Description
STABLE SUSTAINED RELEASE ORAL DOSAGE FORM OF
GABAPENTIN
Technical Field
[1] The present invention relates to stable sustained release oral dosage forms of
gabapentin and methods for making these dosage forms.
Background Art
[2] When a drug dosage form is designed for human consumption, it is desired that the
drug show its maximum therapeutic efficacy with mirdmum side effects. Some of the side effects inherent in the drug can only be minimized if not eliminated, by adjusting the dosing regimen or modifying the bioavailability parameters through designing of dosage forms with sustained release of the drug. But if the drug is susceptible to degradation and forms toxic byproducts over time as such, or due to incompatibility with the excipients present in the dosage form, its consumption can be detrimental to the health of the patient. Various pharmacopeias require that dosage forms be free of these toxic degradation products or, if present, should be within safe permissible limits.
[3] Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a #-amino acid analogue
effective in the treatment of epilepsy. Gabapentin is indicated as an adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults with epilepsy. Gabapentin has also been approved for neuropathic pain in some countries.
[4] Gabapentin has been reported to convert to a toxic lactam compound during
preparation and storage. This lactam formation is also seen in formulations containing gabapentin. The lactam formation in formulation during storage is apparently a result of the catalytic effects of the excipients used. The lactam has toxicity, which exceeds that of gabapentin itself. The lethal dose (LD ) of gabapentin in mice has been reported to be 8,000 mg/kg while that of the corresponding lactam is 300 mg/kg. Consequently, these impurities and the potential formation of such decomposition products during storage of pharmaceutical compositions must be reduced to a minimum for reasons of safety.
[5] Considering the instability of gabapentin in the dosage form and its short half life, it
would be advantageous to design a sustained release dosage form of gabapentin which is stable on storage, has low lactam content and provides therapeutically effective plasma levels of gabapentin over a prolonged period. These stable sustained release dosage forms of gabapentin would not only provide a safe mode of gabapentin therapy but also would provide other benefits, such as maintaining steady plasma levels of gabapentin and the possibility of reducing the total daily dose and frequency of dosing to once or twice a day.
[6] U.S. Patent No. 6,054,482 provides a list of adjuvants which are purported to have
no noticeable influence on the stability of gabapentin. This list includes, among others, hydroxypropylmethylcellulose. Further, U.S. Patent Application no. 2003/0100611 discloses gastric retained dosage forms of gabapentin that contain hydrophilic polymers. Exemplary polymers disclosed include high viscosity or high molecular weight hydroxypropylmethylcellulose. As such, the prior art appears to teach that hy-droxypropyl methylcellulose is compatible with gabapentin.
Disclosure
[7] Summary of the Invention
[8] In one general aspect there is provided a stable sustained release tablet prepared
from granules. The granules include gabapentin; one or more hydrophilic rate-controlling polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gum; and, optionally, one or more pharmaceutical excipients.
[9] Embodiments of the sustained release tablet may include one or more of the
following features. For example, the lactam content of the tablet may not exceed 0.6% by weight of gabapentin when stored for three months at 40°C and 75% relative humidity. The tablet may provide therapeutically effective plasma levels of gabapentin for up to about 24 hours. The sustained release tablet may have a dissolution profile measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37±0.5°C hi 900ml of 0.06N hydrochloric acid of at least 90% of the gabapentin being released in a time between 4 hours and 12 hours. More particularly, at least 90% of the gabapentin may be released in a time between 8 hours and 12 hours.
[10] The gabapentin may make up from about 100 mg to about l,200mg by weight of
the tablet.
[11] The hydroxypropylcellulose may have a viscosity of between about 7 cps and about
30,000 cps. In particular, the hydroxypropylcellulose may have a viscosity of between about 4,000 cps and about 15,000 cps.
[ 12] The polyvinylpyrrolidone derivative may be selected from crospovidone,
copolyvidone and physical mixtures of polyvinylpyrrolidone and polyvinylacetate. The polysaccharide gum may be selected from the group consisting of guar gum, gum arabic, xanthan gum, locust bean gum, gum karaya and gum tragacanth or combinations thereof.
[13] The pharmaceutical excipients may be selected from diluents, binders, lubricants
and glidants. The sustained release tablet may be formulated such that the granules do not contain hydroxymethyl propylcellulose. The sustained release tablet may further include one or more pharmaceutical excipients mixed with the granules.
[14] In another general aspect there is provided a process for the preparation of a stable
sustained release tablet. The process includes:
[ 15] granulating a mixture of gabapentin and one or more hydrophilic rate-controlling
polymers selected from the group consisting of hydroxypropylcellulose; polyvinylpyrrolidone and its derivatives, and polysaccharide gum or combinations thereof with a granulating liquid or a binder solution;
[ 16] drying the granules;
[17] mixing the dried granules with one or more pharmaceutical excipients to form a
blend; and
[18] compressing the blend into a tablet.
[19] Embodiments of the process may include one or more of the following features. For
example, the lactam content of the tablet may not exceed 0.6% by weight of gabapentin when stored for three months at 40°C and 75% relative humidity. The tablet may provide therapeutically effective plasma levels of gabapentin for up to about 24 hours. The sustained release tablet may have a dissolution profile measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37±0.5°C in 900ml of 0.06N hydrochloric acid of at least 90% of the gabapentin being released in a time between 4 hours and 12 hours. More particularly, at least 90% of the gabapentin may be released in a time between 8 hours and 12 hours.
[20] The gabapentin may make up between about 100 mg and about 1,200 mg by weight
of the tablet. The hydroxypropylcellulose may have a viscosity of between about 7 cps and about 30,000 cps. In particular, the hydroxypropylcellulose may have a viscosity of between about 4,000 cps and about 15,000 cps.
[21] The polyvinylpyrrolidone derivative is selected from crospovidone, copolyvidone
and physical mixtures of polyvinylpyrrolidone and polyvinylacetate. The polysaccharide gum is selected from the group consisting of guar gum, gum arabic, xanthan gum, locust bean gum, gum karaya and gum tragacanth or combinations thereof. The other pharmaceutical excipients are selected from diluents, binders, lubricants and glidant.
[22] The process may further include granulating one or more pharmaceutical excipients
with the mixture of gabapentin and one or more hydrophilic rate-controlling polymers.
[23] In another general aspect, there is provided a method of treating a medical
condition. The method includes providing an oral pharmaceutical sustained release tablet prepared from granules comprising gabapentin, one or more hydrophilic rate controlling polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gum and optionally one or more pharmaceutical excipients.
[24] Embodiments of the method of treating may include one or more of the following
features or those described above. For example, the medical condition may be one or both of epilepsy and neuropathic pain.
[25] The details of one or more embodiments of the inventions are set forth in the de-
scription below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
[26] Detailed Description of the Invention
[27] Based on the teaching of the prior art disclosures described above, we prepared
gabapentin tablets with high viscosity and high molecular weight hydroxypropyl methylcellulose. However, contrary to the prior art disclosures, these tablets showed an increase in lactam content on storage (see Examples 5 and 6 and Table 4, herein). Because of the finding that high molecular weight or high viscosity hydroxypropyl methylcellulose actually increases the lactam content, we had to carry out laborious investigations to establish which alkyl substituted cellulose material or hydrophilic polymer is actually compatible with gabapentin.
[28] Surprisingly, as a result of these efforts we discovered that stable sustained release
gabapentin tablets can be prepared using hydrophilic polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gums and one or more pharmaceutically acceptable excipients. When these sustained release tablets were kept for three months at 40 ° C and 75% relative humidity, the lactam content did not exceed 0.6% by weight of gabapentin. These sustained release tablets of gabapentin are believed to be capable of maintaining plasma levels of gabapentin in a therapeutic range over an extended time period for up to about 24 hours. This can be accomplished, for example, by varying the concentration of polymers within the granules and possibly outside the granules.
[29] The stability conditions as defined herein include tolerance of =t 2 ° C in
temperature and a tolerance of ± 5% in relative humidity.
[30] Gabapentin may be present as a free base, hydrated form such as monohydrate or
any other pharmaceutically acceptable salts thereof. Gabapentin may comprise from about 100 mg to about 1200 mg by weight of the tablet.
[31] Hydroxypropylcellulose, as used herein, can be of different viscosity grades such as
sold by Aqualon under the brand name of Klucel® and also by Nippon Soda Co. Ltd, Japan. Suitable grades are those having viscosity of from about 7 to about 30,000 cps. Especially suitable among these hydroxypropylcelluloses are those having viscosity of 4000 to about 30,000 cps. Typically the amount of hydroxypropylcellulose can be from about 3% to about 40%, particularly from about 5% to about 30% and more particularly from about 5% to about 25% by weight of granules.
[32] Polyvinylpyrrolidone or PVP refers to a polymer containing N-vinylpyrrolidone as
the monomeric unit and is known to the pharmaceutical industry under a variety of designations including povidone, polyvidone, polyvidonum, polyvidonum soluble, and poly(l-vinyl-2-pyrrolidone). Cross-linked polyvinylpyrrolidone, known as crospovidone available as Kollidon CL and Kollidon CL-M is also included. The polyvinylpyrrolidone derivatives include among others the copolymer of N-vinyl-2-pyrrolidone and vinyl acetate which is known as copolyvidon, copolyvidone, and copolyvidonum. Physical mixtures of polyvinylpyrrolidone and polyvinyl acetate are also included. These mixtures can be in a ratio such as, but not limited to, 20:80
(PVP: polyvinylacetate) like Kollidon SR. It is apparent that other derivatives of polyvinylpyrrolidone known to those skilled in the art can also be used. Polyvinylpyrrolidone is available in a wide range of molecular weights. Particularly suitable are grades having molecular weights between about 8,000 to about 1,300,000 such as Plasdone K-90, Plasdone K-90D. Typically the amount of polyvinylpyrrolidone and its derivatives can be from about 3% to about 40%, particularly from about 3% to about 30% by weight of granules.
[33] Polysaccharide gums may be selected from the group consisting of guar gum, gum
arabic, xanthan gum, locust bean gum, gum karaya and gum tragacanth. Particularly suitable is guar gum. Typically the amount of polysaccharide gum can be from about 3% to about 80%, particularly from about 3% to about 70% and more particularly from about 3% to about 60% by weight of the granules.
[34] The other pharmaceutical excipients are selected from the group consisting of
diluents, binders, lubricants and glidants. Suitable diluents include powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol, etc. Suitable binders include polyvinylpyrrolidone and its derivatives; xanthan gum, guar gum; cellulose ethers such as carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose (extragranularly only, not intra-granularly), hydroxypropyl cellulose, ethyl cellulose; gelatin, starch and its derivatives. The granulating liquid can be, but is not limited to, water, ethanol, isopropyl alcohol, acetone, dichloromethane and the like. Alternatively, the binder can be dissolved in the granulating liquid and used as a solution. Lubricants can be talc, stearic acid, vegetable oil, calcium stearate, zinc stearate and magnesium stearate and glidants include talc, silicon dioxide and cornstarch.
[35] In one embodiment, stable gabapentin sustained release tablets may be prepared by
[36]
1. Blending gabapentin with hydrophilic rate-controlling polymer(s) like hy-
droxypropylcellulose, polyvinylpyrrolidone and its derivatives or
polysaccharide gum and other pharmaceutical excipients (but not HPMC) in a
mixer.
2. Granulating the blend of step (1) with a granulating liquid or a binder
solution.
3. Drying and sizing the granules.
4. Mixing the sized granules with other pharmaceutical excipients and
compressing into tablet.
[37] In another embodiment, stable gabapentin sustained release tablets may be prepared
by following the steps of [38]
1. Blending gabapentin with a portion of hydroxypropylcellulose in a mixer.
2. Granulating the blend of step (1) with a solution of remaining portion of hy-

[39] [40]
[41] [42]
[43] [44]

droxypropylcellulose in a granulating liquid.
3. Drying and sizing the granules.
4. Mixing the sized granules with other pharmaceutical excipients and
compressing into tablet.
Tablets can additionally be coated with non-rate-controlling polymer(s) compositions like Opadry® sold by Colorcon to impart aesthetic appeal. Such a coating may comprise about 2% by weight of the tablet.
Stable gabapentin sustained release tablets and process for the preparation thereof described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention.
Preformulation studies
In an excipient compatibility study, the compatibility of gabapentin with hydrox-ypropylcellulose, polyvinylpyrrolidone, copolyvidone, guar gum and hydroxypropyl methylcellulose among other pharmaceutical excipients was determined. Gabapentin was mixed with these polymers and the mixture was granulated with purified water, the granules were dried, sized and compressed to form tablets. The tablets were then kept for three months at 40 ° C and 75% relative humidity in sealed HOPE bottles. The stability data is given below in Table 1,
Table 1 Stability data of preformulation studies

(Table Removed)


[45] [46] [47]

2 Months at 40 ° C/75% RH EXAMPLES 1-4

(Table Removed)

[48] [49]
[50] [51]

General Procedure:
Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with remaining portion of hydroxypropylcellulose dissolved in purified water. The granules were dried and sized, mixed with mannitol, copolyvidone (Examples 1, 2 and 4), poloxamer, magnesium stearate and talc and compressed to form a tablet. The tablets were then kept for three months at 40 ° C and 75% relative humidity in sealed HDPE bottles. The stability data is given in Table 2 and shows that the formulations are stable.
Table 2 Stability data of the tablets of Examples 1-4 when stored for three months at 40 ° C and 75% relative humidity (RH).

(Table Removed)

[52]

The dissolution profile of tablets of Examples 1-4 measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37±0.5 ° C in 900 ml of 0.06N hydrochloric acid is given below in Table 3. These profiles show complete release of the

[53]drug over a time ranging between 4 hours and 12 hours.
Table 3 Dissolution profiles of tablets of examples 1- 4 measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37±0.5 ° C in 900ml of 0.06N hydrochloric acid
[54][55] [56]EXAMPLES 5 and 6
[57] [58]
Procedure
Gabapentin was mixed with a portion of hydroxypropylmethylcellulose and mannitol and granulated with the remaining portion of hydroxypropylmethylcellulose dissolved in purified water. The granules were dried and sized, mixed with copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet. These tablets were kept for 3 months at 40 ° C and 75% relative humidity in

[59] [60]
sealed HDPE bottles. The stability data is given in Table 4.
Table 4 Stability data of tablets of example 5 when stored for three months at 40 ° C and 75% relative humidity (RH).
[61] [62]

The data in Table 1 and 4 clearly indicate the incompatibility of Gabapentin with HPMC.
While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

WE CLAIM:
1. A stable sustained release tablet prepared from granules, the granules
comprising :
gabapentin;
one or more hydrophilic rate-controlling polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gum ; and
optionally one or more pharmaceutical excipients;
wherein the tablet has a dissolution profile measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37 ± 0.5°C in 900ml of 0.06N hydrochloric acid of at least 90% of the gabapentin being released in a time between 4 hours and 12 hours and the lactam content of the tablet does not exceed 0.6% by weight of gabapentin when stored for three months at 40 °C and 75% relative humidity.
2. The sustained release tablet according to claim 1 wherein gabapentin
comprises from about 100 mg to about 1,200 mg by weight of the tablet.
3. The sustained release tablet according to claim 1 wherein the hydroxypropyl
cellulose has a viscosity of between about 7 cps and about 30,000 cps.
4. The sustained release tablet according to claim 1 wherein the
polyvinylpyrrolidone derivative is selected from crospovidone, copolyvidone
and physical mixtures of polyvinylpyrrolidone and polyvinylacetate; and the
polysaccharide gum is selected from the group consisting of guar gum, gum
arabic, xanthan gum, locust bean gum, gum karaya and gum tragacanth or a
combinations thereof.
5. The sustained release tablet according to claim 1 wherein the tablet further
comprises one or more pharmaceutical excipients mixed with the granules.
6. The sustained release tablet according to claim 1 and 5 wherein the
pharmaceutical excipients are selected from diluents, binders, lubricants and
giidant.

7. The sustained release tablet according to claim 1 wherein the tablet provides
therapeutically effective plasma levels of gabapentin for upto about 24 hours.
8. A process for the preparation of a stable sustained release tablet according to
claim 1 wherein, the process comprises :
granulating a mixture of gabapentin and one or more hydrophilic rate-controlling polymers with a granulating liquid or a binder solution;
drying the granules;
mixing the dried granules with one or more pharmaceutical excipients to form a blend; and
compressing the blend into a tablet.
9. A stable sustained release tablet of gabapentin substantially prepared and
exemplified herein.