WO2006077492A1

WO2006077492A1 - Sustained release oral dosage forms of gabapentin

Info

Publication number: WO2006077492A1
Application number: PCT/IB2006/000098
Authority: WO
Inventors: Manish Chawla; Rajeev Singh Raghuvanshi; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-01-24
Filing date: 2006-01-23
Publication date: 2006-07-27

Abstract

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.

Description

SUSTAINED RELEASE ORAL DOSAGE FORMS OF GABAPENTIN

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 for up to 24 hours.

Background of the Invention

Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a γ-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 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 formulations during storage is apparently due to the catalytic effects of the excipients used. The lactam has a toxicity that exceeds that of gabapentin itself. The lethal dose (LD₅₀) of gabapentin in mice has been reported to be 8000 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.

U.S. 6,054,482 lists pharmaceutical excipients which are incompatible with gabapentin and also those excipients which do not have any noticeable influence on the stability of gabapentin. The list of compatible excipients, amongst others, includes hydroxypropyl methylcellulose. However, an increase in the lactam content was observed when gabapentin was formulated with hydroxypropyl methylcellulose, and further, the formulation was found to be highly unstable upon storage (Examples 6 and 7 and Table 3).

In the present invention we have discovered that the excipients, and in particular the 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 the above described 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 blood level 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 periods. These stable sustained release dosage forms of gabapentin would not only provide a safe mode of gabapentin therapy but also 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, particularly once a day.

Summary of the Invention

In one general aspect there is provided a sustained release tablet of gabapentin wherein (a) the tablet when administered once or twice daily to a human subject provides a mean time to maximum plasma concentration (T_max) of gabapentin of 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 (b) the 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 there is provided 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 900 ml of 0.06 N 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 there is provided a sustained release tablet of gabapentin wherein (a) the tablet when administered once or twice daily to a human subject provides a mean maximum plasma concentration (C_max) of gabapentin comparable to or less than the Cmax provided by an immediate release dosage form of gabapentin administered thrice a day for a similar cumulative daily dose and (b) the sustained release tablet when administered once or twice daily to the human subject provides substantially constant plasma levels of gabapentin for up to 24 hours. In another general aspect there is provided a sustained release tablet of gabapentin wherein the tablet when administered once or twice daily to a human subject provides an AUC_0-24hr comparable to an AUCo_-24hr provided by an immediate release dosage form administered thrice a day for a similar cumulative daily dose.

Embodiments of the above sustained release tablets may include one or more of the following features. For example, the tablet may include gabapentin intragranularly and rate-controlling polymer extragranularly. The rate controlling polymer may be one or more of 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 cellulosic polymer may be one or more of hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and combinations thereof. The sustained release tablet may further include one or more additional pharmaceutical excipients selected from diluents, lubricants, glidants, binders and like. The diluent may be one or more of powdered sugar, calcium phosphate, calcium sulphate, macrocrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol and combinations thereof. The lubricant may be one or more of talc, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate and combinations thereof. The glidant may be one or more of talc, silicon dioxide, corn starch and combinations thereof. The binder may be one or more of polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer, xanthan gum, guar gum, cellulose gums such as carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, gelatin, starch pregelatinised starch and combinations thereof.

The sustained release 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.

The tablets may be administered once per day. The tablets may be administered twice per day.

In another general aspect there is provided a stable sustained release tablet of gabapentin that includes gabapentin intragranularly and rate controlling polymer extragranularly, wherein: the tablet when kept for 3 months at 40⁰C 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: a mean maximum plasma concentration (C_max) of gabapentin to a human subject comparable to or less than the C_max provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose, a mean time to maximum plasma concentration (T_max) of gabapentin of 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 an AUC_0-24hr comparable to an AUCo_-24hr provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose. The tablets may be administered once per day. The tablets may be administered twice per day.

In another general aspect there is provided a process for preparing a stable sustained release tablet of gabapentin, the process including granulating a mixture comprising gabapentin, one or more pharmaceutical excipients and optionally one or more rate-controlling polymers with a granulating liquid; and drying, sizing and mixing the granules with one or more rate controlling polymers and compressing the blend into a tablet, wherein the sustained release tablet when kept for 3 months at 40⁰C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin, the sustained release tablet when administered once or twice daily provides a mean time to maximum plasma concentration (T_max) 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 the sustained release 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 there is provided a method of treating a medical condition responsive to gabapentin, the method including administering a sustained release tablet of gabapentin to a human subject, wherein the tablet when administered once or twice daily provides mean time to maximum plasma concentration (T_max) of gabapentin of 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 sustained release tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours. Embodiments of the method may include one or more of the following features or those described above. For example, the medical condition may be epilepsy or neuropathic pain. The tablets may be administered once per day. The tablets may be administered twice per day. In another general aspect there is provided a method of orally administering gabapentin to a patient to maintain a substantially constant plasma levels of gabapentin for up to 24 hours, the method including administering a sustained release dosage form of gabapentin once or twice daily.

Embodiments of the method may include one or more of the following features or those described above. For example, the tablets may be administered once per day. The tablets may be administered twice per day.

Description of the Drawings

Figure 1 is a graph showing the mean plasma concentration-time profiles measured in a multi-dose crossover study using the tablets of Example 8 containing 900 nig gabapentin administered twice daily (A); two tablets of Example 8 containing 900 mg gabapentin administered together (B), and Neurontin® 600 mg immediate release tablets administered three times daily (R).

Figure 2 is a graph showing the mean plasma concentration-time profiles measured in a single dose crossover study using the tablets of Example 8 containing 900 mg gabapentin administered twice daily (A); two tablets of Example 8 containing 900 mg gabapentin administered together (B), and Neurontin® 600 mg immediate release tablets administered three times daily (R).

Figure 3 is a graph showing the mean plasma concentration-time profiles measured in a second single dose crossover study using the tablets of Example 10 containing 450 mg gabapentin administered twice daily (A); two tablets of Example 10 containing 450 mg gabapentin administered together (B), and Neurontin® 300 mg immediate release tablets administered three times daily (R).

Detailed Description of the Invention

As is known in the 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 helps 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 should help improve patient compliance and increase the chances of successfully completing a dosage regimen for the treatment of the 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 its corresponding lactam, it is imperative that any dosage form of gabapentin should, if not be free of lactam, have a 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 the gabapentin tablets 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 a tolerance of ± 2⁰C 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 the 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, mixtures 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. and include Methocel K4MCR, Methocel Kl 5MCR and Methocel KlOOMCR. 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 a viscosity of from about 7 cps to about 30,000 cps. Especially suitable among these hydroxypropylcelluloses are those having a viscosity of 1,000 cps to about 15,000 cps, particularly suitable are those having a viscosity of 4,000 cps 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 is 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 preparing 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; and

2. drying and mixing the granules of step 1 with a rate controlling polymer and other pharmaceutical excipients such as diluents, lubricants, glidants and binders and compressing the blend into a tablet using appropriate tooling.

In another embodiment, the process for preparing stable gabapentin sustained release tablets includes the following steps:

1. granulating a mixture comprising gabapentin and hydroxypropylcellulose with a solution/dispersion of hydroxypropylcellulose; and 2. drying and mixing the granules with hydroxypropyl methylcellulose or hydroxypropylcellulose and other pharmaceutical excipients such as 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 are further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

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Table 1. Formulation Details of Examples 1-10

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 hydroxypropyl methylcellulose, 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 a second portion of hydroxypropylcellulose dissolved in an 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 the 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 hydroxypropyl methylcellulose and granulated with the remaining portion of hydroxypropyl methylcellulose 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 The same procedure was followed as in Example 6 except that half the amount of hydroxypropyl methylcellulose 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 hydroxypropyl methylcellulose, 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 a second portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried and sized, mixed with hydroxypropyl methylcellulose, 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 a second portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried and sized, mixed with hydroxypropyl methylcellulose 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 three months at 40⁰C in sealed HDPE bottles and tested for stability. The resulting stability data is provided in Table 2. Table 3 contains the dissolution profile of the 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.

Table 2. Stability data of tablets of Examples 1-10 when stored for three months at 40⁰C and 75% relative humidity (RH).

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 the 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 the case of Example 7 where the amount of hydroxypropyl methylcellulose was increased from the intragranular to the extragranular phase in comparison to the tablets of Example 6 containing hydroxypropyl methylcellulose in the 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

Bioavailability studies i) Mulήdose 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 is given in Figure 1. Table 4 depicts the various comparative mean pharmacokinetic parameters. The T_max and C_max 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) given thrice a day.

H) 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 T_max and C_max are derived from the first dose.

Table 5. Mean pharmacokinetic parameters of sustained release gabapentin tablets of Eexample 8 when given once a day; twice a day; and reference formulation (Neurontin 600 mg IR) given thrice a day.

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 T_max and C_max are derived from the first dose.

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Table 6. Mean pharmacokinetic parameters of sustained release gabapentin tablets of Eexample 10 when given once a day; twice a day; and reference formulation (Neurontin 300 mg IR) given thrice a day.

As demonstrated above, the sustained release tablets of gabapentin provide extended T_maχ 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 C_maχ values of the test product were comparable to the Ci_nax values of the reference product indicating that sustained release characteristics of the tablets did not affect the maximum plasma levels attained by following the administration. This further indicates that the tablets provided plasma levels of gabapentin within the therapeutic range and maintained appropriate bioavailability as indicated by similar AUCo_-24 given by a conventional formulation for a similar cumulative dose.

Claims

WE CLAIM: 1. A sustained release tablet of gabapentin wherein (a) the tablet when administered once or twice daily to a human subject provides a mean time to maximum plasma concentration (T_max) of gabapentin of 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 (b) the tablet when administered once or twice daily in the human subject provides substantially constant plasma levels of gabapentin for up to 24 hours, 2. 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. 3. A sustained release tablet of gabapentin wherein (a) the tablet when administered once or twice daily to a human subject provides mean maximum plasma concentration (C_max) of gabapentin comparable to or less than the C_max provided by an immediate release dosage form of gabapentin administered thrice a day for a similar cumulative daily dose and (b) the sustained release tablet when administered once or twice daily to the human subject provides substantially constant plasma levels of gabapentin for up to 24 hours. 4. A sustained release tablet of gabapentin wherein the tablet when administered once or twice daily to a human subject provides an AUC_0-24hr comparable to an AUC_0-24h_r provided by an immediate release dosage form administered thrice a day for a similar cumulative daily dose. 5. The sustained release tablet according to claims 1 -4 wherein the tablet comprises gabapentin intragranularly and rate-controlling polymer extragranularly. 6. The sustained release tablet according to any one of claims 1, 2 or 4 wherein the tablet is administered once daily. 7. The sustained release tablet according to any one of claims 1, 2 or 4 wherein the tablet is administered twice daily. 8. 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. 9. The sustained release tablet according to claim 8 wherein the cellulosic polymer is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and combinations thereof. 10. The sustained release tablet according to claim 1-4 wherein the tablet further comprises one or more additional pharmaceutical excipients selected from diluents, lubricants, glidants, binders and like. 11. The sustained release tablet according to claim 10 wherein the diluent comprises one or more of powdered sugar, calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol and combinations thereof. 12. The sustained release tablet according to claim 10 wherein the lubricant comprises one or more of talc, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate and combinations thereof. 13. The sustained release tablet according to claim 10 wherein the glidant comprises one or more of talc, silicon dioxide, corn starch and combinations thereof. 14. The sustained release tablet according to claim 10 wherein the binder comprises one or more of polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer, xanthan gum, guar gum, cellulose gums such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, starch pregelatinised starch and combinations thereof. 15. The sustained release tablet according to any preceding claim wherein the tablet when kept for 3 months at 40⁰C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin. 16. A stable sustained release tablet of gabapentin comprising gabapentin intragranularly and rate controlling polymer extragranularly, wherein: the tablet when kept for 3 months at 4O⁰C 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: a mean maximum plasma concentration (C_max) of gabapentin to a human subject comparable to or less than the C_max provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose, a mean time to maximum plasma concentration (T_max) of gabapentin of 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 an AUC_0-24hr comparable to an AUCo_-24hr provided by an immediate release dosage form administered thrice a day for similar cumulative daily dose. 17. The sustained release tablet according to claim 16 wherein the tablet is administered once daily. 18. The sustained release tablet according to claim 16 wherein the tablet is administered twice daily. 19. A process for preparing a stable sustained release tablet of gabapentin, the process comprising: granulating a mixture comprising gabapentin, one or more pharmaceutical excipients and optionally one or more rate-controlling polymers with a granulating liquid; and drying, sizing and mixing the granules with one or more rate controlling polymers and compressing the blend into a tablet, wherein the sustained release tablet when kept for 3 months at 40⁰C and 75% relative humidity, the lactam content does not exceed 0.4% by weight of gabapentin, the sustained release tablet when administered once or twice daily provides a mean time to maximum plasma concentration (T_max) of gabapentin to a human subj ect 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 the sustained release tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours. 20. A method of treating a medical condition responsive to gabapentin, the method comprising administering a sustained release tablet of gabapentin to a human subject, wherein the tablet when administered once or twice daily provides mean time to maximum plasma concentration (T_max) of gabapentin of 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 sustained release tablet when administered once or twice daily in the human subject, provides substantially constant plasma levels of gabapentin for up to 24 hours. 21. The method according to claim 20 wherein the medical condition is epilepsy or neuropathic pain. 22. A method of orally administering gabapentin to a patient to maintain a substantially constant plasma levels of gabapentin for up to 24 hours, the method comprising administering a sustained release dosage form of gabapentin once or twice daily.