Claims:5. CLAIMS
I/We Claim:
1. A stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising: (a) hydroxypropylmethyl cellulose, (b) anhydrous dibasic calcium phosphate, and (c) one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the composition is in the form of a tablet.

3. The pharmaceutical composition of claim 1, wherein the composition is coated.

4. The pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable excipients includes a binder, a disintegrant, a lubricant, a glidant, a buffering agent, a surfactant, and/or an antioxidant.

5. The pharmaceutical composition of claim 1, wherein the enacarbil or pharmaceutically acceptable salts thereof is present in an amount of about 30% to about 70% by weight of the composition.

6. The pharmaceutical composition of claim 1, wherein the hydroxypropylmethyl cellulose is present in an amount of about 5% to about 30% by weight of the composition.

7. The pharmaceutical composition of claim 4, wherein said surfactant is sodium lauryl sulphate and is present in an amount of about 0.5% to about 10% by weight of the composition.
8. The pharmaceutical composition of claim 1, wherein the anhydrous dibasic calcium phosphate is present in amount of about 1% to about 40% by weight of the composition.

9. The pharmaceutical composition of claim 1, wherein the composition when placed in 900ml of 10mM phosphate buffer with 1% sodium lauryl sulphate having pH 7.4 and at 370C and agitated at 50rpm (USP type II apparatus), releases not more than about 30% at 1hour, between about 30 to 60% at 4hours, not less than about 70% in 12 hours and not less than about 80% in 24 hours of gabapentin enacarbil or pharmaceutically acceptable salts thereof.

10. A stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising: (a) hydroxypropylmethyl cellulose, (b) anhydrous dibasic calcium phosphate, and (c) one or more pharmaceutically acceptable excipients; wherein at least 90% of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns.

11. A stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and an extragranular portion, wherein said intragranular portion comprises (a) gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) hydroxypropylmethyl cellulose, (c) anhydrous dibasic calcium phosphate, (d) sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) anhydrous dibasic calcium phosphate, (b) sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient.

12. A stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and extragranular portion, wherein said intragranular portion comprises (a) about 30 to about 70% by weight of gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) about 5 to about 30% by weight of hydroxypropylmethyl cellulose, (c) about 10 to about 40% by weight of anhydrous dibasic calcium phosphate, (d) about 0.5 to about 10% by weight of sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) about 1 to about 50% by weight of anhydrous dibasic calcium phosphate, (b) about 0.5 to about 10% by weight of sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient.
, Description:FORM 2
THE PATENTS ACT, 1970
(39 Of 1970)
AND
THE PATENTS RULES, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10; rule13)
1. TITLE OF THE INVENTION:
A PHARMACEUTICAL COMPOSITION OF GABAPENTIN ENACARBIL OR SALT THEREOF
2. APPLICANT(S)
(a) Name: GLENMARK PHARMACEUTICALS LIMITED
(b) Nationality: Indian
(c) Address: B. D. SAWANT MARG, CHAKALA, ANDHERI (E), MUMBAI - 400 099
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a stable pharmaceutical composition comprising gabapentin enacarbil or pharmaceutically acceptable salts thereof.
PROVISIONAL COMPLETE
The following specification describes the invention The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
FIELD OF THE INVENTION
The present invention provides a stable pharmaceutical compositions comprising gabapentin enacarbil or pharmaceutically acceptable salts thereof and the process of preparation thereof. The invention also relates to the use of said pharmaceutical compositions for the treatment of restless legs syndrome or post herpetic neuralgia.

BACKGROUND OF THE INVENTION
Gabapentin was initially developed by Parke-Davis as Neurontin® Capsules for treatment of epilepsy. It is currently marketed in three dosage forms, i.e., capsule, tablet, and oral solution, for treatment of epilepsy and post-herpetic neuralgia.
Gabapentin enacarbil is a non-ester prodrug for gabapentin was developed by XenoPort. In April 2011, USFDA approved Horizant™ which is marketed as extended release tablets containing 600 mg of the gabapentin enacarbil (equivalent to 312 mg gabapentin). It is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults as well as for the management of Postherpetic Neuralgia (PHN) in adults.
Restless legs syndrome (RLS) is a movement disorder and is clinically defined by the presence of four criteria: (1) an urge to move the limbs with or without sensations, (2) worsening at rest, (3) improvement with activity, and (4)?worsening in the evening or night. The majority of patients have primary (idiopathic) RLS. Secondary (symptomatic) causes of RLS include iron deficiency, peripheral neuropathy, uremia, sleep apnea, Parkinson’s disease, multiple sclerosis, pregnancy, and medications (antidepressants, antihistamines and dopamine antagonists). There are multiple therapeutic options for the treatment of RLS such as dopamine agonists (pramipexole, ropinirole and rotigotine), a-2d agents (pregabalin, gabapentin, and gabapentin enacarbil) and benzodiazepines receptors agonist (such as clonazepam and zolpidem). a-2d agents are considered first-line treatments for patients experiencing RLS, particularly when pain is present. Adverse effects of dopamine agonists may limit their use. Some patients report augmentation of RLS symptoms with long-term dopaminergic treatment. Augmentation results in an earlier onset, and possible intensification of symptoms.
Postherpetic neuralgia (PHN) is a complication of shingles, which is caused by the chickenpox (herpes zoster) virus. PHN affects nerve fibers and skin, causing burning pain that lasts long after the rash and blisters of shingles disappear. Strategies to manage PHN include herpes zoster vaccination, antiviral agents, and tricyclic antidepressant (TCA) medication. The American Society of Anesthesiologists Chronic Pain task force suggests first line therapy to be single or multiple agents including a secondary amine TCA (nortriptyline, desipramine, or amitriptyline), a selective serotonin and noradrenaline reuptake inhibitor (duloxetine, venlafaxine), or the GABA analogs (gabapentin, pregabalin or gabapentin enacarbil).
?-aminobutyric acid (GABA) analogs such as pregabalin, gabapentin, and gabapentin enacarbil interacts with the a2d-1 subunit of the voltage-dependent calcium channel, leading to a reduction in Ca2+ influx into presynaptic nerve terminals and inhibition of the release of excitatory neurotransmitters. Gabapentin is absorbed by low-capacity solute transporters located in the small intestine that become saturated at therapeutic doses. As a result, the bioavailability of gabapentin is not dose proportional. Bioavailability decreases as the dose is increased. The bioavailability is 60% at 300?mg and =40% at doses of 1600–4800?mg. Gabapentin is eliminated unchanged by renal excretion and has a half-life of 5–7?h. The short half-life and its variable bioavailability limit its use.
As discussed in US patents 6,818,787, a significant problem with many GABA analogs is intramolecular reaction of the ?-amino group with the carboxyl functionality to form the ?-lactam, as exemplified for gabapentin below.

US patents 6,818,787 further states that gabapentin enacarbil is a novel prodrug of gabapentin designed to overcome the pharmacokinetic limitations of gabapentin. Gabapentin enacarbil is recognized as a substrate by high-capacity nutrient transporters, monocarboxylase transport type 1 (MCT-1) and sodium-dependent multivitamin transporter (SMVT), which are widely distributed in the intestine. The pathway for absorption is not saturated at clinically useful doses providing dose-proportional absorption and improved bioavailability as compared to gabapentin. Non-ester linkage in gabapentin enacarbil also inhibits spontaneous ?-lactam ring formation, thereby eliminating the difficulties in formulating because of its toxicity.
Gabapentin enacarbil ((±)-1-([a-isobutanoyloxyethoxy)carbonyl]-aminomethyl1)-1-cyclohexane acetic acid) contains one chiral center. The compound exists as a racemate of S-(XP17814) and R-(XP17815) enantiomers.

US patents 6,818,787 and 8,048,917 discloses methods for using prodrugs of GABA analogs, including a generically claimed gabapentin enacarbil and methods for using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders. Further, US patent 8,026,279 discloses a crystalline form of gabapentin enacarbil. US patent 8,114,909 discloses methods of using prodrugs of gamma aminobutyric acid (GABA) analogs and pharmaceutical compositions thereof to treat or prevent restless legs syndrome in humans.
PCT application WO2011133675 discloses a stabilized composition comprising a non-crystalline gabapentin enacarbil and at least one crystallization-inhibiting compound, wherein the stabilized composition is defined as a composition wherein non-crystalline/ amorphous form of gabapentin enacarbil does not convert into crystalline form. PCT application WO 2010102252 and US patent 8,795,725 discloses sustained release oral dosage forms of a gabapentin prodrug with different drug loading capacity.
According to Biopharmaceutics Classification System (BCS), gabapentin enacarbil is classified as a BCS Class 2 compound (low solubility, high permeability). Limited drug absorption due to poor solubility of BCS Class 2 drug results in poor bioavailability, ultimately hampering its therapeutic effectiveness. The solubility depends on the physical form of the drug.
Accordingly, there is a continuing need in the art for an improved and a stable pharmaceutical compositions of gabapentin enacarbil for the treatment of conditions such as RLS and PHN.

SUMMARY OF THE INVENTION
In general aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising: (a) hydroxyalkyl cellulose, (b) anhydrous dibasic calcium phosphate, and (c) one or more pharmaceutically acceptable excipients.

In first aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising: (a) hydroxypropylmethyl cellulose, (b) anhydrous dibasic calcium phosphate, and (c) one or more pharmaceutically acceptable excipients.

In one embodiment of this aspect, the pharmaceutical composition is in the form of a tablet. In another embodiment of this aspect, the pharmaceutical composition is coated. In still another embodiment of this aspect, the one or more pharmaceutically acceptable excipients includes a binder, a disintegrant, a lubricant, a glidant, a buffering agent, a surfactant, and/or an antioxidant. In still another embodiment of this aspect, the enacarbil or pharmaceutically acceptable salts thereof is present in an amount of about 30% to about 70% by weight of the composition. In still another embodiment of this aspect, the hydroxypropylmethyl cellulose is present in an amount of about 5% to about 30% by weight of the composition.

In one embodiment of this aspect, the pharmaceutical composition when placed in 900ml of 10mM phosphate buffer with 1% sodium lauryl sulphate having pH 7.4 and at 370C and agitated at 50rpm (USP type II apparatus), releases not more than about 30% at 1hour, between about 30 to 60% at 4hours, not less than about 70% in 12 hours and not less than about 80% in 24 hours of gabapentin enacarbil or pharmaceutically acceptable salts thereof.

In another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising: (a) hydroxypropylmethyl cellulose, (b) anhydrous dibasic calcium phosphate, and (c) one or more pharmaceutically acceptable excipients; wherein at least 90% of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns.

In another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and an extragranular portion, wherein said intragranular portion comprises (a) gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) hydroxypropylmethyl cellulose, (c) anhydrous dibasic calcium phosphate, (d) sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) anhydrous dibasic calcium phosphate, (b) sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient.

In still another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and extragranular portion, wherein said intragranular portion comprises (a) about 30 to about 70% by weight of gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) about 5 to about 30% by weight of hydroxypropylmethyl cellulose, (c) about 10 to about 40% by weight of anhydrous dibasic calcium phosphate, (d) about 0.5 to about 10% by weight of sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) about 1 to about 50% by weight of anhydrous dibasic calcium phosphate, (b) about 0.5 to about 10% by weight of sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient.
In still another aspect of the invention, the invention compositions are prepared by dry granulation method which includes roller compaction and slugging, or by direct compression method.

In still another aspect of the invention, the invention compositions can be used for the treatment of restless legs syndrome or post herpetic neuralgia.

DETAILED DESCRIPTION OF THE INVENTION

In general aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising: (a) hydroxypropylmethyl cellulose, (b) anhydrous dibasic calcium phosphate, and (c) one or more pharmaceutically acceptable excipients.

According to Biopharmaceutics Classification System (BCS), gabapentin enacarbil is classified as a BCS Class 2 compound which have a low solubility and a high permeability. Limited drug absorption due to poor solubility of BCS Class 2 drug results in poor bioavailability, ultimately hampering its therapeutic effectiveness. The solubility depends on the physical form of the drug. Inventors of the present application have surprisingly found that by reducing the particle size of gabapentin enacarbil below 100 micron, preferably below 50 micron and more preferably below 15 micron resulted in a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof. Further, the invention compositions showed improved impurity profile and dissolution profile when prepared using a dry granulation method.

“Gabapentin enacarbil” of the said invention can be in a crystalline or amorphous form.

“Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a gabapentin enacarbil that is pharmaceutically acceptable and that possesses the desired pharmacological activity. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

“Wt %” refers to the weight of a component or ingredient relative to the total dry weight of a composition or dosage form, e.g., weight percent. For example, a dosage form comprising 40 wt % of gabapentin enacarbil and that weighs 1000 mg contains 400 mg of gabapentin enacarbil.

“Stable formulation” refers to a formulation wherein the impurities are within acceptable limits during accelerated studies and during storage/ shelf life of product.
In one embodiment of the invention, the pharmaceutical composition is in the form of a tablet. Alternatively, in another embodiment, the invention compositions can be prepared in the form of a capsule, minitablet, minicapsule, oral suspension or solution. The formulation can also prepared as injectable, topical, or implant. The more preferred dosage form is tablet.

In another embodiment of the invention the pharmaceutical composition is coated. The coating can be a pharmaceutically acceptable coating such as film coating using pharmaceutically acceptable excipients known to a person skilled in the art.

In still another embodiment of this aspect, the enacarbil or pharmaceutically acceptable salts thereof is present in an amount of about 30% to about 70% by weight of the composition. Alternatively, in another embodiment, the enacarbil or pharmaceutically acceptable salts thereof is present in an amount of about 40% or about 50% or about 60% by weight of the composition. In one embodiment of the invention, the enacarbil or pharmaceutically acceptable salts thereof is present in an amount of 50%, more specifically about 51%.

In still another embodiment of this aspect, the enacarbil or pharmaceutically acceptable salts thereof is present from 100mg to about 1000mg, or from about 200mg to about 800mg, or from about 300mg to about 600mg per unit dosage form. Alternatively, the enacarbil or pharmaceutically acceptable salts thereof is present in about 300mg or 600mg per unit dosage form.

In one embodiment of the invention, the composition comprises hydroxyalkyl cellulose. The hydroxyalkyl celluloses are selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, and hydroxylethyl ethyl cellulose, or a mixture thereof. In still another embodiment of this aspect, the hydroxypropylmethyl cellulose is present in an amount of about 5% to about 30% by weight of the composition. In another embodiment, the hydroxypropylmethyl cellulose is present in an amount of about 6% or about 7% or about 8% or about 9% of about 10% or about 15% or about 20% or about 25% by weight of the composition. Alternatively, in another embodiment, the hydroxypropylmethyl cellulose is present in an intragranular portion of the composition. In another embodiment, the hydroxypropylmethyl cellulose is present in an extratragranular portion of the composition. In another embodiment, the hydroxypropylmethyl cellulose is present in both an intragranular and extratragranular portion of the composition. In one embodiment, preferred amount of hydroxypropylmethyl cellulose is about 7.5% by weight of the composition.

In one embodiment of the invention, the pharmaceutical composition comprises anhydrous dibasic calcium phosphate. In another embodiment, the pharmaceutical composition comprises anhydrous dibasic calcium phosphate in an intragranular portion. In another embodiment, the pharmaceutical composition comprises anhydrous dibasic calcium phosphate in an extragranular portion. In another embodiment, the pharmaceutical composition comprises anhydrous dibasic calcium phosphate in both intragranular and extragranular portion. In still another embodiment, anhydrous dibasic calcium phosphate is present in amount of about 1% to about 40% by weight of the composition. In still another embodiment, anhydrous dibasic calcium phosphate is present in amount of about 5% or about 10% or about 15% or about 20% of about 25% or about 30% or about 35% by weight of the composition. In still another embodiment, anhydrous dibasic calcium phosphate is present in about 15% to about 30% by weight, or about 20% to about 25% by weight in an intragranular portion of the composition. In still another embodiment, anhydrous dibasic calcium phosphate is present in about 0.5% to about 15% by weight, or 1.5% to about 10% by weight or about 2% to about 5% by weight in an extragranular portion of the composition. In preferred embodiment, anhydrous dibasic calcium phosphate is present in amount of about 24% in an intragranular portion and/or about 1.7% in an extragranular portion of the composition.

In still another embodiment of the invention the composition contains one or more pharmaceutically acceptable excipients which includes a binder, a disintegrant, a lubricant, a glidant, a buffering agent, a surfactant, and/or an antioxidant.

Binder suitable for use herein include, but are not limited to, starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols. Binder in the said invention can be used at a concentration of 1-15 wt%.

Disintegrant suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Disintegrant in the said invention can be used at a concentration of 1-15 wt%.

Lubricants and anti-adherents can be included in dosage forms of the present disclosure to aid in processing. Examples of useful lubricants and/or anti-adherents include calcium stearate, glyceryl behenate, glyceryl monostearate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, sodium lauryl sulfate, sodium dodecyl sulfate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate, and combinations of any of the foregoing. Lubricant in the said invention can be used at a concentration of 1-10 wt%.

Glidants can be included in dosage forms of the present disclosure to reduce sticking effects during processing, film formation, and/or drying. Examples of useful glidants include talc, magnesium stearate, glycerol monostearate, colloidal silicon dioxide, precipitated silicon dioxide, and combinations of any of the foregoing. In certain embodiments, a glidant is colloidal silicon dioxide. Glidant in the said invention can be used at a concentration of 1-5 wt%.

Surfactants, include, but are not limited to, cetyl alcohol, sodium lauryl sulfate, the Spans and Tweens which are commercially available from ICI Americas, Inc. Ethoxylated oils, including ethoxylated castor oils, such as Cremophor EL which is commercially available from BASF. Surfactant in the said invention can be used at a concentration of 0.5-10 wt%. In preferred embodiment, surfactant is present in either in an intragranular or in an extragranular or both portion of the inventions. In another preferred embodiment, sodium lauryl sulfate is surfactant and is present in about 1% in an intragranular portion and/or about 1% in an extragranular portion of the composition.

In another embodiment of the invention, least 90% (D90) of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns, or about 80 microns, or about 70 microns, or about 60 microns, or about 50 microns, or about 40 microns, or about 30 microns, or about 20 microns, or about 10 microns. In another embodiment of the invention, least 50% (D50) of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns, or about 80 microns, or about 70 microns, or about 60 microns, or about 50 microns, or about 40 microns, or about 30 microns, or about 20 microns, or about 10 microns or about 5 microns. In still another embodiment of the invention, least 10% (D10) of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns, or about 80 microns, or about 70 microns, or about 60 microns, or about 50 microns, or about 40 microns, or about 30 microns, or about 20 microns, or about 10 microns or about 5 microns, or about 2.5 microns.

In one embodiment of the invention, the pharmaceutical composition when placed in 900ml of 10mM phosphate buffer with 1% sodium lauryl sulphate having pH 7.4 and at 370C and agitated at 50rpm (USP type II apparatus), releases not more than about 30% at 1hour, between about 30 to 60% at 4hours, not less than about 70% in 12 hours and not less than about 80% in 24 hours of gabapentin enacarbil or pharmaceutically acceptable salts thereof. In preferred embodiment, the pharmaceutical composition when placed in 900ml of 10mM phosphate buffer with 1% sodium lauryl sulphate having pH 7.4 and at 370C and agitated at 50rpm (USP type II apparatus), releases about 25% at 1hour, about 45% at 4hours, about 80% in 12 hours and about 95% in 24 hours of gabapentin enacarbil or pharmaceutically acceptable salts thereof.

In another embodiment of the invention, the pharmaceutical composition is stable and wherein the water content (Measured by KF method) is not more than 5%. Further, the invention composition is stable and shows not more than 2% of total impurities.

In another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising: (a) hydroxypropylmethyl cellulose, (b) anhydrous dibasic calcium phosphate, and (c) one or more pharmaceutically acceptable excipients; wherein at least 90% of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns.

In another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and an extragranular portion, wherein said intragranular portion comprises (a) gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) hydroxypropylmethyl cellulose, (c) anhydrous dibasic calcium phosphate, (d) sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) anhydrous dibasic calcium phosphate, (b) sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient.

In still another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and an extragranular portion, wherein said intragranular portion comprises (a) gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) hydroxypropylmethyl cellulose, (c) anhydrous dibasic calcium phosphate, (d) sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) anhydrous dibasic calcium phosphate, (b) sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient; wherein at least 90% of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns.

In still another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and extragranular portion, wherein said intragranular portion comprises (a) about 30 to about 70% by weight of gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) about 5 to about 30% by weight of hydroxypropylmethyl cellulose, (c) about 10 to about 40% by weight of anhydrous dibasic calcium phosphate, (d) about 0.5 to about 10% by weight of sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) about 1 to about 50% by weight of anhydrous dibasic calcium phosphate, (b) about 0.5 to about 10% by weight of sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient.

In still another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and extragranular portion, wherein said intragranular portion comprises (a) about 51% by weight of gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) about 7.5% by weight of hydroxypropylmethyl cellulose, (c) about 24% by weight of anhydrous dibasic calcium phosphate, (d) about 1% by weight of sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) about 1.7% by weight of anhydrous dibasic calcium phosphate, (b) about 1% by weight of sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient.
In still another aspect of the invention, there is provided a stable pharmaceutical composition of gabapentin enacarbil or pharmaceutically acceptable salts thereof comprising an intragranular and extragranular portion, wherein said intragranular portion comprises (a) about 51% by weight of gabapentin enacarbil or pharmaceutically acceptable salts thereof, (b) about 7.5% by weight of hydroxypropylmethyl cellulose, (c) about 24% by weight of anhydrous dibasic calcium phosphate, (d) about 1% by weight of sodium lauryl sulphate, and (e) a pharmaceutically acceptable excipient; and said extragranular portion comprises (a) about 1.7% by weight of anhydrous dibasic calcium phosphate, (b) about 1% by weight of sodium lauryl sulphate, and (c) a pharmaceutically acceptable excipient, wherein at least 90% of particles of gabapentin enacarbil or pharmaceutically acceptable salts thereof has size less about 100 microns.

In still another aspect of the invention, the invention compositions are prepared by dry granulation method which includes roller compaction and slugging, or by direct compression method.

In still another aspect of the invention, the invention compositions can be used for the treatment of restless legs syndrome or post herpetic neuralgia.

EXAMPLES
The following examples further illustrate the invention, but are not limiting.
Example 1:
Composition Mg/tab (% w/w)
Gabapentin enacarbil 30-70
Dibasic calcium phosphate 21 24 25 27 30
Hypromellose 10 7.5 15 12 8
Sodium lauryl sulphate 3 2 4 3 5
Talc 8 8 8 8 8
Colloidal silicon dioxide 3 3 3 4 3
Magnesium stearate 4 3.5 4 3.5 5

Manufacturing Process:
Sift gabapentin enacarbil, dibasic calcium phosphate, hypromellose, talc, colloidal silicon dioxide & sodium lauryl sulphate. Load the sifted materials into a bin blender and mix for 10-20 minutes. Sift magnesium stearate and lubricate blend by mixing for 3-8 minutes. Charge the lubricated blend into roller compactor and mill the compacted ribbons in oscillating granulator. Compress the lubricated blend into tablets of average weight 1000-1200 mg.
Dissolution Profile:
Dissolution Parameters 10mM Phosphate Buffer at pH 7.4 with 1% SLS, 900ml, USP Type II apparatus, 50 rpm
Time (hr) % Drug released
1 19
4 48
12 88
24 99

Example 2:
Composition Mg/tab (% w/w)
Gabapentin Enacarbil 30-70
Dibasic calcium Phosphate 1-50
Hypromellose 1-15
Hydrogenated Castor Oil 1-15
Sodium Lauryl Sulphate 1-5
Talc 1-10
Colloidal silicon dioxide 0.1-1
Magnesium Stearate 0.5-5

Manufacturing Process:
Sift gabapentin enacarbil, dibasic calcium phosphate, hypromellose & hydrogenated castor oil, talc, colloidal silicon dioxide & sodium lauryl sulphate. Load the sifted materials into a bin blender and mix for 10-20 minutes. Sift magnesium stearate and lubricate blend by mixing for 3-8 minutes. Charge the lubricated blend into roller compactor and mill the compacted ribbons in oscillating granulator. Compress the lubricated blend into tablets of average weight 1000-1200 mg.
Dissolution Profile:
Dissolution Parameters 10mM Phosphate Buffer at pH 7.4 with 1% SLS, 900ml, USP Type II apparatus, 50 rpm
Time (hr) % Drug released
1 20
4 52
12 97
24 100

Example 3:
Composition Mg/tab (% w/w)
Gabapentin Enacarbil 30-70
Calcium Carbonate 1-50
Lactose 10-15
Hypromellose 1-15
Sodium Lauryl Sulphate 1-5
Talc 1-10
Colloidal silicon dioxide 0.1-1
Magnesium Stearate 0.5-5

Manufacturing Process:
Sift gabapentin enacarbil, calcium carbonate, hypromellose, talc, colloidal silicon dioxide & sodium lauryl sulphate. Load the sifted materials into a bin blender and mix for 10-20 minutes. Sift magnesium stearate and lubricate blend by mixing for 3-8 minutes. Charge the lubricated blend into roller compactor and mill the compacted ribbons in oscillating granulator. Compress the lubricated blend into tablets of average weight 1000-1200mg.
Dissolution Profile:
Dissolution Parameters 10mM Phosphate Buffer at pH 7.4 with 1% SLS, 900ml, USP Type II apparatus, 50 rpm
Time (hr) % Drug released
1 10
4 32
12 80
24 100

Example 4:
Composition Mg/tab (% w/w)
Gabapentin Enacarbil 30-70
Calcium Carbonate 1-25
Lactose 1-25
Hypromellose 1-15
Sodium Lauryl Sulphate 1-5
Talc 1-10
Colloidal silicon dioxide 0.1-1
Magnesium Stearate 0.5-5

Manufacturing Process:
Sift gabapentin enacarbil, calcium carbonate, lactose, hypromellose, talc, colloidal silicon dioxide & sodium lauryl sulphate. Load the sifted materials into a bin blender and mix for 10-20 minutes. Sift magnesium stearate and lubricate blend by mixing for 3-8 minutes. Charge the lubricated blend into roller compactor and mill the compacted ribbons in oscillating granulator. Compress the lubricated blend into tablets of average weight 1000-1200mg.

Example 5:
Composition Mg/tab (% w/w)
5A 5B 5C
Intragranular
Gabapentin enacarbil 51 51 51
Anhydrous Dibasic calcium Phosphate (Fujicalin SG) 23 20 25
Hypromellose 2208 7.5 10 15
Sodium Lauryl Sulphate (Kolliphor SLS fine) 1 2 4
Talc (Luzenac pharma) 6 8 10
Colloidal silicon dioxide(Aerosil 200 Pharma) 0.68 0.82 1
Magnesium stearate (Perteck) 0.8 0.9 1
Extragranular
Anhydrous Dibasic calcium Phosphate (Fujicalin SG) 1.72 2 2.5
Sodium Lauryl Sulphate (Kolliphor SLS fine) 1 1.5 2
Talc (Luzenac pharma) 2 2.5 3
Colloidal silicon dioxide (Aerosil 200Pharma) 1 1.5 2
Magnesium stearate (Parteck ) 2.5 3 4

Manufacturing Process:
Sift intragranular gabapentin enacarbil, Anhydrous Dibasic calcium Phosphate (Fujicalin SG), Hypromellose, talc, colloidal silicon dioxide & sodium lauryl Sulphate. Load the sifted materials into a bin blender and mix for 10-20 minutes. Sift intragranular magnesium stearate and lubricate blend by mixing for 3-8 minutes. Charge the lubricated blend into roller compactor and mill the compacted ribbons in oscillating granulator. Load milled granules and sifted extragranular materials except extragranular magnesium stearate in bin blender and mix for 10 – 20minutes. Sift extragranular magnesium stearate and lubricate blend by mixing for 3-8 minutes. Compress the lubricated blend into tablets of average weight 1000-1200mg.
Dissolution profile:
Dissolution Parameters 10mM Phosphate Buffer at pH 7.4 with 1% SLS, 900ml, USP Type II apparatus, 50 rpm
Time (hr) % Drug released
1 16
4 45
12 89
24 97

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.