U.S. patent application number 10/156213 was filed with the patent office on 2002-12-26 for liquid pharmaceutical compositions.
Invention is credited to Kulkarni, Neema M., Meyer-Wonnay, Hans, Schneider, Michael, Silbering, Steven B..
Application Number | 20020198261 10/156213 |
Document ID | / |
Family ID | 26968180 |
Filed Date | 2002-12-26 |
United States Patent
Application |
20020198261 |
Kind Code |
A1 |
Kulkarni, Neema M. ; et
al. |
December 26, 2002 |
Liquid pharmaceutical compositions
Abstract
A liquid pharmaceutical composition of a GABA analog comprising
at least one polyhydric alcohol containing 2 to 6 carbon atoms
having a pH of about 5.5 to about 7.0 and additionally a
two-component liquid pharmaceutical composition comprising a first
component comprising a powder mixture comprising a GABA analog and
a solid polyhydric alcohol, and a second component comprising a
liquid base are described, as well as methods to prepare the
compositions and a method for treating cerebral diseases, including
epilepsy, faintness attacks, hypokinesia and cranial traumas,
neurodegenerative disorders, depression, mania and bipolar
disorders, anxiety, panic, inflammation, renal colic, insomnia,
gastrointestinal damage, incontinence, pain, including neuropathic
pain, muscular pain, skeletal pain, and migraine using a
therapeutically effective amount of the pharmaceutical
compositions.
Inventors: |
Kulkarni, Neema M.;
(Randolph, NJ) ; Schneider, Michael; (Denzlingen,
DE) ; Silbering, Steven B.; (Forest Hills, NY)
; Meyer-Wonnay, Hans; (Emmendingen, DE) |
Correspondence
Address: |
Karen DeBenedictis
Warner-Lambert Company
2800 Plymouth Road
Ann Arbor
MI
48105
US
|
Family ID: |
26968180 |
Appl. No.: |
10/156213 |
Filed: |
May 28, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60293832 |
May 25, 2001 |
|
|
|
60343733 |
Oct 25, 2001 |
|
|
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Current U.S.
Class: |
514/561 ;
514/738 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
25/22 20180101; A61P 19/00 20180101; A61P 29/00 20180101; A61P
25/20 20180101; A61K 9/0095 20130101; A61P 25/06 20180101; A61P
25/08 20180101; A61P 25/00 20180101; A61P 25/04 20180101; A61P
25/24 20180101; A61P 1/04 20180101; A61P 13/00 20180101; A61P 21/00
20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/561 ;
514/738 |
International
Class: |
A61K 031/195; A61K
031/045 |
Claims
What is claimed is:
1. A liquid pharmaceutical composition of a GABA analog comprising
at least one polyhydric alcohol containing 2 to 6 carbon atoms and
wherein said composition has a pH of about 5.5 to about 7.0.
2. The composition according to claim 1, wherein the polyhydric
alcohol contains 3 to 5 carbon atoms and wherein the content of
polyhydric alcohol is about 25% to about 75% weight/volume
(w/v).
3. The composition according to claim 2, wherein the polyhydric
alcohol is selected from the group consisting of glycerol, xylitol,
sorbitol, mannitol, and a mixture of glycerol and xylitol, and
wherein the content of polyhydric alcohol is about 40% to about 75%
weight/volume (w/v).
4. The composition according to claim 1, wherein the pH is about
6.0 to about 7.0.
5. The composition according to claim 1, comprising one or both of:
(a) an additional preservative; and (b) an additional flavor
improver which does not contain an aldehyde or keto
functionality.
6. A method for preparing a liquid pharmaceutical composition of a
GABA analog comprising: Step (1) adding a polyhydric alcohol
containing 2 to 6 carbon atoms to water; Step (2) adding a GABA
analog to the solution from Step (1); and Step (3) optionally,
adjusting the ph of the composition to about 5.5 to about 7.0 to
afford the liquid pharmaceutical composition.
7. The method according to claim 6, wherein the polyhydric alcohol
is a mixture of glycerol and xylitol.
8. The method according to claim 6, wherein the content of
polyhydric alcohol is about 25% to 75% (w/v) and the pH is about 6
to about 7.
9. A two-component liquid pharmaceutical composition of a GABA
analog comprising (a) a first component comprising a powder mixture
of a GABA analog and a solid polyhydric alcohol; (b) a second
component comprising a liquid base wherein the powder component
from (a) is added to the liquid base from (b) to afford a liquid
pharmaceutical composition.
10. A method for preparing a two-component liquid pharmaceutical
composition of a GABA analog comprising: Step (1) mixing a GABA
analog with a solid polyhydric alcohol to afford a powder mixture;
Step (2) mixing a polyhydric alcohol with a sweetener and a flavor
in water to afford a liquid base; and Step (3) adding the powder
mixture to the liquid base to afford the liquid pharmaceutical
composition.
11. The method according to claim 10, wherein the GABA analog is
gabapentin or pregabalin.
12. The composition according to claim 1 or claim 9 wherein the
GABA analog is gabapentin or pregabalin.
13. The composition according to claim 1 or claim 9 wherein said
composition has less than 0.5% by weight of the corresponding
lactam of the GABA analog.
14. An aqueous oral pharmaceutical composition of gabapentin or
pregabalin, characterized by a content of at least 25% (w/v) of at
least one polyhydric aliphatic alcohol containing 2 to 6 carbon
atoms and a pH of about 5.5 to about 7.0 containing, less than 0.5%
(w/w) of gabapentin lactam or pregabalin lactam, respectively,
after storage at 2.degree. C. to 10.degree. C. for 18 months to 2
years.
15. The pharmaceutical composition according to claim 1 or claim 13
for the treatment of a subject suffering from cerebral diseases,
including epilepsy, faintness attacks, hypokinesia and cranial
traumas, neurodegenerative disorders, depression, mania and bipolar
disorders, anxiety, panic, inflammation, renal colic, insomnia,
gastrointestinal damage, incontinence, pain, including neuropathic
pain, muscular pain, skeletal pain, and migraine.
Description
FIELD OF THE INVENTION
[0001] This invention relates to liquid pharmaceutical compositions
comprising a gamma-aminobutyric acid (GABA) analog and processes
for the preparation of the same as well as methods of using such
compositions to treat subjects, including human subjects, suffering
from certain cerebral diseases, including epilepsy, faintness
attacks, hypokinesia and cranial traumas, neurodegenerative
disorders, depression, mania and bipolar disorders, anxiety, panic,
inflammation, renal colic, insomnia, gastrointestinal damage,
incontinence, pain, including neuropathic pain, muscular pain,
skeletal pain, and migraine.
BACKGROUND OF THE INVENTION
[0002] GABA is an inhibitory amino acid found in the mammalian
central nervous system (CNS). It has been reported that
dysfunctions with GABA neurotransmission in the CNS may contribute
or even cause psychiatric and neurological diseases such as
epilepsy, schizophrenia, Parkinson's disease, Huntington's Chorea
and dyskinesia (Saletu B., et al., International Journal of
Clinical Pharmacology, Therapy, and Toxicology, 1986;
24:362-373).
[0003] Gabapentin (1-(aminomethyl)-cyclohexaneocetic acid): 1
[0004] was designed as a GABA analog that would cross the
blood-brain barrier. Gabapentin was found to have anticonvulsant
and antispastic activity with extremely low toxicity in man.
Gabapentin is presently marketed under the trademark Neurontin.RTM.
as adjunctive therapy in the treatment of partial seizures in
patients with epilepsy.
[0005] U.S. Pat. Nos. 4,024,175 and 4,087,544 disclose the use of
gabapentin for the treatment of certain forms of epilepsy,
faintness attacks, hypokinesia, and cranial traumas. Additionally,
gabapentin brings about an improvement of cerebral functions and
thus is useful in treating geriatric patients. U.S. Pat. No.
5,084,479 discloses the use of gabapentin in neurodegenerative
disorders. U.S. Pat. No. 5,025,035 discloses the use of gabapentin
in treating depression; U.S. Pat. No. 5,510,381 discloses the use
of gabapentin in treating mania and bipolar disorders. U.S. Pat.
No. 5,792,796 discloses the use of gabapentin in treating anxiety
and panic. U.S. Pat. No. 6,127,418 discloses the use of gabapentin
in treating gastrointestinal damage; U.S. Pat. Nos. 4,894,476 and
4,960,931 disclose a novel crystalline monohydrate form of
gabapentin; and U.S. Pat. Nos. 5,133,451; 5,319,135; 5,362,883;
5,693,845; 5,091,567; and 5,068,413 disclose processes for
preparing gabapentin as well as intermediates used in these
processes. All of the aforementioned U.S. Patents are incorporated
herein by reference.
[0006] Pregabalin ((S)-4-amino-3-(2-methylpropyl)butanoic acid)
2
[0007] is another GABA analog disclosed in U.S. Pat. No. 5,563,175
for the treatment of seizure disorders including epilepsy, which is
herein incorporated by reference.
[0008] U.S. Pat. No. 6,117,906 discloses the use of pregabalin in
treating anxiety; U.S. Pat. No. 6,001,876 discloses the use of
pregabalin in treating pain; U.S. Pat. No. 6,127,418 discloses the
use of pregabalin in treating gastrointestinal damage; and U.S.
Pat. Nos. 5,599,973; 5,608,090; 5,684,189; 5,710,304; 5,616,793;
5,629,447; 5,637,767; 5,840,956; 6,046,353; and 6,028,214 disclose
processes for preparing pregabalin as well an intermediate used in
these processes. All of the aforementioned U.S. Patents are
incorporated herein by reference.
[0009] U.S. Pat. No. 4,024,175 discloses the administration of
gabapentin enterally or parenterally within wide dosage ranges in
liquid and solid form. Subsequently, it was disclosed in U.S. Pat.
No. 6,054,482, which is herein incorporated by reference, that
gabapentin was converted to a lactam, i.e.,
2-azaspiro[4.5]decan-3-one: 3
[0010] Furthermore, lactam formation unexpectedly occurred in the
solid phase and under dry storage conditions. Since the gabapentin
lactam displayed a certain toxicity, levels of this compound must
be reduced to a minimum for reasons of safety. In further
investigations, it was confirmed that liquid formulations of
gabapentin undergo cyclization to form lactam much more readily
than in the solid state. Additionally, it was discovered that
gabapentin has a very bitter taste. Finally, there is a need to
administer high doses of gabapentin in the treatment of certain
diseases. In some cases, doses of up to 1500 mg per day are given
to patients.
[0011] In view of the above issues, pharmaceutical compositions of
gabapentin have been limited to solid dosage forms, such as
capsules and tablets.
[0012] Pregabalin, similar to gabapentin, also is prone to
cyclization to a lactam, i.e., 4-isobutyl-pyrrolidin-2-one: 4
[0013] Thus, there is a need for a liquid pharmaceutical
composition of GABA analogs. In particular, liquid formulations of
gabapentin and pregabalin would be desirable for the treatment of
small children and elderly patients, since these patient groups
require doses of gabapentin or pregabalin which are easy to swallow
and which can be individually dosed.
[0014] The object of the present invention is a liquid
pharmaceutical composition which is amenable to high concentrations
of a GABA analog, is stable, has low levels of lactam, and has an
agreeable taste.
[0015] We have surprisingly and unexpectedly found that a GABA
analog can be formulated in a stable liquid pharmaceutical
composition having low levels of the GABA analog lactam with a pH
of about 5.5 to about 7.0 containing at least one polyhydric
alcohol. Additionally, the present composition has an agreeable
taste.
SUMMARY OF THE INVENTION
[0016] Accordingly, a first aspect of the present invention is a
liquid pharmaceutical composition of a GABA analog comprising at
least one polyhydric alcohol containing 2 to 6 carbon atoms having
a pH of about 5.5 to about 7.0.
[0017] A second aspect of the present invention is a method for
preparing a liquid pharmaceutical composition of a GABA analog
comprising:
[0018] Step (1) adding a polyhydric alcohol containing 2 to 6
carbon atoms to water;
[0019] Step (2) adding a GABA analog to the solution from Step (1);
and
[0020] Step (3) optionally adjusting the pH of the composition to
about 5.5 to about 7.0 to afford the liquid pharmaceutical
composition.
[0021] A third aspect of the present invention is a two-component
liquid pharmaceutical composition of a GABA analog comprising:
[0022] (a) a first component comprising a powder mixture of a GABA
analog and a solid polyhydric alcohol;
[0023] (b) a second component comprising a liquid base wherein the
powder component from (a) is added to the liquid base from (b) to
afford a liquid pharmaceutical composition.
[0024] A fourth aspect of the present invention is a method for
preparing a two-component liquid pharmaceutical composition of a
GABA analog comprising:
[0025] Step (1) mixing a GABA analog with a solid polyhydric
alcohol to afford a powder mixture;
[0026] Step (2) mixing a polyhydric alcohol with a sweetener and a
flavor in water to afford a liquid base; and
[0027] Step (3) adding the powder mixture to the liquid base to
afford the liquid pharmaceutical composition.
[0028] A fifth aspect of the present invention is a liquid
pharmaceutical composition of a GABA analog having less than 0.5%
by weight of its corresponding lactam.
[0029] A sixth aspect of the present invention is a method of using
a liquid pharmaceutical composition of a GABA analog to treat
subjects, including human subjects, suffering from cerebral
diseases, including epilepsy, faintness attacks, hypokinesia and
cranial traumas, neurodegenerative disorders, depression, mania and
bipolar disorders, anxiety, panic, inflammation, renal colic,
insomnia, gastrointestinal damage, incontinence, pain, including
neuropathic pain, muscular pain, skeletal pain, and migraine.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The term "polyhydric alcohol" refers to an alkyl or
aliphatic alcohol containing from 2 to 6 carbon atoms and 2 to 6
hydroxyl groups, such as, for example, glycerol, xylitol, sorbitol,
mannitol, and the like.
[0031] The term "GABA analog" refers to a compound derived from or
based upon the structure of gamma-aminobutyric acid, such as, for
example, gabapentin, pregabalin, and the like. Other GABA analogs
that can be employed in the liquid pharmaceutical compositions of
this invention are those referred to in Great Britain provisional
patent application 0125807.8, which was filed on Oct. 26, 2001,
Great Britain provisional patent application 0109635.3, which was
filed on Apr. 19, 2001, and the corresponding PCT patent
application that claims priority from the two foregoing provisional
applications and which was filed in April of 2002. The foregoing
applications are incorporated herein by reference in their
entirties. Examples of GABA analogs that are referred to in the
foregoing references are set forth below. 5
[0032] wherein R.sup.1 and R.sup.2 are each independently selected
from H, straight or branched alkyl of 1-6 carbon atoms, cycloalkyl
of from 3-6 carbon atoms, phenyl and benzyl, subject to the proviso
that, except in the case of a tricyclooctane compound of formula
(XVII), R.sup.1 and R.sup.2 are not simultaneously hydrogen.
[0033] Suitable compounds (including salts, solvates and pro-drugs
thereof) are:
[0034] ((1R,5S)-3-Aminomethyl-
1,5-dimethyl-bicyclo[3.2.0]hept-3-yl)-aceti- c acid;
[0035]
[0036]
((1S,5R)-3-Aminomethyl-1,5-dimethyl-bicyclo[3.2.0]hept-3-yl)-acetic
acid;
[0037]
((1R,5S)-3-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-acetic
acid;
[0038]
((1S,5R)-3-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-acetic
acid;
[0039]
((1S,2S,5R)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-acet-
ic acid;
[0040] ((1R,2S,5S)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.
]hex-2-yl)-acetic acid;
[0041]
((1S,2R,5R)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-acet-
ic acid;
[0042]
((1R,2R,5S)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-acet-
ic acid;
[0043] ((1R,5R,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic
acid;
[0044] ((1S,5R,5S,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic
acid;
[0045] ((1R,5R,6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic
acid;
[0046] ((1S,5S,6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic
acid;
[0047]
cis-((1S,2R,4S,5R)-3-Aminomethyl-2,4-dimethyl-bicyclo[3.2.0]hept-3--
yl)-acetic acid;
[0048]
trans-((1S,2R,4S,5R)-3-Aminomethyl-2,4-dimethyl-bicyclo[3.2.0]hept--
3-yl)-acetic acid;
[0049]
((1S,5R,6S,7R)-3-Aminomethyl-6,7-dimethyl-bicyclo[3.2.0]hept-3-yl)--
acetic acid;
[0050]
((1S,5R,6R,7S)-3-Aminomethyl-6,7-dimethyl-bicyclo[3.2.0]hept-3-yl)--
acetic acid;
[0051]
((1R,2S,5S)-7-Aminomethyl-3,3-dimethyl-bicyclo[3.3.0.0]oct-7-yl)-ac-
etic acid;
[0052] ((1R,6R,7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic
acid;
[0053] ((1S,6S,7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic
acid;
[0054] ((1R,6R,7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic
acid;
[0055] ((1R,6S,7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic
acid;
[0056] ((1R,7R,8S)-8-Aminomethyl-bicyclo[5 .2.0]non-8-yl)-acetic
acid;
[0057] ((1S,7S,8S)-8-Aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic
acid;
[0058] ((1R,7R,8R)-8-Aminomethyl-bicyclo[5 .2.0]non-8-yl)-acetic
acid;
[0059] ((1R,7S,8R)-8-Aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic
acid.
[0060] [((1R,5R,6S)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic
acid;
[0061] [(1S,5S,6R)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic
acid;
[0062] (1RS,5RS,6RS)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic
acid; and
[0063] [(1RS,6RS,7SR)-7-(Aminomethyl)bicyclo[4.2.0]oct-7-yl]acetic
acid.
[0064] The liquid pharmaceutical compositions of the present
invention comprise a GABA analog, such as, for example, gabapentin,
pregabalin, and the like.
[0065] Gabapentin may readily be prepared as described in U.S. Pat.
Nos. 5,132,451; 5,319,135; 5,362,883; 5,693,845; 5,091,567; and
5,068,413.
[0066] Pregabalin may readily be prepared as described in U.S. Pat.
Nos. 5,563,175; 5,599,973; 5,608,090; 5,684,189; 5,710,304;
5,616,793; 5,629,447; 5,637,767; 5,840,956; 6,046,353; and
6,028,214.
[0067] In preparing liquid pharmaceutical compositions of the
compounds of the present invention, pharmaceutically acceptable
carriers are solids and liquids.
[0068] Liquid form preparations include solutions, suspensions and
emulsions, for example, water or certain glycol solutions. For
parenteral injections, liquid preparations can be formulated in
solution in aqueous polyethylene glycol solutions.
[0069] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, and stabilizing and thickening agents as
desired.
[0070] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as, natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other
well-known suspending agents.
[0071] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0072] In the liquid pharmaceutical compositions of the present
invention, it was found that if the formulation is buffered to a pH
of about 5.5 to about 7.0 undesired lactam formation can be
substantially avoided. However, this limits the use of certain
adjuvants or carriers that can be used, such as, for example,
taste-correcting acids or preservatives. Preservatives especially
suited for oral compositions usually display their optimum
antimicrobial activity in the acid range. Furthermore, the
solubility of the usual preservatives, such as a paraben, sorbic
acid, or benzoic acid decreases at low storage temperatures
required for the liquid compositions of the present invention.
Thus, precipitations and/or insufficient antimicrobial activity due
to low concentration of the preservative at these low temperatures
is to be expected. Salts of the usual preservatives have better
solubility, but as a rule their antimicrobial activity is too
weak.
[0073] In the development of the liquid pharmaceutical compositions
of the present invention, it was shown that theoretically most
alcohols possess a preserving and stabilizing action in aqueous
solution. However, certain alcohols had undesirable properties and
were not useful in the present pharmaceutical compositions. For
example, ethyl alcohol is not desirable for pediatric formulations,
propylene glycol and benzyl alcohol have an unpleasant taste, and
chlorobutanol is not sufficiently stable at a pH of about 5.5 to
about 7.0.
[0074] Surprisingly and unexpectedly, it was found that polyhydric
alcohols containing 2 to 6 carbon atoms, preferably 3 to 6 carbon
atoms, such as, for example, glycerol, xylitol, sorbitol, mannitol,
and the like can be used as adjuvants for oral liquid gabapentin
and pregabalin compositions. Preferably, glycerol and/or xylitol
are used in the liquid compositions of the first aspect of the
present invention. These adjuvants can be used in high
concentration in the desired pH range of about 5.5 to about 7.0.
Preferably, between a pH of about 6.0 to about 7.0. They not only
act as preservatives and have a stabilizing effect on the active
components, but they also substantially mask the bitter taste of
the active components as a result of their sweet taste and
additionally are noncariogenic. Thus, the use of one or more
polyhydric alcohols allows the preparation of acceptably tasting
syrups of a GABA analog especially gabapentin or pregabalin which,
when cooled to refrigeration temperatures of about 2.degree. to
about 10.degree. C., have a storage stability of at least 2 years.
The polyhydric alcohols may be used in a concentration range of
about 25% to about 75% (weight/volume, w/v), preferably about 30%
to 75% (w/v) and most preferably about 40% to about 75% (w/v). In
general, it is not necessary to add additional preservatives to the
liquid compositions of the present invention. However, the addition
of another preservative may be advantageous (for example, in the
case of sterile-filled syrups when the container is used for
multiple doses to prevent contamination of the container). In the
case of a sterile-filled syrup, care must be taken in choosing an
additional preservative that can be used in the desired pH range
(about 5.5 to about 7.0) that does not interact with the active
components and does not accelerate lactam formation. We have found
that benzethonium chloride can be used as an additional
preservative.
[0075] Additionally, flavor improvers can be added to the liquid
compositions of the present invention to enhance the taste masking
action of the polyhydric alcohols. However, only adjuvants which do
not contain a reactive aldehyde or keto functionality can be used,
since these functionalities react with the active components.
Furthermore, the flavor improvers must not alter the desired pH
range of about 5.5 to about 7.0. For example, fruity compositions
have proved to be especially effective, such as, for example,
aniseed, strawberry and peppermint or aniseed, huckleberry, and
peppermint, and the like.
[0076] A storage temperature of about 2.degree. C. to about
10.degree. C., preferably about 2.degree. C. to about 8.degree. C.
and more preferably about 4.degree. C. to about 7.degree. C. is
required to ensure the stability of the active components and the
taste of the liquid composition.
[0077] Furthermore, a liquid pharmaceutical composition of a GABA
analog contains less than 0.5% (weight/weight, w/w) of the GABA
analog lactam, preferably 0.4% (w/w) of lactam after storage at
about 2.degree. C. to about 10.degree. C., preferably about
2.degree. C. to about 8.degree. C. for 18 months to 2 years,
preferably 18 months.
[0078] The syrup-like pharmaceutical compositions of the present
invention can be filled into single or multiple dose containers.
For example, single dose containers can be a double sachet of
coated aluminum foil which contains two half doses. An example of
multiple-dose containers are glass or plastic bottles, preferably
with childproof closures. The multiple dose container is variable
in dosage volume and can be provided with an appropriate dosage
aid, such as, a measurement beaker, measurement pipette, and the
like.
[0079] Another aspect of the present invention is a two-component
liquid pharmaceutical composition of a GABA analog such as, for
example, gabapentin, pregabalin and the like. The composition
comprises a first component comprising a powder mixture of a GABA
analog and a solid polyhydric alcohol, such as, for example,
sorbitol, xylitol, mannitol, and the like, preferably sorbitol, and
a second component comprising a liquid syrup base containing a
polyhydric alcohol, such as, for example, glycerol and the like,
and one or more flavoring agents, such as, for example, artificial
menthol flavor, artificial aniseed flavor, artificial blueberry
flavor, and sugar and water. The liquid pharmaceutical composition
is prepared by dissolving the powder blend into the syrup vehicle
at the time the product is dispensed to the patient. The liquid
composition once prepared should be stored at about 2.degree. C. to
about 10.degree. C., preferably about 2.degree. C. to about
8.degree. C., and more preferably about 4.degree. C. to about
7.degree. C. However, the liquid composition may be stored at room
temperature for about 2 months without exceeding undesired levels
of lactam as previously described.
[0080] Dosages of gabapentin and pregabalin are well-known in the
art, and the skilled practitioner will readily be able to determine
the dosage amount required for a subject based upon weight and
medical history.
[0081] In general, dosages of gabapentin and pregabalin are
disclosed in the aforementioned U.S. Patents. In particular,
dosages of gabapentin are disclosed in U.S. Pat. Nos. 4,024,175;
4,087,544; and 6,054,482 and pregabalin in U.S. Pat. No.
5,563,175.
[0082] The following nonlimiting examples illustrate the inventors'
preferred methods for preparing and using the liquid pharmaceutical
compositions of the present invention.
General Process for Preparing a Liquid Composition of
Gabapentin
[0083] Water and glycerol are heated to 40.degree. C. to 50.degree.
C., and xylitol is added with stirring. An endothermic reaction
results from the dissolution of the xylitol, and the solution is
cooled. After the xylitol is dissolved, the solution is cooled to
30.degree. C. to 40.degree. C., and gabapentin is added with
stirring. After the gabapentin is completely dissolved, the flavor
is added with stirring at 25.degree. C. to 30.degree. C. The
homogeneous solution is adjusted to a pH of 5.5 to 7.0, with an
acid, such as, 0.1N hydrochloric acid (HCl), or base such as 0.1N
sodium hydroxide (NaOH), and filtered.
[0084] Using the above general procedure, liquid compositions of
pregabalin may be prepared.
[0085] Table 1 contains representative liquid compositions of
gabapentin.
1TABLE 1 Liquid Composition of Gabapentin Example 1.sup.a Example 2
Example 3 Example 4 Gabapentin 2.000 5.000 5.000 5.000 Xylitol
20.000 30.000 30.000 29.940 Strawberry/anise 1.000 -- -- 1.000
flavor Huckleberry/anise -- 1.000 1.000 -- flavor Glycerol 95%
50.000 40.000 30.000 43.790 Hydrochloric acid, -- 7.720 -- -- 0.1 N
Sodium hydroxide, -- -- 0.770 -- 0.1 N Purified water 27.000 16.280
33.230 20.27 pH value 6.2 5.5 7.0 6.5 .sup.aAmounts are in grams
per 100 mL.
General Process for Preparing a Two-Component Liquid Composition of
Gabapentin
[0086] Step [A] Powder Blend
[0087] Gabapentin or gabapentin monohydrate (U.S. Pat. No.
4,894,476) is blended with sorbitol.
[0088] Step [B] Syrup Base
[0089] A sorbitol solution, glycerol, granular sugar, menthol
flavor, artificial aniseed flavor, and artificial blueberry flavor
are dissolved in distilled water.
[0090] Step [C] Final Syrup
[0091] The syrup is prepared by dissolving the powder blend from
Step [A] into the syrup base from Step [B]. The powder blend is
stored in aluminum pouches and the syrup base is stored in a glass
bottle at room temperature. After preparing the syrup
extemporaneously, the syrup is stored under refrigeration.
[0092] Using the above general procedure, two-component liquid
compositions of pregabalin may be prepared.
[0093] Table 2 contains a representative liquid composition of
gabapentin.
2TABLE 2 Two-Component Liquid Composition of Gabapentin Powder
Blend Gabapentin Monohydrate 9.90 g (Equivalent to 9.00 g
gabapentin) Sorbitol 22.50 g Syrup Base Sorbitol Solution 225.00 g
Glycerin, USP 180.00 g Sugar, Granular 45.00 g Artificial Menthol
Flavor.sup.a 56.25 mg Artificial Aniseed Flavor.sup.b 22.50 mg
Artificial Blueberry Flavor 4.275 g Water, Distilled qs.sup.c to
450 mL .sup.aActually 2.5% solution of menthol in alcohol is
weighed. .sup.bActually 2.5% solution of aniseed in water is
weighed. .sup.cQuantity sufficient
* * * * *