Technical Field of the Invention
The present invention relates to stable sustained release oral dosage forms of gabapentin and process for the preparation thereof wherein the dosage form provides substantially constant plasma levels of gabapentin up to 24 hours.
Background of the Invention
Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is a y-amino butyric 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 of the countries.
Gabapentin has been reported to convert to a toxic lactam compound (Impurity A) during preparation and storage. This lactam formation is also seen in formulations containing gabapentin. The cause of lactam formation in formulation during storage is apparently also the catalytic effects of excipients used. The lactam has toxicity, which exceeds that of gabapentin itself. The lethal dose (LD50) of gabapentin in mice has been reported to be 8000mg/kg while that of the corresponding lactam is 300mg/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.
US Pat. No. 6,054,482 lists pharmaceutical excipients which are incompatible with gabapentin and also the excipients which do not have any noticeable influence on the stability of gabapentin. The list of compatible excipients among others includes hydroxypropylmethylcellulose. However, an increase in the lactam content was observed when gabapentin was formulated with hydroxypropyl methylcellulose and the formulation was found to be highly unstable upon storage (Examples 6 & 7 and Table 3).
In the present invention we have discovered that the excipients particularly rate-controlling polymers which are incompatible with gabapentin can also be used in
gabapentin compositions without compromising the stability of gabapentin. This has been achieved by
a) extragranular addition of the rate controlling polymers, or
b) intragranular addition of a part of the rate controlling polymer and extragranular addition of the remaining part of the rate controlling polymer.
This process results in an improved stability of the Gabapentin compositions as when compared to the formulations prepared with the whole of the rate controlling polymer added intragranularly. The present process resulted in gabapentin compositions with further reduced lactam content.
In addition to stability problem, gabapentin has a relatively short half-life (5-7 hours), which leads to substantial fluctuations in the plasma concentration of the drug. Frequent dosing is necessary to maintain reasonably stable plasma concentrations. The effective dose of gabapentin is 900 to 1800 mg/day and is given thrice a day. This results in a series of "peaks" and valleys, which provides an inconsistent therapeutic response to the drug therapy. Such fluctuations in drug blood levels provide a patient with a short window of appropriate blood concentration of gabapentin for optimum therapy. 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 prolonged period. These stable sustained release dosage forms of gabapentin would not only provide a safe mode of gabapentin therapy but also other benefits like 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, particularly once a day.
Summary of the Invention
In one general aspect it relates to a sustained release tablet of gabapentin wherein the tablet when administered once or twice daily provides mean maximum plasma concentration (Cmax) of gabapentin to a human subject comparable to or less than the Cmax provided by an immediate release dosage form of gabapentin administered thrice a day for similar cumulative daily dose.
In another general aspect, it relates to a sustained release tablet of gabapentin wherein the tablet when administered once or twice daily provides mean maximum plasma concentration (Cmax) of gabapentin to a human subject comparable to or less than the Cmax provided by an immediate release dosage form of gabapentin administered thrice a day for similar cumulative daily dose and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect, it relates to a sustained release tablet of gabapentin wherein the tablet when administered once or twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in the sustained release tablet and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect it relates to a sustained release tablet of gabapentin wherein the tablet when administered once or twice daily provides mean maximum plasma concentration (Cmax) of gabapentin to a human subject comparable to or less than the Cmax provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose; mean time to maximum plasma concentration (Tmax) of gabapentin about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in sustained release tablet; and AUC0-24hr comparable to AUC0-24hr provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose.
In another general aspect, it relates to a sustained release tablet of gabapentin wherein the tablet exhibits the following in-vitro dissolution profile, when 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;
- at most about 45% of the drug is released in 1 hour;
- at most about 80% of the drug is released in 4 hours and
- at most about 95% of the drug is released in 8 hours.
In another general aspect, it relates to a sustained release tablet of gabapentin wherein the tablet exhibits the following in-vitro dissolution profile, when 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;
- at most about 45% of the drug is released in 1 hour;
- at most about 80% of the drug is released in 4 hours and
- at most about 95% of the drug is released in 8 hours; and
wherein the tablet when administered once or twice daily provides Cmax to a human subject comparable to or less than the Cmax provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose.
In another general aspect, it relates to a sustained release tablet of gabapentin wherein the tablet exhibits the following in-vitro dissolution profile, when 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;
- at most about 45% of the drug is released in 1 hour;
- at most about 80% of the drug is released in 4 hours and
- at most about 95% of the drug is released in 8 hours; and
wherein the tablet when administered once or twice daily provides Cmax to a human subject comparable to or less than the Cmax provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect, it relates to a sustained release tablet of gabapentin wherein the tablet exhibits the following in-vitro dissolution profile, when 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;
- at most about 45% of the drug is released in 1 hour;
- at most about 80% of the drug is released in 4 hours and
- at most about 95% of the drug is released in 8 hours; and
wherein the tablet when administered once or twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the first of the three doses of an immediate release tablet having one-third the amount of gabapentin and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect, it relates to a stable sustained release tablet of gabapentin wherein the tablet comprises gabapentin intragranulariy and rate controlling polymer extragranularly and wherein the said tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin and wherein the said tablet exhibits the following in-vitro dissolution profile, when 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;
- at most about 45% of the drug is released in 1 hour;
- at most about 80% of the drug is released in 4 hours and
- at most about 95% of the drug is released in 8 hours;
In another general aspect, it relates to a stable sustained release tablet of gabapentin wherein the tablet comprises gabapentin intragranulariy and rate controlling polymer extragranularly and wherein the said tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin and the tablet when administered once or twice daily provides mean maximum concentration (Cmax) of gabapentin to a human subject comparable to or less than the Cmax provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect, it relates to a stable sustained release tablet of gabapentin wherein the tablet comprises gabapentin intragranularly and rate controlling polymer extragranularly and wherein the said tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin and wherein the tablet when administered once or twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the first of the three doses of an immediate release tablet having one-third the amount of gabapentin as that in sustained release tablet and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect, it relates to a stable sustained release tablet of gabapentin wherein the tablet comprises gabapentin intragranularly and rate controlling polymer extragranularly and wherein the said tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin and wherein the tablet when administered once or twice daily provides mean maximum plasma concentration (Cmax) of gabapentin to a human subject comparable to or less than the Cmax provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose; mean time to maximum plasma concentration (Tmax) of gabapentin about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in the sustained release tablet; and AUC0-24hr comparable to AUC0-24hr provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose.
In one general aspect, it relates to a process for the preparation of a stable sustained release tablet of gabapentin wherein the process comprises
granulating a mixture comprising gabapentin, other pharmaceutical excipients and
optionally rate-controlling polymer with a granulating liquid;
drying, sizing and mixing the granules with rate controlling polymer and
compressing the blend into a tablet; and wherein the said tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin and the said tablet when administered once or twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the
first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in sustained release tablet and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect, it relates to a method of treating a medical condition responsive to gabapentin wherein the method comprises administering a sustained release tablet of gabapentin wherein the tablet when administered once or twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in sustained release tablet and wherein the said tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
In another general aspect, it relates to a method of orally administering gabapentin to a patient to maintain substantially constant plasma levels of gabapentin for up to 24 hours, which method comprises administering a sustained release dosage form of gabapentin once or twice daily.
Detailed Description of the invention
As is known in the prior art, it is desirable in the treatment of a number of diseases, both therapeutically and prophylactically to provide the active pharmaceutical ingredient in a sustained release form. Desirably the sustained release provides a generally constant rate of release over an extended period. The present gabapentin tablets provide sustained release of gabapentin which help maintain therapeutic blood levels of gabapentin over an extended period, particularly from about 12 hours to about 24 hours. The conventional immediate release formulation of gabapentin is taken thrice a day which compromises patient compliance due to frequent dosing. The sustained release tablets of the invention are designed to reduce the frequency of dosing to twice a day and more particularly once a day which would help improve patient compliance
and increase the chances of successfully completing a dosage regimen for the treatment of intended medical condition.
The term "substantially constant plasma levels" means low fluctuation index in comparison to an immediate release dosage form administered thrice a day.
Given the fact that gabapentin is amenable to degradation into corresponding lactam, it is imperative that any dosage form of gabapentin should, if not free, have lactam content within permissible pharmacopoeal limits. Therefore, in one embodiment, it is one of the objects of the invention to provide stable sustained release tablets of gabapentin which provide sustained release of gabapentin over a period of up to 24 hours. It has been observed that for a given rate-controlling polymer, the stability of gabapentin tablet is influenced by the amount of the polymer that is present intragranularly or extragranularly. The stability is improved when the amount of rate-controlling polymer is decreased in the intragranular phase.
The process of the invention provides flexibility and broadens the range of pharmaceutical excipients, particularly rate-controlling polymers for preparing stable sustained release dosage forms of gabapentin. The rate controlling polymers which show incompatibility with gabapentin can still be used to prepare stable compositions when a major portion of the same is added extragranularly. The process is economical and can be easily carried out to prepare stable sustained release tablets of gabapentin. The process gives stable gabapentin sustained release tablets which provide substantially constant plasma levels of gabapentin for a period of up to about 24 hours.
Granules can be prepared by wet granulation or dry granulation process.
Therefore in one embodiment, granules can be prepared by blending gabapentin, other pharmaceutical excipients and optionally a part of the rate-controlling polymer; granulating with a binder; drying; sizing; mixing with rate-controlling polymer and other extragranular excipients; and compressing to make tablets.
In another embodiment granules can be prepared by blending gabapentin, other pharmaceutical excipients and optionally a part of rate controlling polymer; compacting
or slugging the above blend; sizing; mixing with rate-controlling polymer and other extragranular excipients; and compressing to make tablets.
The stability conditions as defined herein include tolerance of ± 2°C in temperature and a tolerance of ± 5% in relative humidity.
Gabapentin may be present as a free base, hydrated form such as monohydrate or any other pharmaceutically acceptable salt thereof. Gabapentin may comprise from about 100 mg to about 1200 mg by weight of the tablet.
The rate-controlling polymer may be either hydrophilic or hydrophobic in nature; particularly suitable are polymers that swell in aqueous media. The amount of polymer in the tablet relative to gabapentin depends upon the rate of drug release required and also upon the type and molecular weight of the polymer and other excipients present in the formulation. The rate-controlling polymer may be present intragranularly and extragranularly or may be added completely in the extragranular phase. The intragranular or extragranular rate-controlling polymers may be same or different. The amount of intragranular rate-controlling polymer may depend on the type being used and also on the extent of incompatibility with gabapentin. In general, the amount of the rate-controlling polymer in the dosage form may vary from about 5% to about 80% by weight of the tablet, in particular from about 5 to about 70%, more particularly from about 5 to 60% by weight of the tablet. The intragranular rate-controlling polymer may comprise from about 0% to about 50% by weight of the granules while the extragranular polymer may comprise form 5% to about 80% by weight of the tablet. Examples of suitable rate-controlling polymers include polyvinylpyrrolidone (PVP) and its derivative like copolyvidone, mixture of PVP and polyvinylacetate like Kollidon SR; cellulosic polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose; vinyl acetate copolymers; polysaccharides (such as alginate, xanthan gum, guar gum etc.), starch and starch based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof. Particularly suitable are hydroxypropyl methylcellulose and hydroxypropylcellulose. Hydroxypropyl methylcellulose can be of different viscosity grades having viscosity from about 100 cps to about 100,000 cps, in particular about 4000 cps to about 15,000 cps. Suitable types are sold under the trade name Methocel by Dow Chemical Co. such as Methocel
K4MCR, Methocel K15MCR and Methocel K100MCR. Hydroxypropylcellulose can also 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 1000 to about 15,000 cps, particularly suitable are those having a viscosity of 4000 to about 15,000 cps. Besides the above, cellulose derivatives such as ethyl cellulose or cellulose acetate, methacrylates, acrylic acid polymers and copolymers, high molecular weight polyvinyl alcohols and waxes such as fatty acids and glycerides are also included.
The sustained release gabapentin tablets as described herein may further comprise other additives or pharmaceutical excipients such as diluents, lubricants, binders, etc.
Suitable diluents include powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol, etc.
Lubricants can be talc, stearic acid, vegetable oil, calcium stearate, zinc stearate and magnesium stearate and glidants include talc, silicon dioxide and cornstarch.
The binders include polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer; xanthan gum, guar gum; cellulose ethers such as carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose; gelatin, starch and its derivatives.
The granulating liquid can be, but not limited to, water, ethanol, isopropyl alcohol, acetone, dichloromethane and the like. Alternatively, the binder can be dissolved/dispersed in the granulating liquid.
In one embodiment, the process for the preparation of stable gabapentin sustained release tablets includes the following steps:
1. granulating a mixture comprising gabapentin and optionally a rate controlling polymer with a solution/dispersion of a binder;
2. drying and mixing the granules of step 1 with a rate controlling polymer and other pharmaceutical excipients like diluents, lubricants, glidants and binders and compressing the blend into a tablet using appropriate tooling.
In another embodiment, the process for the preparation of stable gabapentin sustained release tablets includes the following steps:
1. granulating a mixture comprising gabapentin and hydroxypropylcellulose with a solution/dispersion of hydroxypropylcellulose;
2. drying and mixing the granules with hydroxypropylmethylcellulose or hydroxypropylcellulose and other pharmaceutical excipients like diluents, lubricants, glidants and binders and compressing the blend into a tablet using appropriate tooling.
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.
The stable gabapentin tablets described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention
Table 1: Examples 1-10

(Table Removed)
Procedure:
Examples 1 and 2
Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with a second portion of hydroxypropylcellulose dissolved in purified water. The granules were dried and sized, mixed with extragranular hydroxypropylmethylcellulose, hydroxypropylcellulose (example 2), mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
Examples 3 and 4
Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with second portion of hydroxypropylcellulose dissolved in isopropyl alcohol/dichloromethane mixture. The granules were dried and sized, mixed with the extragranular portion of hydroxypropylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
Example 5
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, poloxamer, magnesium stearate and talc and compressed to form a tablet.
Example 6
Gabapentin was mixed with a portion of hydroxypropylmethylcellulose and granulated with remaining portion of hydroxypropylmethylcellulose dissolved in purified water. The granules were dried and sized, mixed with mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
Example 7
Same procedure was followed as in example 6 except that half the amount of hydroxypropylmethylcellulose was added extragranularly.
Example 8
Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with the remaining portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried, mixed with hydroxypropylmethylcelluiose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
Example 9
Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with second portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried and sized, mixed with hydroxypropylmethylcelluiose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
Example 10
Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with second portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried and sized, mixed with hydroxypropylmethylcelluiose and the extragranular portion of hydroxypropylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
Tablets of examples 1-10 were kept for 3 months at 40°C in sealed HDPE bottles. The stability data is given in Table 2. The dissolution profile of tablets of examples 1-4 and 8-10 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 is given in Table 3.
Table 2 Stability data of tablets of examples 1-10 when stored for 3 months at 40°C and 75% relative humidity (RH).

(Table Removed)
The stability data clearly shows that stability of gabapentin formulation is substantially increased as the portion of intragranular rate controlling polymer is decreased. Tablets of examples 1, 2, 8, 9 and 10 containing extragranular hydroxypropyl methylcellulose are more stable in comparison to tablets of examples 6 and 7 containing intragranular hydroxypropyl methylcellulose. Further, the tablets of examples 3 and 4 containing intragranular as well as extragranular hydroxypropylcellulose showed improved stability in comparison to tablets of example 5 containing only intragranular hydroxypropylcellulose. A more stable formulation was obtained in case of example 7 when the amount of hydroxypropyl methylcellulose was increased from intragranular to extragranular phase in comparison to tablets of example 6 containing hydroxypropyl methylcellulose in intragranular phase only.
Table 3 Dissolution profiles of tablets of examples 1-4 and 8-10 as 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

(Table Removed)
Bioavailability studies
i) Multidose crossover study
A randomized, three-treatment, three-period, three-sequence, multi-dose, and crossover
bioavailability study was carried out in 24 healthy, adult male, human subjects under fed
conditions. The tablets of example 8 containing 900 mg gabapentin administered twice daily (A); two tablets of example 8 containing 900 mg gabapentin administered at once (B) were compared with Neurontin® 600 mg immediate release tablets as reference administered three times daily (R). The graph of mean plasma concentration-time profiles of A, B and R are given in Figure 1. Table 4 depicts the various comparative mean pharmacokinetic parameters. The Tmax and Cmax are derived from the first dose.
Table 4 Mean pharmacokinetic parameters of sustained release gabapentin tablets of example 8 when given once a day; twice a day; and reference formulation (Neurontin 600 mg IR) thrice a day.

(Table Removed)
ii) Single dose crossover study
A randomized, three-treatment, three-period, three-sequence, single dose, crossover bioavailability study was carried out in 24 (22 completed the study) healthy, adult male, human subjects under fed conditions. The tablets of example 8 containing 900 mg gabapentin administered twice daily (A); two tablets of example 8 containing 900 mg gabapentin administered at once (B) were compared with Neurontin® 600 mg immediate release tablets as reference administered three times daily (R). The graph of mean plasma concentration-time profiles of A, B and R are given in Figure 2. Table 5 depicts the various comparative mean pharmacokinetic parameters. The Tmax and Cmax are derived from the first dose.
Table 5 Mean pharmacokinetic parameters of sustained release gabapentin tablets of example 8 when give once a day; twice a day; and reference formulation (Neurontin 600 mg IR) thrice a day.

(Table Removed)
iii) Another randomized, three treatment, three-period, six sequence, single dose crossover study was carried out in 24 healthy, adult male, human subjects under fed conditions. The tablets of example 10 containing 450 mg gabapentin administered twice daily (A); two tablets of example 10 containing 450 mg gabapentin administered at once (B) were compared with Neurontin® 300 mg immediate release tablets as reference administered three times daily (R). The graph of mean plasma concentration-time profiles of A, B and R are given in Figure 3. Table 6 depicts the various comparative mean pharmacokinetic parameters. The Tmax and Cmax are derived from the first dose.
Table 6. Mean pharmacokinetic parameters of sustained release gabapentin tablets of example 10 when given once a day; twice a day; and reference formulation (Neurontin 300 mg IR) thrice a day.

(Table Removed) As demonstrated above, the sustained release tablets of gabapentin provide extended Tmax in comparison to an immediate release tablet demonstrating the suitability of the present formulations in terms of maintaining the substantially constant plasma levels up to 24 hours. Also the mean Cmax values of test were comparable to the Cmax values of the reference indicating that sustained release characteristics of the tablets did not affect the maximum plasma levels attained by following the administration. It further indicates that the tablets provided plasma levels of gabapentin within the therapeutic range and maintained appropriate bioavailability as indicated by similar AUC0-24 given by a conventional formulation for a similar cumulative dose.

WE CLAIM:
A sustained release tablet of gabapentin wherein the tablet when administered twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in sustained release tablet and wherein the said tablet when administered twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
A sustained release tablet of gabapentin wherein the tablet exhibits the following in-vitro dissolution profile, when 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;

at most about 45% of the drug is released in 1 hour;
at most about 80% of the drug is released in 4 hours and
at most about 95% of the drug is released in 8 hours.

A sustained release tablet of gabapentin wherein the tablet when administered twice daily provides mean maximum plasma concentration (Cmax) of gabapentin to a human subject comparable to or less than the Cmax provided by an immediate release dosage form of gabapentin administered thrice a day for similar cumulative daily dose and wherein the said tablet when administered twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
A sustained release tablet of gabapentin wherein the tablet when administered twice daily provides AUCo-24hr to a human subject comparable to AUCo-24hr provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose.
The sustained release tablet according to claims 1-4 wherein the tablet comprises gabapentin intragranularly and rate-controlling polymer extragranularly.
The sustained release tablet according to claim 5 wherein the rate controlling polymer is selected from polyvinylpyrrolidone and its derivatives; cellulosic polymer; vinyl acetate copolymers; alginate, xanthan gum, guar gum; starch and starch based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives, ethyl cellulose, cellulose acetate, methacrylates, acrylic acid polymers and copolymers, high molecular weight polyvinyl alcohols, waxes and combinations thereof.
The sustained release tablet according to claim 6 wherein the cellulosic polymer is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and combinations thereof.
The sustained release tablet according to claim 1-4 wherein the tablet further comprises other pharmaceutical excipients selected from diluents, lubricants, glidants, binders and like.
The sustained release tablet according to claim 8 wherein the diluent is selected
from powdered sugar, calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol and combinations thereof.
The sustained release tablet according to claim 8 wherein the lubricant is selected from talc, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate and combinations thereof.
The sustained release tablet according to claim 8 wherein the glidant is selected from talc, silicon dioxide, corn starch and combinations thereof.
The sustained release tablet according to claim 8 wherein the binder is selected from polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer, xanthan gum, guar gum, cellulose gums such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, starch pregelatinised starch and combinations thereof.
The sustained release tablet according to any preceding claim wherein the tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin.
A stable sustained release tablet of gabapentin wherein the tablet comprises gabapentin intragranularly and rate controlling polymer extragranularly and wherein the said tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin and wherein the tablet when administered twice daily provides mean maximum plasma concentration (Cmax) of gabapentin to a human subject comparable to or less than the Cmax provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose; mean time to maximum plasma concentration (Tmax) of gabapentin about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in sustained release tablet; and AUCo-24hr comparable to AUC0-24hr provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose.
A process for the preparation of a stable sustained release tablet of gabapentin wherein the process comprises:
granulating a mixture comprising gabapentin, other pharmaceutical excipients and optionally rate-controlling polymer with a granulating liquid; drying, sizing and mixing the granules with rate controlling polymer and compressing the blend into a tablet; and
wherein the said tablet when kept for 3 months at 40°C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin and the said tablet when administered twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in sustained release tablet and wherein the said tablet when administered twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
A method of treating a medical condition responsive to gabapentin wherein the method comprises administering a sustained release tablet of gabapentin wherein the tablet when administered twice daily provides mean time to maximum plasma concentration (Tmax) of gabapentin to a human subject which is about 4 hours to about 16 hours of the first of the three doses of an immediate release dosage form having one-third the amount of gabapentin as that in sustained release tablet and wherein the said tablet when administered twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours.
The method according to claim 16 wherein the medical condition is epilepsy or neuropathic pain.
A method of orally administering gabapentin to a patient to maintain a substantially constant plasma levels of gabapentin for up to 24 hours, which method comprises administering a sustained release dosage form of gabapentin twice daily.