The present invention relates to orally administered extended release pharmaceutical compositions of gabapentin enacarbil. It also relates to the processes for the preparation of said extended release compositions. It further relates to the use of extended release pharmaceutical compositions for the treatment of restless legs syndrome, postherpetic neuralgia, epilepsy, pain, depression, anxiety, psychosis, and other related disorders.
BACKGROUND OF THE INVENTION
Gabapentin enacarbil is an antiepileptic and analgesic drug. It is a non-ester prodrug for gabapentin. It is chemically known as (l-{[({(lRS)-l-[(2-Methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl}cyclohexyl) acetic acid and is represented by the following formula as:
o I o
o
Gabapentin enacarbil is marketed in the United States as an extended release tablet dosage form in 300 mg and 600 mg strengths under the brand name Horizant® by Arbor Pharmaceuticals. The marketed dosage form of gabapentin enacarbil is indicated for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in and management of postherpetic neuralgia (PHN) in adults.
U.S. Patent No. 6,818,787, assigned to Xenoport, discloses gabapentin enacarbil as a prodrug of gabapentin.
U.S. Patent No. 8,026,279, assigned to Xenoport, discloses a crystalline polymorph of gabapentin enacarbil.

U.S. Patent No. 8,795,725, assigned to Xenoport, discloses sustained release oral tablet of gabapentin enacarbil comprising 40 wt % to 65 wt % gabapentin enacarbil, glyceryl behenate, and 30 wt % to 50 wt % dibasic calcium phosphate.
U.S. Publication No. 2011/0263701, assigned to Teva, discloses a stabilized composition comprising a non-crystalline gabapentin enacarbil and at least one crystallization-inhibiting compound.
PCT Publication No. 2020/165633, assigned to Glenmark, discloses a composition comprising gabapentin enacarbil or pharmaceutically acceptable salts thereof, hydroxypropylmethyl cellulose, and anhydrous dibasic calcium phosphate.
There is a continuing need in the art for alternate oral extended release pharmaceutical compositions of gabapentin enacarbil. The present invention is directed to oral pharmaceutical extended release compositions of gabapentin enacarbil which are robust and are expected to exhibit desired pharmaceutical technical attributes such as assay, dissolution, stability, hardness, bulk density, tapped density, and friability.
OBJECTS AND SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide an oral pharmaceutical extended release composition of gabapentin enacarbil and a process for its preparation.
It is another object of the present invention to provide an oral pharmaceutical extended release composition of gabapentin enacarbil comprising gabapentin enacarbil, a release-retarding agent, and at least one or more pharmaceutically acceptable excipients.
It is another object of the present invention to provide an extended release composition of gabapentin enacarbil comprising gabapentin enacarbil, a release-retarding agent, and at least one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from
3

the group comprising of diluents, lubricants, anti-adherents, glidants, surfactants, solubilizers, disintegrants, film-forming polymer, opacifiers, plasticizers, colorants, and combinations thereof.
It is another object of the present invention to provide an extended release composition of gabapentin enacarbil comprising gabapentin enacarbil, a release-retarding agent, and at least one or more pharmaceutically acceptable excipients, wherein the extended release composition is expected to exhibit desirable technical attributes like assay, dissolution, stability, hardness, bulk density, tapped density, and friability.
It is another object of the present invention to provide an extended release composition of gabapentin enacarbil comprising gabapentin enacarbil, a release-retarding agent, and at least one or more pharmaceutically acceptable excipients, wherein the composition is prepared by dry granulation (e.g. slugging, roller compaction), wet granulation, direct compression, extrusion, spheronization, or melt granulation.
It is another object of the present invention to provide a method for treating a disorder comprising administering an extended release composition comprising gabapentin enacarbil, a release-retarding agent, and at least one or more pharmaceutically acceptable excipients, wherein the disorder is a restless legs syndrome, postherpetic neuralgia, epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, arthritis, insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence, or ethanol withdrawal syndrome.
It is another object of the present invention to provide an extended release composition comprising gabapentin enacarbil, a release-retarding agent, and at least one or more pharmaceutically acceptable excipients, for use in the treatment of restless legs syndrome, postherpetic neuralgia, epilepsy, pain (especially, neuropathic pain and muscular and skeletal pain), depression, anxiety, psychosis,

faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, arthritis, insomnia, gastrointestinal disorders, hot flashes, urinary incontinence, and ethanol withdrawal syndrome.
DETAILED DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by following detailed description of the invention and study of the included examples.
As used herein, the term "composition", "formulation", "dosage form", is intended to encompass a drug product comprising gabapentin enacarbil, and other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with "formulation", "dosage form", "extended release composition", "controlled release composition", "modified release composition", "sustained release composition", "prolonged release composition", "delayed release composition", "programmed release composition", "timed release composition" and are used synonymously throughout the specification. Pharmaceutical compositions of the invention include, but are not limited to, multiparticulates, pellets, beads, spherules, beadlets, microcapsules, millispheres, microspheres, powder, granules, spheroids, tablets, capsules, sprinkles, sachet, inlay tablets, matrix tablet, osmotic tablet, MUPS tablet, tablet-in-tablet, mini-tablet, tablet-in-capsule, single layer and bilayer tablet, trilayer tablet or the like. The pharmaceutical compositions of the present invention are suitable for at least once daily administration. Solid oral dosage forms are particularly selected from the group comprising of tablets with an extended release matrix, functionally coated tablets, capsules, pellets, and granules. Particularly, the dosage form is an extended release matrix tablet or multiparticulate tablet of gabapentin enacarbil. articularly, the dosage form is an extended release matrix tablet of gabapentin enacarbil.
As used herein, the term "gabapentin enacarbil" is used in a broad sense to include not only "gabapentin enacarbil" per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, stereoisomers, diastereoisomers, metabolites, prodrugs, crystalline and amorphous

forms or mixtures thereof. Gabapentin enacarbil is present in an amount from about 20% to about 97% by weight of the composition. Particularly, the gabapentin enacarbil is present in an amount from about 30% to about 95% by weight, from about 35% to about 85% by weight, from about 40% to about 95% by weight, from about 50% to about 95% by weight, from about 60% to about 95% by weight, from about 70% to about 95% by weight, from about 71% to about 95% by weight, from about 75% to about 95% by weight, from about 80% to about 95% by weight, from about 81% to about 95% by weight, from about 85% to about 95% by weight, from about 85% to about 90% by weight of the composition.
The term "release retarding agent(s)" as used herein, refers to one or more pharmaceutical ingredients that provide extended release, controlled release, modified release, sustained release, prolonged release, delayed release, programmed release, timed release, or pulsatile release of gabapentin enacarbil. In certain non-limiting embodiments, the "release retarding agent(s)" may also provide a combination of immediate and/or extended release, controlled release, modified release, sustained release, prolonged release, and delayed release of gabapentin enacarbil.
The term "extended release" as used herein, refers to a release profile to provide effective delivery of gabapentin enacarbil over an extended period of time, such as being between about 1 hour to about 2, 4, 6, 8, 12, 24 hours, or more. Extended release includes modified release, controlled release, sustained release, prolonged release, delayed release, programmed release, multiphase release, pulsatile release, and the like and mean broadly that the active agent is released at a predetermined rate that is different or slower than immediate release. An extended release composition is one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms e.g., immediate release tablets.

The term "immediate release," as used herein, implies that an active ingredient is released from the composition over a short period of time typically less than one hour.
The term "excipient" means a pharmacologically inactive component such as release retarding agents, diluents, binders, glidants, disintegrants, lubricants, surfactants, solubilizers, film-forming polymers, opacifiers, plasticizers, colorants, and/or combinations thereof.
Co-processed excipients are also covered under the scope of the present invention. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
The term "therapeutically effective amount" or "effective amount' as used herein, refers to the amount of active ingredient that elicits a biological response to prevent, inhibit, ameliorate or mitigate a disease.
The term "core" as used herein, refers to a pharmaceutical composition without coating. The phrase "inert core," as used herein, includes a core that may be microcrystalline cellulose spheres, sugar spheres, non-pariel seeds, dibasic calcium phosphate bead, mannitol bead, silica bead, tartaric acid pellet, wax based pellet, and water-insoluble and non-swellable beads.
The term "multiparticulate" as used herein refers to a plurality of discrete or aggregated particles, pellets, powder, granules, beads, spheroids, spheres, microspheres, spherules, beadlets, multiparticulates, microcapsules, millispheres, and the like or mixture thereof, irrespective of their size, shape or morphology.
The term "matrix tablet" refers to a tablet comprising a "controlled release matrix" or "extended release matrix". A "matrix tablet" may or may not comprise a functional coating.
The term "stable," as used herein, refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40±2°C and 75±5% relative humidity (R.H.) or at 25±2°C and 60±5% R.H. for a period of at

least one month, for a period of at least two months, particularly for a period of at least three months, and more particularly for a period of at least six months.
The term "substantially free" as used herein refers to the extended release pharmaceutical composition of gabapentin enacarbil or its pharmaceutically acceptable salts thereof, which is devoid of said element/component/excipient/impurity or may contain less than 10% or less than 5% or less than 2% or preferably less than 1%, or more preferably less than 0.5% of the said element/component/excipient/impurity. Preferably, "substantially free" as used herein refers to the extended release composition of gabapentin enacarbil or its pharmaceutically acceptable salts thereof, which contain less than 2% or preferably less than 1% of the said element/component/excipient/impurity. More preferably, "substantially free" as used herein refers to the extended release composition of gabapentin enacarbil or its pharmaceutically acceptable salts thereof, which contain less than 100 ppm of the said impurity. "Substantially free" as used herein refers to the extended release composition of gabapentin enacarbil or its pharmaceutically acceptable salts thereof, which contain less than 30 ppm or 20 ppm of the said impurity.
As used herein, the term "about" means ± approximately 10% of the indicated value.
As used in this specification, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a process" includes one or more processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation.
The following aspects and embodiments further describe the objects of the present invention in accordance with the best mode of practice, however, disclosed invention is not restricted to the particular embodiments hereinafter described.

In accordance with one embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, a release retarding agent, and one or more pharmaceutically acceptable excipients.
In accordance with one embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, a release retarding agent, and one or more pharmaceutically acceptable excipients, wherein the composition is free of glyceryl behenate or dibasic calcium phosphate or both.
In accordance with another embodiment of the present invention, there is provided a composition comprising gabapentin enacarbil in an extended release matrix.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil in an amount from about 20% by weight to about 97% by weight of the total weight of the composition, a release retarding agent, and one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil in an amount from about 35% by weight to about 85% by weight of the total weight of the composition, a release retarding agent, and one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil in an amount from about 71% by weight to about 97% by weight of the total weight of the composition, a release retarding agent, and one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil in an amount from about 81% by weight to about 97% by weight of the total weight of the

composition, a release retarding agent, and one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is free of a fatty compound as a release retarding agent.
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is free of glyceryl behenate as a release retarding agent.
In accordance with another embodiment of the present invention, the extended release composition is free of hydroxypropylmethyl cellulose as a release retarding agent.
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is free of dibasic calcium phosphate.
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is free of a fatty compound as a release retarding agent and dibasic calcium phosphate.
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is free of glyceryl behenate as a release retarding agent and dibasic calcium phosphate.
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is free of hydroxypropylmethyl cellulose as a release retarding agent and dibasic calcium phosphate.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil in an amount from about 71% by weight to about 97% by weight of the total weight of the composition, hydroxypropylmethyl cellulose as a release retarding agent, and one or more other pharmaceutically acceptable excipients.

In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil in an amount from about 71% by weight to about 79% by weight of the total weight of the composition, hydroxypropylmethyl cellulose as a release retarding agent, and one or more pharmaceutically acceptable excipients.
In accordance with one embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, a release retarding agent, and one or more pharmaceutically acceptable excipients, wherein the release retarding agent is selected from a pH-dependent release retarding agent, a pH-independent release retarding agent, and/or combinations thereof.
In accordance with one embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, a release retarding agent, and one or more pharmaceutically acceptable excipients, wherein the release retarding agent is present in an amount of about 0.01% to about 60% by weight of the composition.
In accordance with one embodiment of the present invention, the ratio of gabapentin enacarbil to release retarding agent is in the range of 1: 0.01 to 1: 50 by weight.
In accordance with one embodiment of the present invention, the ratio of gabapentin enacarbil to release retarding agent is in the range of 1: 0.01 to 1: 20 by weight. The ratio of gabapentin enacarbil to release retarding agent is particularly in the range of 1: 0.01 to 1: 15, particularly in the range of 1: 0.01 to 1: 10, particularly in the range of 1: 0.01 to 1: 5, particularly in the range of 1: 0.01 to 1: 1.
In accordance with one embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, a release retarding agent, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from diluents, binders, glidants, disintegrants, lubricants, surfactants, solubilizers, film-forming polymers, opacifiers, plasticizers, colorants, and combinations thereof.

In accordance with one embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, a release retarding agent, and one or more pharmaceutically acceptable excipients, wherein the composition exhibits a dissolution profile wherein:
(i) not more than about 30% of the drug is released in 1 hour,
(ii) about 30 to 60% of the drug is released in 4 hours,
(iii) not less than about 70% of the drug is released in 12 hours, and
(iv) not less than about 80% of the drug is released in 24 hours,
when placed in 900 ml of 10 mM phosphate buffer with 1% sodium lauryl sulphate having pH 7.4 at 37°C and agitated at 50 rpm (USP Type II apparatus).
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is a tablet, capsule, granules, or pellets.
In accordance with another embodiment of the present invention, the extended release composition of gabapentin enacarbil is a matrix tablet.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the extended release composition comprises:
a. about 20% to about 97% by weight of gabapentin enacarbil,
b. about 0.05% to about 60% by weight of release retarding agent,
c. about 0.1% to about 7% by weight of lubricant, and
d. one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the extended release composition comprises:

a. about 20% to about 97% by weight of gabapentin enacarbil,
b. about 0.05% to about 60% by weight of release retarding agent,
c. about 1% to about 70% by weight of diluent,
d. about 0.1% to about 7% by weight of lubricant,
e. about 0.05% to about 4% by weight of glidant,
f optionally a surfactant, and
g. optionally one or more other pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the extended release composition comprises:
a. about 20% to about 97% by weight of gabapentin enacarbil,
b. about 0.05% to about 60% by weight of release retarding agent,
c. about 1% to about 70% by weight of diluent,
d. about 0.1% to about 7% by weight of lubricant,
e. about 0.01% to about 10% by weight of surfactant, and
f optionally one or more other pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition is prepared by dry granulation (e.g. slugging, roller compaction), wet granulation (e.g. rapid mixture granulation, fluid bed granulation, spray drying), direct compression, extrusion, spheronization, dry blending, or melt granulation, multi-particulate based technology-pelletization, and drug-ion exchange resin complexation.

In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition is stable.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition does not contain non-crystalline gabapentin enacarbil.
In accordance with 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 accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition is expected to be bioequivalent to the marketed extended release tablet of gabapentin enacarbil (Horizant®).
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition is suitable for at least once or twice daily dosing.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition is used for the treatment of restless legs syndrome and post herpetic neuralgia.
In accordance with another embodiment of the present invention, there is provided a process of preparing extended release gabapentin enacarbil composition, comprising the steps of:
i) mixing gabapentin enacarbil, release retarding agent, and one or more other
pharmaceutically acceptable excipients, ii) compacting the mixture of step i) to form slugs, iii) milling the slugs of step ii) to form granules, and

iv) lubricating the granules of step iii), and
v) compressing the lubricated granules of step iv) into a tablet or filling them into a capsule. In accordance with another embodiment of the present invention, there is provided a process of preparing extended release gabapentin enacarbil composition, comprising the steps of:
i) mixing gabapentin enacarbil, release retarding agent, and one or more other
pharmaceutically acceptable excipients, ii) compacting the mixture of step i) to form compacted ribbons, iii) milling the ribbons of step ii) to form granules, and iv) lubricating the granules of step iii), and
v) compressing the lubricated granules of step iv) into a tablet or filling them into a capsule.
In accordance with another embodiment of the present invention, there is provided a process of preparing extended release gabapentin enacarbil composition, comprising the steps of:
i) granulating gabapentin enacarbil, release retarding agent, and one or more
pharmaceutically acceptable excipients using a binder solution, ii) drying the granules of step i), iii) lubricating the dried granules of step ii), and
iv) compressing the lubricated granules of step iii) into a tablet or filling them into a capsule.
In accordance with another embodiment of the present invention, there is provided a process of preparing extended release gabapentin enacarbil composition, comprising the steps of:
i) preparing core comprising gabapentin enacarbil, and one or more
pharmaceutically acceptable excipients; ii) dissolving/dispersing a release-controlling agent and one or more pharmaceutically acceptable coating excipients in a suitable solvent; and

iii) applying the coating composition of step ii) over the core of step i).
Preferable solvents for wet granulation and solvents for coating include, but are not limited to, aqueous, non-aqueous, alcoholic, hydro-alcoholic, ether, acidic solvents, water, esters such as ethyl acetate, ketones such as acetone, alcohols such as methanol, ethanol (including ethanol 95%), isopropanol, butanol, dichloromethane, chloroform, dimethyl acetamide, dimethyl sulfoxide, ether (such as tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane and combinations thereof), diethyl ether, hydrochloric acid (such as IN hydrochloric acid), mixtures of one or more alcohols and water and any combinations or mixtures thereof.
Nitrosamines are potent carcinogens in animals and probable carcinogens in humans. Nitrosamines and their precursors can be potentially found throughout a manufacturing process such as in contaminated raw material/intermediates/ excipients used in the manufacturing process. The most probable reason for nitrosamine impurity generation is the interaction of secondary amines/tertiary amines with nitrite in acid conditions. Excipients used in the development of solid oral compositions such as disintegrants, diluents, binders can carry trace levels of nitrate or nitrite impurities. Thus there is a need for a method for determining and reducing the level of impurities in gabapentin enacarbil compositions and removing those impurities. The inventors propose to reduce or substantially completely remove the nitrosamine impurities which may form during the development of extended release composition of gabapentin enacarbil by the selection of suitable excipients, manufacturing process, and process variables, and using a specific ratio of excipients used in the preparation of compositions.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition is substantially free of nitrosamine impurities.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the

composition contains less than 100 ppm of nitrosamines impurities. Particularly, the extended release composition contains less than 60 ppm of nitrosamines impurities, less than 50 ppm of nitrosamines impurities, less than 40 ppm of nitrosamines impurities, less than 30 ppm of nitrosamines impurities, less than 20 ppm of nitrosamines impurities, and less than 10 ppm of nitrosamines impurities.
In accordance with another embodiment of the present invention, there is provided an extended release composition comprising gabapentin enacarbil, wherein the composition contains less than 0.1% of nitrosamine impurities. Preferably, the extended release composition of gabapentin enacarbil contains less than 0.01% of nitrosamine impurities.
In another embodiment, the extended release composition includes particle size of gabapentin enacarbil, having a particle size distribution such that D90 is less than about 200 urn, D50 is less than about 100 urn and D10 is less than about 50 urn. Particularly, D90 is between about 5 urn to about 100 urn, between about 5 urn to about 50 urn, between about 5 urn to about 30 urn, between about 5 urn to about 20 urn, and between about 5 urn to about 15 urn. The particle size of gabapentin enacarbil can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy, Fraunhofer diffraction, and any other technique known in the art.
The pharmaceutical compositions of the present invention comprise gabapentin enacarbil in an amount from about 100 mg to about 2000 mg. In some embodiments, gabapentin enacarbil is present in an amount particularly from about 100 mg to about 2000 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1000 mg, from about 200 mg or about 1200 mg, and from about 300 mg to about 600 mg.
The release retarding agent is selected from the group comprising a pH-dependent release retarding agent, a pH-independent release retarding agent, and/or combinations thereof. The release retarding agent is present in an amount of about 0.05% w/w to about 70% w/w of the composition. The release retarding agent is

present particularly in an amount of about 0.1% w/w to about 60% w/w of the composition, particularly in an amount of about 0.1% w/w to about 30% w/w of the composition, particularly in an amount of about 0.1% w/w to about 20% w/w of the composition, particularly in an amount of about 0.1% w/w to about 10% w/w of the composition.
Suitable pH-dependent release retarding agents are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit® E 100, Eudragit® E PO, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L100-55 and Eudragit® L30 D-55, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinates, hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate, hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate, vinyl acetate phthalates, vinyl acetate succinate, cellulose acetate trimelliate, polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate, zein, shellac, and combinations thereof.
Suitable pH-independent release retarding agents are selected from the group comprising cellulosic polymers such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, ethyl cellulose and carboxy methylcellulose, acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL (acrylic copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups), Eudragit® NE 30 D, gums e.g., xanthan gum, guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic and gellan gum, triglycerides, polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide, polyvinyl alcohol, polyvinyl acetate, fatty

compounds such as waxes e.g. beeswax, carnauba wax, paraffin wax, and glycowax, castor wax, and, lipids e.g. hydrogenated vegetable oils, Lubritab® (hydrogenated cottonseed oil), fatty acids or their salts/derivatives e.g., Gelucires®, glyceryl ester such as glyceryl monostearate, glyceryl behenate (Compritol®), glyceryl palmitostearate, lauroyl macrogol glyceride and stearoyl macrogol glyceride, lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol and palmitoyl alcohol, polyvinyl polymers, a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR, and combinations thereof. Preferably, the extended release compositions of gabapentin enacarbil are free of glyceryl behenate.
Suitable diluents or fillers are selected from the group comprising microcrystalline cellulose (MCC), silicified microcrystalline cellulose, microfine cellulose, sucrose, dextrose, glucose, lactose, maltose, fructose, sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, dextrates, dextrin, maltodextrin, starch, modified starches, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, magnesium carbonate, magnesium oxide, polydextrose, sodium alginate, sodium chloride, magnesium aluminometasilicate, fats, waxes, fatty alcohols or fatty acid esters, mineral oils, vegetable oils, and or mixtures thereof. The diluent is present in an amount of about 1% w/w to about 95% w/w of the composition, in an amount of about 1% w/w to about 80% w/w of the composition in an amount of about 1% w/w to about 70% w/w of the composition, in an amount of about 3% w/w to about 50% w/w of the composition, in an amount of about 3% w/w to about 30% w/w of the composition, in an amount of about 3% w/w to about 20% w/w of the composition, and in an amount of about 3% w/w to about 10% w/w of the composition.
Suitable binders are selected from the group comprising gums such as guar gum, acacia, alginic acid, and sodium alginate, carbomers, dextrin, maltodextrin, celluloses e.g., methylcellulose, ethylcellulose, hydroxethyl cellulose,

hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, and carboxymethyl cellulose sodium, povidone, dextrose, polydextrose, starch, pregelatinized starch, microcrystalline cellulose, polymethacrylates including acrylic copolymers, gelatin, and mixtures thereof. The binder is present in an amount of about 0.01% w/w to about 40% w/w of the composition.
Suitable disintegrants are selected from the group comprising carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, sodium starch glycolate, starch (potato starch, corn starch, etc.), pregelatinized starch, low substituted hydroxypropyl cellulose, polacrillin potassium, alginic acid, sodium alginate, microcrystalline cellulose, silicified microcrystalline cellulose, guar gum, colloidal silicon dioxide, docusate sodium, magnesium aluminium silicate, methyl cellulose, and combinations thereof. The disintegrant is present in an amount of about 0.01% w/w to about 30% w/w of the composition.
Suitable glidants are selected from the group comprising colloidal silica and/or colloidal silicon dioxide (e.g. Aerosil® 200), magnesium trisilicate, calcium phosphate tribasic, magnesium oxide, magnesium silicate, calcium silicate, talc, and combinations thereof. The glidants are present in an amount of about 0.01% w/w to about 15% w/w of the composition. More particularly, the glidants are present in an amount of about 0.5% w/w to about 10% w/w of the composition, in an amount of about 0.5% w/w to about 5% w/w of the composition.
Suitable lubricants/ anti-adherents are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, medium-chain triglycerides, polyethylene glycol, and combinations thereof. The lubricants are present in an amount of about 0.01% w/w to about 10% w/w of the composition, particularly in an amount of about 0.1% to about 7% w/w of the composition and in an amount of about 0.1% w/w to about 5% w/w of the composition.

Suitable surfactants or wetting agents are selected from the group comprising non-ionic, anionic, cationic, or zwitterionic surfactants, and combinations thereof. Suitable examples of surfactants are sodium lauryl sulfate, cetrimide, polyethylene glycols, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters (Spans) such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters (Polysorbates) such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene-polyoxypropylene block copolymers such as poloxamers (e.g. poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), and combinations thereof. Particularly, surfactants or wetting agents are non-ionic. The surfactants or wetting agents are present in an amount of about 0.01% to about 20% w/w of the composition. Particularly, the surfactants or wetting agents are present in an amount of about 0.01% to about 10% w/w, in an amount of about 0.01% w/w to about 5% w/w, in an amount of about 0.01% w/w to about 3% w/w, and more particularly from about 0.01% w/w to about 1% w/w of the composition.
Suitable plasticizers are selected from the group comprising triethyl citrate, triacetin, glycerol, polyethylene glycol, lecithin, dibutyl phthalate, dibutyl sebacate, and diethyl phthalate. The plasticizers are present in an amount of about 0.01% to about 10% w/w of the composition, particularly from about 0.01% to 5% w/w, from about 0.01% to 1% w/w of the composition.
Various water-soluble polymers are used to form a barrier or seal or film over the core. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, vinylpyrrolidone vinyl acetate copolymer (PVP/VA) polymers, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof,

shellac and derivatives thereof. The water-soluble polymers may be present in an amount of about 0.01% w/w to about 10% w/w of the composition.
Suitable coloring agents are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural juice concentrates; pigments such as iron oxide, titanium dioxide, and zinc oxide; and combinations thereof.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples described in detail. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The following examples are provided to illustrate embodiments of the disclosure but they are by no means intended to limit its scope.
EXAMPLES
Examples 1-4. Extended Release Tablets of Gabapentin Enacarbil

Ingredients Category Quantity (% w/w)

Example 1 Example
2 Example 3 Example 4
Gabapentin enacarbil Active ingredient 20-97 71-95 35-85 30-75
Microcrystalline
cellulose/ Starch/
Lactose/ Calcium
carbonate/ Dibasic
calcium phosphate/
Magnesium carbonate/
Magnesium oxide/
Mannitol/ Pregelatinized
starch/ combinations
thereof Diluent 0.1-80 2-25 1-55 5-60
Methacrylic acid
copolymer (Eudragit RL,
Eudragit RS, Eudragit Release
retarding
agent 0.1-70 1-20 1-20 1-15

NE30D, EudragitLlOO,
EudragitSlOO)/
Hydroxypropyl
Cellulose/Hydroxypropyl
methyl cellulose /Ethyl
cellulose/ Povidone/
/Polyethylene
oxide/Kollidon SR/
combinations thereof
Talc Anti-adherent 0-10 0.1-10 0.1-8 0.1-10
Colloidal silicon dioxide Glidant 0-15 0.1-4 0.1-2 0.1-5
Sodium lauryl sulfate /
Tween 80/ Poloxamer/
Span 20 Surfactant 0-10 0-4 0-3 0-3
Microcrystalline
cellulose/
Hydroxypropyl methyl
cellulose / Povidone/
Pregelatinized starch Binder 0-40 0-10 0-5 0-20
Croscarmellose sodium /
Crospovidone / Sodium
Starch Glycolate Disintegrant 0-30 0-10 0-5 0-15
Magnesium stearate Lubricant 0.1-10 0.1-3 0.1-3 0.1-3
Water/ Ethanol/ Hydroalcoholic solvent Solvent q.s. - - -
Procedure:
i). Gabapentin enacarbil, diluent (s), release retarding agent, glidant, anti-adherent,
binder (if present), surfactant (if present) are blended.
ii). The blend of step i) is optionally lubricated and compacted,
iii). A binder solution is prepared in a solvent,
iv). The compact of step ii) is milled to form granules or the blend of step i) is granulated with the binder solution of iii) to form granules
v) The granules of step iv) are mixed with surfactant (if present), disintegrant (if present), and lubricated, and
vi) The lubricated granules of step v) are compressed to form tablet.

Examples 5-7. Extended Release Tablets of Gabapentin Enacarbil

Ingredients Category Quantity (% w/w)

Example
5 Example 6 Example 7
Gabapentin enacarbil Active ingredient 35-85 45.1-60 55.0
Microcrystalline cellulose/ Starch/ Pregelatinized starch Diluent 1-60 20-50 21.2
Methacrylic acid copolymer
(Eudragit RL, Eudragit RS,
Eudragit NE 30D, Eudragit
L100, Eudragit SI00)/
Hydroxypropyl
Cellulose/Hydroxypropyl
methyl cellulose /Ethyl
cellulose/
Povidone/Poly ethylene
oxide/Kollidon SR/
combinations thereof Release
retarding
agent 1-20 1-20 16.0
Talc Anti-adherent 0.1-8 0-8 5.0
Colloidal silicon dioxide Glidant 0.1-2 0.1-2 0.3
Sodium lauryl sulfate Surfactant 0-3 0-3 1.0
Magnesium stearate Lubricant 0.1-3 0.1-3 1.5
Procedure:
i). Gabapentin enacarbil, diluent (s), release retarding agent, glidant, anti-adherent,
surfactant (if present) are blended,
ii). The blend of step i) is optionally lubricated and compacted,
iii). The compact of step ii) is milled to form granules,
iv) The granules of step iii) are mixed with surfactant (if present) and lubricated, and
v) The lubricated granules of step iv) are compressed to form tablet.

Examples 8-10. Extended Release Tablets of Gabapentin Enacarbil (with
extended release coating)

Ingredients Category Quantity (% w/w)

Example 8 Example 9 Example 10
Gabapentin enacarbil Active ingredient 20-97 35-85 52.0
Microcrystalline cellulose/
Starch/ Lactose/ Calcium
carbonate/ Dibasic calcium
phosphate/ Magnesium
carbonate/ Magnesium oxide/
Mannitol/ Pregelatinized starch/ combinations thereof Diluent 0.1-80 5-65 29.4
Talc Anti-adherent 0-10 0-10 4.0
Colloidal silicon dioxide Glidant 0-15 0.1-5 0.3
Sodium lauryl sulfate Surfactant 0-10 0-3 1.0
Microcrystalline cellulose/
Hydroxypropyl methyl
cellulose / Povidone/
Pregelatinized starch Binder 0-40 0-20 1.0
Croscarmellose sodium /
Crospovidone / Sodium
Starch Glycolate Disintegrant 0-30 0-15 1.0
Magnesium stearate Lubricant 0.1-10 0.1-3 1.0
Water/ Ethanol/ Hydroalcoholic solvent Solvent q.s. -
Extended Release Coating
Methacrylic acid copolymer
(Eudragit RL, Eudragit RS,
EudragitNE 30D, Eudragit
L100, Eudragit SI00)/
Hydroxypropyl
Cellulose/Hydroxypropyl
methyl cellulose /Ethyl
cellulose/ Povidone/
/Polyethylene oxide/Kollidon
SR combinations thereof Release retarding agent 0.1-70 1-15 10.0
Triethyl citrate/ Dibutyl sebacate/ Povidone Plasticizer/ Pore former 0-10 0-10 0.3
Water/ Ethanol/ Isopropyl
alcohol/ Hydroalcoholic
solvent Solvent q.s. q.s. q.s.

Procedure:
i). Gabapentin enacarbil, diluent (s), release retarding agent, glidant, anti-adherent,
binder (if present), surfactant (if present) are blended.
ii). The blend of step i) is optionally lubricated and compacted,
iii). A binder solution is prepared in a solvent,
iv). The compact of step ii) is milled to form granules or the blend of step i) is granulated with the binder solution of iii) to form granules
v) The granules of step iv) are mixed with surfactant (if present), disintegrant (if present), and lubricated, and
vi) The lubricated granules of step v) are compressed to form tablet.
vii) Release retarding agent, plasticizer/pore former are dispersed in solvent to form a coating dispersion,
viii) The tablet of step vi) is coated with coating dispersion of step vii).

WE CLAIM:

1. An extended release composition comprising gabapentin enacarbil, a release retarding agent, and one or more pharmaceutically acceptable excipients, wherein the composition is free of glyceryl behenate or dibasic calcium phosphate or both.
2. The extended release composition as claimed in claim 1, wherein the gabapentin enacarbil is present in an amount from about 35% to about 85% by weight of the composition.
3. The extended release composition as claimed in claim 1, wherein the ratio of gabapentin enacarbil to release retarding agent is in the range of 1: 0.01 to 1: 20 by weight.
4. The extended release composition as claimed in claim 1, wherein the composition is free of a fatty compound and/ or hydroxypropylmethyl cellulose as a release retarding agent.
5. The extended release composition as claimed in claim 1, wherein the release retarding agent is selected from a pH-dependent release retarding agent, a pH-independent release retarding agent, and combinations thereof.
6. The extended release composition as claimed in claim 1, wherein the
pharmaceutically acceptable excipients are selected from diluents, binders, glidants,
disintegrants, lubricants, surfactants, solubilizers, film-forming polymers,
opacifiers, plasticizers, colorants, and combinations thereof.
7. The extended release composition as claimed in claim 1, wherein the composition
exhibits a dissolution profile wherein:
(i) not more than about 30% of the drug is released in 1 hour,
(ii) about 30% to 60% of the drug is released in hours,
(iii) not less than about 70% of the drug is released in 12 hours, and
(iv) not less than about 80% of the drug is released in 24 hours,

when placed in 900 ml of 10 mM phosphate buffer with 1% sodium lauryl sulphate having pH 7.4 at 37°C and agitated at 50 rpm (USP Type II apparatus).
8. The extended release composition as claimed in claim 1, wherein the composition
comprises:
a. about 20% to about 97% by weight of gabapentin enacarbil,
b. about 0.05% to about 60% by weight of release retarding agent,
c. about 0.1% to about 7% by weight of lubricant, and
d. one or more pharmaceutically excipients.
9. The extended release composition as claimed in claim 1, wherein the composition
is substantially free of nitrosamine impurities.
10. The extended release composition as claimed in claim 1, wherein the
composition is a matrix tablet.