
I I ' H - CH z-0-CH z-i-
Me
H
H I I ~ ~ ~E -H -CHZ--~~
1~e
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WO 99/59572 PCTNS99/10186
- 31 -
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.
C1
-H - CH a ~ -H \ / CI
bie
11 C1
-H - CH z N -H \ / C1
Me
-H -CHz-0-CHz~N~ -H \ / F
J
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WO 99/59572 PCTNS99/10186
- 3Z -
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 \ /
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WO 99/59572 PCT/US99/10186
- 33 -
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 \ /
\ /
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WO 99/59572 PCT/US99/10186
- 34 -
Table 1 (Cont'd)
NN=CHz/ ~CHZCOOH
Rz
_R~ -Hz _R. _Rz
--H -CHz-NH \ / -H -CHi-'~ \ / tBu
\ /
-H --N -H -CHz-~ \ / Br
\ /
C1
-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
C1
-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
0
C1
-H -CHz-CHz-S-CH \~/ I -H
~/'NH Z
-H -CHZ-CH1-5-CH \ / Br 0
_H _~~ 0
~Me
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WO 99/59572 PCTNS99/10186
- 35 -
: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,
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WO 99/59572 PCT/US99/10186
- 36 -
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
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WO 99/59572 PCT/US99/10186
- 37 -
Table
NH=CHZ-C -CHzC00H
/\
R, R=
~R ~
\R= C Ra
%~.~-S Me
i
~ /
C1 NHz
Br COON
C1 C1
~~C1
F3r ~Br
Br
C F , Me
O H Me
Me
~~~ M a
O Me
Me
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WO 99/59572 PCT/US99/10186
- 38 -
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
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WO 99/59572 PCT/US99/10186
- 39 -
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
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WO 99/59572 PCT/US99/10186
- 40 -
'Table Z ( Cont' d )
NH~CHr ~~ CHaCOOH
R, R=
/C\Rs lC\Rs
Me
\5 /
C1
C 1 1.
Me
\ /
S
O ~ O
%/~S \ /
C1
~,~'~ N H
j -C F ,
J
%~ M a
C1 %~Ma
~(~~..M a
Ma
'~~/
/ \
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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
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WO 99/59572 PCTNS99/10186
- 42 -
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
CA 02325045 2000-09-20
WO 99/59572 PC'T/US99/10186
- 43 -
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
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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
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- 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
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WO 99/59572 PCT/US99/10186
- 46 -
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.
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WO 99/59572 PCT/US99/10186
47 -
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.
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- ~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
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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.
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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
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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
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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
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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,
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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
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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
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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.
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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
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
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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
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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
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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
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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
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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 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
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invention can be expected to greatly contribute to the
development of a stabilized pharmaceutical composition
containin,; the 4-amino-3-substituted-butanoic acid derivative.
