DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

OXCARBAZEPINE MODIFIED-RELEASE FORMULATIONS FOR ORAL USE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24
PLOT NO.1, SURVEY NO.83/1
HYDERABAD KNOWLEDGE CITY
RAIDURG PANMAKTHA
RANGA REDDY DISTRICT
HYDERABAD - 500 032
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION

The present invention provides solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof, comprising a homogeneous matrix comprising Oxcarbazepine or salts thereof, a matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients and wherein said composition does not contain pH-dependent soluble polymer. There is also provided process of preparing such composition and its use in the treatment of epileptic seizures.

BACKGROUND OF THE INVENTION

Oxcarbazepine is an anticonvulsant and mood-stabilizing drug, used primarily in the treatment of epilepsy. Oxcarbazepine product is disclosed in U.S Patent No 3,642,775. Its chemical name is 10, l l-Dihydro-10-oxo-5H-dibenz[b,f]-azepine-5-carboxamide. Oxcarbazepine has a molecular weight of 252.27 with the following structural formula:

Oxcarbazepine extended release tablets are currently marketed in the USA under brand name Oxtellar XR™, while Oxcarbazepine immediate release tablets are currently marketed in the USA under brand name Trileptal™, where both the dosage forms are approved for treatment of partial-onset seizures.

The need for a controlled-release dosage form for drugs taken chronically such as Oxcarbazepine and derivatives is self-evident. Patient compliance is greatly improved with controlled-release (CR) dosage forms. Also, there are significant clinical advantages such as better therapeutic efficacy as well as reduced side effects with controlled-release dosage forms.
U.S. Patent Nos. 7,722,898, 7,910,131, 8,617,600, 8,821,930, 9,119,791, 9,351,975, 9,370,525, 9,855,278, 10,220,042, 8,017,149, 8,211,464 & 9,119,792 discloses controlled-release preparations of Oxcarbazepine and derivatives thereof comprising polymers having pH-dependent solubility.

U.S. Patent Application No. 2004/0142033 discloses sustained-release formulations of Oxcarbazepine that are characterized by the release of 55% - 85% of the drug in 15 minutes, and up to 95% in 30 minutes.

U.S. Patent No. 7,037,525 discloses Oxcarbazepine having improved bioavailability with a hydrophilic permeable outer coating.

U.S. Patent No. 6,296,873 discloses sustained-release delivery systems for carbamazepine and its derivatives.

The inventors of the present invention have found that although several formulations have been suggested in the art for sustained-release or controlled-release of Oxcarbazepine and formulations with functional coating, but due to poor solubility of Oxcarbazepine or salts thereof, its release from a sustained release dosage form may be rather incomplete. Various formulations suggested in the art employs polymers having pH dependent solubility.

However, despite the known forms of Oxcarbazepine, it is always desirable to provide modified-release pharmaceutical formulations of Oxcarbazepine, particularly which exhibits desired or even improved release profile of Oxcarbazepine by legitimate selection of excipients and formulation structure. Thus, there still exists an enduring need for an alternate improved formulation of Oxcarbazepine and also there remains a need to develop a modified-release pharmaceutical formulations of Oxcarbazepine with improved bioavailability and release profile using conventional techniques and equipment which is easy to manufacture and cost effective thereby decreasing patient non-compliance.
The brand product Oxtellar XR™, is a controlled-release preparation with sigmoidal release profiles, ensured by using release promoting agent comprising a polymer having pH-dependent solubility selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinyl acetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, and Eudragit L100-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) and methyl acrylate-methacrylic acid copolymers.

Inventors of the present invention developed a pharmaceutical formulation without using any polymer which has pH-dependent solubility and by matching sigmoidal release profile of controlled release formulation using suitable combination of matrix forming polymer with different viscosity (swelling property), an acidifying agent and a solubilizer to form a porous matrix and to promote drug release.

The inventors of the present invention have surprisingly found that by forming a modified-release pharmaceutical composition comprising matrix of oxcarbazepine or salts thereof with matrix forming polymer, and by avoiding the use of excipients having pH-dependent solubility, the composition may exhibit improved bioavailability of oxcarbazepine or salts thereof. Further, the inventors of the present invention have also found that such formulation of oxcarbazepine can exhibit excellent storage stability and the process is cost effective.

SUMMARY OF INVENTION

Aspects of the present invention relates to solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof without release promoting agent comprising a polymer having pH-dependent solubility.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition of Oxcarbazepine comprising: a core, which comprises homogeneous matrix comprising Oxcarbazepine or salts thereof, matrix forming polymer, acidifying agent, solubilizer and one or more other pharmaceutically acceptable excipients, wherein said composition does not contain pH-dependent soluble polymer.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition of Oxcarbazepine comprising: a core, which comprises homogeneous matrix comprising Oxcarbazepine or salts thereof, matrix forming polymer, one or more release rate-controlling polymers, acidifying agent, solubilizer and one or more other pharmaceutically acceptable excipients, wherein said composition does not contain pH-dependent soluble polymer.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition of Oxcarbazepine comprising homogeneous matrix comprising Oxcarbazepine or salts thereof and matrix forming polymer which is selected from the group consisting of cellulosic polymers, alginates, gums, cross-linked polyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol. Cellulosic polymers include, but are not limited to hydroxypropyl methyl cellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone. Hydroxypropyl methyl cellulose being the most preferred.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof is devoid of release promoting agent comprising a polymer having pH-dependent solubility selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, and Eudragit L100-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) and methyl acrylate-methacrylic acid copolymers.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising a solubilizer to promote drug release by forming a porous matrix.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof comprising a homogeneous matrix by means of combination of two or more different viscosity polymers especially hydroxypropyl methyl cellulose polymer in different ratios such as 1:20 to 20:1, where hydroxypropyl methyl cellulose polymers viscosity ranges from 3 cps to 2 lakh cps with varying substitution types such as 2910, 2906 2208.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising; 40% to 65% by weight of Oxcarbazepine or salts thereof, 2% to 20% by weight of matrix forming polymer, and 20% to 40% by weight of one or more other excipients.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising; 40% to 65% by weight of Oxcarbazepine or salts thereof, 10% to 15% by weight of matrix forming polymer, 5% to 10% by weight of solubilizer, 0.1% to 2% by weight of acidifying agent and 20% to 40% by weight of one or more other excipients.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising; 40% to 65% by weight of Oxcarbazepine or salts thereof, 2% to 20% by weight of matrix forming polymer, 2% to 20% by weight of release rate-controlling polymer and 20% to 40% by weight of one or more other excipients.

In an another aspect, the present invention provides a solid oral modified-release pharmaceutical composition comprising Oxcarbazepine in an amount of about 40% to about 65% by weight, Hydroxypropyl methylcellulose in an amount of about 2% to about 20 % by weight, Povidone in an amount of about 2% to about 10 % by weight, Silicified microcrystalline cellulose in an amount of about 2 % to about 20 % by weight, Sodium lauryl sulfate in an amount of about 2 % to about 10% by weight, Fumaric acid in an amount of 0.1% to 2% by weight and Magnesium stearate in an amount of about 0.1 % to about 2% by weight.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising Oxcarbazepine or salts thereof in an amount of about 40% to about 65% by weight, Hydroxypropyl methylcellulose in an amount of about 2% to about 20 % by weight, Povidone in an amount of about 2% to about 10% by weight, Silicified microcrystalline cellulose in an amount of about 2% to about 20 % by weight, Sodium lauryl sulfate in an amount of about 2 % to about 10% by weight, Lactose monohydrate in an amount of about 2% to about 10% by weight, Pregelatinized starch in an amount of about 0.5% to about 5% by weight, Magnesium stearate in an amount of about 0.1% to about 2% by weight, and Fumaric acid in an amount of about 0.1% to about 2% by weight.

In an another aspect, the present invention relates to solid oral modified-release composition of Oxcarbazepine or salts thereof comprising a core of matrix of Oxcarbazepine or salts thereof, wherein core is coated with one or more film forming polymers.

In an another aspect, polymers in the film forming layer may include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate and waxes such as polyethylene glycol or macrogol.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising Oxcarbazepine, matrix forming polymer and/or release rate-controlling polymers, and solubilizer and other excipients are typically combined and wet granulated using a granulating fluid.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising:
(a) a core, which comprises a homogeneous matrix comprising Oxcarbazepine or salts thereof, matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.
(b) Film coating.

In an another aspect, the present invention relates to solid oral modified-release pharmaceutical composition comprising:
(a) a core, which comprises a homogeneous matrix comprising Oxcarbazepine or salts thereof, matrix forming polymer, one or more release rate-controlling polymers, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.
(b) Film or functional coating.

In an another aspect, the present invention provides a solid oral modified-release pharmaceutical composition of Oxcarbazepine and a process for preparing the same by using wet granulation or melt extrusion process.

In an another aspect, the present invention relates to a process of preparing the solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof, which process comprises steps of:
(a) preparing a core matrix of Oxcarbazepine by granulating Oxcarbazepine or salts thereof with matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.
(b) coating the homogeneous matrix core with one or more film forming polymers.
In an another aspect, the present invention relates to a process of preparing the solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof, which process comprises steps of:
(a) preparing a core matrix of Oxcarbazepine by granulating Oxcarbazepine or salts thereof with matrix forming polymer, one or more release rate-controlling polymers, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.
(b) coating the homogeneous matrix core with one or more film forming polymers.

In an another aspect, the present invention relates to a process of preparing the solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof and, which process comprises steps of:
a. sifting of all ingredients,
b. dry mixing of step (a) in Rapid Mixer Granulator, and
c. granules were prepared by Rapid Mixer Granulator using Hydro-alcoholic solution as the granulating liquid.
d. wet granules of step (c) were dried using fluid bed processor.
e. dry granules of step (d) were screened by suitable mesh and oversized granules were sized using co-mill screened by suitable mesh, and
f. blending the mixture of step (e) with lubricant;
g. formulating the lubricated blend of step (f) in to a solid oral dosage form; and
h. coating the solid oral dosage form of step (g) with film forming polymers.

In a further aspect, the invention relates to a method of treating partial seizures comprising administering the formulation as defined herein to a patient in need thereof, wherein said formulation is a tablet and is administered orally.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a solid oral modified-release pharmaceutical composition comprising Oxcarbazepine or salts thereof, matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients, wherein said composition does not contain pH-dependent soluble polymer. More particularly, the invention relates to a solid oral modified-release pharmaceutical composition comprising Oxcarbazepine or salts thereof, matrix forming polymer, one or more release rate controlling polymers, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients, wherein said composition does not contain pH-dependent soluble polymer.

In embodiments, the term "Oxcarbazepine" as used herein refers to Oxcarbazepine base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.

In embodiments, the term "modified release" as used herein means release, which is not immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release.

In embodiments, the term "modified release dosage form" as used herein can be described as dosage forms whose 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 a solution or an immediate release dosage form.

In embodiments, the term "functional coating" is a coating that significantly modifies release characteristics of oxcarbazepine or salt thereof from a formulation when administered.

In embodiments, the solid oral modified-release pharmaceutical composition in accordance with the present invention comprises a core, which comprises a homogeneous matrix of Oxcarbazepine or salts thereof and one or more other pharmaceutical acceptable excipients.

In embodiments, the solid oral modified-release pharmaceutical composition in accordance with the present invention comprises a core comprising a homogeneous matrix of Oxcarbazepine or salts thereof, wherein homogeneous matrix comprises matrix forming polymer.

In embodiments, the solid oral modified-release pharmaceutical composition in accordance with the present invention comprises a core comprising a homogeneous matrix of Oxcarbazepine or salts thereof, wherein homogeneous matrix comprises matrix forming polymer and one or more release rate-controlling polymers.

In embodiments, the solid oral modified-release pharmaceutical composition in accordance with the present invention comprises a core comprising a homogeneous matrix of Oxcarbazepine or salts thereof, wherein homogeneous matrix comprises a solubilizer and an acidifying agent.

In embodiments, the solid oral modified-release pharmaceutical composition comprises a core comprising a homogeneous matrix of Oxcarbazepine or salts thereof, wherein homogeneous matrix comprises matrix forming polymer, a solubilizer, an acidifying agent, fillers, binders, disintegrating agents, lubricants and one or more other pharmaceutical acceptable excipients and coating of the solid oral modified-release pharmaceutical composition with film forming polymers.

In embodiments, the amount or the type of release-controlling polymers selection depends on the desired release profile, and is optimized for achieving a desired in vitro release profile, which is predicted based on the in vitro/in vivo correlations and efficacy study results. Preferably, the release profile provides an immediate bolus of drug and extended release of the drug at a relatively constant rate for an extended period of time (over 12 hours or more).

In embodiments, the solid oral modified-release pharmaceutical composition comprises:
(a) a core comprising a homogeneous matrix of Oxcarbazepine or salts thereof, matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.
(b) coating the homogeneous matrix core with one or more film forming polymers.

In embodiments, the solid oral modified-release composition is prepared by a process which comprises steps of:
(a) sifting oxcarbazepine or salts thereof, matrix forming polymer and one or more pharmaceutically acceptable excipients;
(b) granulating the sifted mixture of step (a) to form granules, and
(c) formulating the granules of step (b) in a solid dosage form.

In embodiments, Oxcarbazepine, matrix forming polymer, release rate-controlling polymers, and other excipients are typically combined and wet granulated using a granulating fluid. However, other methods of forming granules such as slugging, and roller compaction can also be used to manufacture matrix granules. Matrix tablets can also be made by direct compression. In wet granulation, typical granulating fluids are: water, a mixture of water and alcohol, anhydrous alcohol. Wet granules can be made in any granulating device such as mixers, high shear granulators, and fluid bed granulators. Granules can be dried in appropriate drying equipment such as fluid bed dryers, ovens etc. Granules can also be air-dried. Dried granules can be milled using appropriate milling device to achieve a particular particle size distribution. Granules can be blended with other excipients and tableted on a tablet press.

In embodiments, the present invention relates to a process of preparing the solid oral modified-release pharmaceutical composition of Oxcarbazepine or salts thereof, which process comprises steps of:
(a) preparing a core matrix of Oxcarbazepine by granulating Oxcarbazepine or salts thereof with matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.
(b) coating the homogeneous matrix core with one or more film forming polymers.

In embodiments, the present invention provides a method of treating partial seizures, which method comprises of administering a solid oral modified-release pharmaceutical composition comprising: a core comprising homogeneous matrix of Oxcarbazepine or salts thereof, wherein homogeneous matrix comprises Oxcarbazepine, matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.

In embodiments, the present invention provides a method of treating partial seizures, which method comprises of administering a solid oral modified-release pharmaceutical composition comprising:
(a) core comprising homogeneous matrix of Oxcarbazepine or salts thereof, wherein homogeneous matrix comprises Oxcarbazepine, matrix forming polymer, one or more release rate-controlling polymers, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients.
(b) coating the core with one or more film forming polymers.

In embodiments, the amount of Oxcarbazepine in the composition may range from about 10% w/w to about 80% w/w of the composition. Preferably, the amount of Oxcarbazepine in the composition ranges from about 20% w/w to about 70% w/w of the composition. More preferably, the amount of Oxcarbazepine in the composition ranges from about 40% w/w to about 65% w/w of the composition.

In embodiments, a dose unit comprises 150 to 600 mg of the Oxcarbazepine, such as 150mg, 300mg and 600mg of the Oxcarbazepine per dose unit.

In embodiments, the present invention provides solid oral modified-release pharmaceutical composition comprising a homogeneous matrix by means of combination of two or more different viscosity polymers especially HPMC polymer in different ratios such as 1:20 to 20:1, where HPMC polymers viscosity ranges from 3 cps to 2 lakh cps with varying substitution types such as 2910, 2906 2208. Matrix forming polymer can be selected from the group consisting of cellulosic polymers, alginates, gums, cross-linked polyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol.

In embodiments, the present invention provides solid oral modified-release pharmaceutical composition comprising a solubilizer to promote drug release by forming a porous matrix.

In embodiments, the solid oral modified-release pharmaceutical composition of the invention further may comprise one or more pharmaceutical acceptable excipients suitable for oral administration. Such excipients may be selected from binders, fillers, filler-binders, disintegrants, glidants, solubilizers, acidifying agent, alkalizers, antiadherents, sweeteners, flavouring and colouring agents.

In embodiments, preferred matrix forming polymers are the cellulosic compounds hydroxypropyl methyl cellulose, hydroxypropyl cellulose and polyvinylpyrrolidone (Povidone), alginates, Shellac, gums, cross-linked polyacrylic acid, carageenan, polyethylene oxides, and polyvinyl alcohol. Preferable polymers are selected from Hydroxypropyl methyl cellulose and polyvinylpyrrolidone (Povidone) or mixtures thereof.

In embodiments, the solid oral modified-release pharmaceutical composition comprise matrix forming polymer in an amount of about 2% to about 40 % w/w of the composition; preferably in an amount of about 2% to 30% w/w of the composition; more preferably 2% to 20% w/w of the composition.

In embodiments, release rate-controlling polymers suitable for use in the composition of the present invention comprise water soluble or water insoluble substances or mixtures thereof. Preferably, rate-controlling polymers are water soluble and/or water insoluble polymers.
In embodiments, release rate-controlling polymers suitable for use in core matrix of the solid oral modified-release pharmaceutical composition of the present invention are selected from a group comprising alginates (Sodium alginate), Shellac, cellulosic polymers, such as hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, and ethyl cellulose; gums such as guar and xanthan gums; cross-linked polyacrylic acid derivatives such as Carbomers (aka CarbopolTM) available in various molecular weight grades; carageenan; polyvinyl pyrrolidone and its derivatives such as crospovidone; polyethylene oxides; and polyvinyl alcohol.
In embodiments, the solid oral modified-release pharmaceutical composition comprises release rate-controlling polymers in an amount of about 2% to about 40% w/w of the composition; preferably in an amount of about 2% to 30% w/w of the composition; more preferably 2% to 20% w/w of the composition.

In one embodiment, the solid oral modified-release pharmaceutical composition comprises an acidifying agent, into the matrix-based core tablets to create an acidic micro environmental pH. The acidifying agent may be an organic acid. Examples of organic acid include, but are not limited to, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, fumaric acid, maleic acid, glutamic acid, succinic acid, aspartic acid, and acetic acid.

In embodiments, the solid oral modified-release pharmaceutical composition comprises an acidifying agent in an amount of about 0.1% to about 2% w/w of the composition.

In embodiments, the solid oral modified-release pharmaceutical composition comprises a solubilizer. Exemplary solubilizers preferred in this invention include surface active agents such as sodium docusate, sodium lauryl sulfate, Tweens® and Spans (PEO modified sorbitan monoesters and fatty acid sorbitan esters), poly(ethylene oxide)-polypropylene oxide-poly(ethylene oxide) block copolymers (aka Pluronics™); complexing agents such as low molecular weight polyvinyl pyrrolidone and low molecular weight hydroxypropyl methyl cellulose; molecules that aid solubility by molecular entrapment such as cyclodextrins and alkalizing agents such as meglumine and sodium hydroxide.

In embodiments, the solid oral modified-release pharmaceutical composition comprise solubilizers in an amount of about 2% to about 10% w/w of the composition.

In embodiments, the solid oral modified-release pharmaceutical composition provided herein comprises excipients which act as fillers. Certain non-limiting examples of fillers include starches, microcrystalline cellulose or silicified microcrystalline cellulose, maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, fully pregelatinized starch, cellulose, mannitol, erythritol, lactose, such as lactose monohydrate and lactose anhydrous, calcium salts, such as calcium hydrogen phosphate dihydrate, anhydrous dibasic calcium phosphate, sorbitol, xylitol, or mixtures thereof. Preferable fillers are selected from lactose, microcrystalline cellulose, silicified microcrystalline cellulose or mixtures thereof.

In embodiments, the solid oral modified-release pharmaceutical composition comprises filler in an amount of about 5% to about 40 % w/w of the composition; preferably in an amount of about 5% to 30% w/w of the composition; more preferably 5% to 25 % w/w of the composition.

In embodiments, the solid oral modified-release pharmaceutical composition provided herein includes a binder which hold ingredients in the formulation together. Exemplary binders are selected from, but not limited to polyvinyl pyrrolidone (Povidone), copolymers of vinylpyrrolidone with other vinylderivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum and starch. Polyvinyl pyrrolidone (Povidone) is being most preferred.

In embodiments, the solid oral modified-release pharmaceutical composition comprises binder in an amount of about 2% to about 20% w/w of the composition; preferably in an amount of about 2% to 15% w/w of the composition; more preferably 2% to 10% w/w of the composition.

In embodiments, the solid oral modified-release pharmaceutical composition provided herein includes disintegrant. Exemplary disintegrants are selected from, but not limited to cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), silicified microcrystalline cellulose, microcrystalline cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, hydroxypropyl methylcellulose and hydroxypropyl cellulose.

In embodiments, the solid oral modified-release pharmaceutical composition comprises disintegrant in an amount of about 1% to about 20% w/w of the composition; preferably in an amount of about 1% to 10% w/w of the composition; more preferably 1% to 5% w/w of the composition.

In embodiments, the solid oral modified-release pharmaceutical composition provided herein includes Lubricants and/or glidants aids in the processing of powder materials. Exemplary lubricants are selected from, but not limited to, calcium stearate, magnesium stearate, glycerol behenate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, and zinc stearate, used either alone or combinations thereof. Exemplary glidants include, but not limited to, talc, silicon dioxide, cornstarch and the like used either alone or in combination thereof.

In embodiments, the solid oral modified-release pharmaceutical composition of the present invention may be in the form suitable for oral administration, such as tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, a bilayer tablet and a trilayer tablet or combinations thereof.

In embodiments, the solid oral modified-release pharmaceutical composition of the present invention may include rate-controlling excipients suitable for use in the functional coating over the homogeneous matrix core selected from, but not limited to, methyl acrylate-methacrylic acid copolymers (available commercially under Eudragit® brand, e.g. Eudragit® L100-55), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, sodium alginate and stearic acid, hydroxypropyl cellulose, hypromellose or polyvinyl alcohol or mixtures thereof.

In embodiments, the solid oral modified-release pharmaceutical composition in accordance with the present invention further may be coated with one or more film forming polymers. The film forming polymer coating is provided preferably over the controlled release homogeneous matrix core.

In embodiments, polymers in the film forming layer may include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate and waxes such as polyethylene glycol or Macrogol.

Preferred coatings are Opadry® II Brown (Polyvinyl Alcohol; Polyethylene Glycol, Titanium Dioxide; Talc, Yellow Iron Oxide and Red Iron Oxide), Opadry® White (Hypromellose, Talc & Titanium dioxide), Opadry® Yellow (Hypromellose, Talc, Titanium dioxide & Iron oxide yellow), Opadry® Pink (Hypromellose, Titanium dioxide, Talc, Iron oxide red and Iron oxide yellow), Opadry® II pink (Polyvinyl alcohol, Polyethylene glycol, Titanium dioxide, Talc, Red iron oxide and Yellow iron oxide), WincoatTM WT-19012P Brown (Polyvinyl alcohol, Polyethylene glycol 3350, Titanium dioxide, Talcum, Red iron oxide, Black Iron Oxide and Yellow iron oxide), WincoatTM WT-19049P Brown (Polyvinyl alcohol, Polyethylene glycol 3350, Titanium dioxide, Talcum and Red iron oxide), WincoatTM WT-18033P Yellow (Polyvinyl alcohol, Polyethylene glycol 3350, Titanium dioxide, Talcum and Yellow iron oxide).

In embodiments, the present invention provides a solid oral modified-release pharmaceutical composition comprising Oxcarbazepine in an amount of about 40% to about 65% by weight, hydroxypropyl methylcellulose in an amount of about 2% to about 20% by weight, Povidone in an amount of about 2% to about 10% by weight, silicified microcrystalline cellulose in an amount of about 2 % to about 20% by weight, Sodium Lauryl Sulfate in an amount of about 2% to about 10% by weight, Lactose monohydrate in an amount of about 2% to about 10% by weight, Pregelatinized starch in an amount of about 0.5% to about 5% by weight, Magnesium stearate in an amount of about 0.1% to about 2% by weight, and Fumaric acid in an amount of about 0.1 % to about 0.5 % by weight.

In embodiments, the present invention provides a solid oral modified-release pharmaceutical composition comprising Oxcarbazepine in an amount of about 40% to about 65% by weight, hydroxypropyl methylcellulose in an amount of about 2% to about 20 % by weight, Povidone in an amount of about 2% to about 10 % by weight, silicified microcrystalline cellulose in an amount of about 2 % to about 20 % by weight, Sodium Lauryl Sulfate in an amount of about 2% to about 10% by weight and magnesium stearate in an amount of about 0.1% to about 2% by weight.

In embodiments, the present invention provides a process for the preparation of the solid oral modified-release pharmaceutical composition of Oxcarbazepine is prepared by a process which comprises steps of:
a. sifting of all ingredients (Oxcarbazepine, Silicified microcrystalline cellulose, Povidone, Hypromellose, Lactose monohydrate, Pregelatinized starch, Fumaric acid and Sodium lauryl sulfate)
b. dry mixing of step (a) in Rapid Mixer Granulator, and
c. granules were prepared by Rapid Mixer Granulator using Hydro-alcoholic solution as the granulating liquid.
d. wet granules of step (c) were dried using fluid bed processor.
e. dry granules of step (d) were screened by suitable mesh and oversized granules were sized using co-mill screened by suitable mesh, and
f. blending the mixture of step (e) with Magnesium stearate;
g. formulating the lubricated blend of step (f) in to a solid oral dosage form; and
h. coating the solid oral dosage form of step (g) with a film forming polymers.

In embodiments, the solid oral modified-release pharmaceutical composition of Oxcarbazepine is prepared by a process which comprises steps of:
a. sifting Oxcarbazepine, Hydroxypropylmethyl cellulose and silicified microcrystalline cellulose.
b. separately dissolving Sodium lauryl sulfate and Povidone in water;
c. granulating pre-sifted mixture of step (a) using solution of step (b);
d. drying & sifting the granules of step (c);
e. blending mixture of step (d) with lubricant;
f. formulating the lubricated blend of step (e) in to a solid oral dosage form; and
g. coating the solid oral dosage form of step (f) with a film forming polymers.

In embodiments, the present invention provides a process for the preparation of the solid oral modified-release pharmaceutical composition of Oxcarbazepine is prepared by a process which comprises steps of:
a. sifting of all ingredients (Oxcarbazepine, Silicified microcrystalline cellulose, Povidone, Hypromellose, Lactose monohydrate, Pregelatinized starch, Fumaric acid and Sodium lauryl sulfate)
b. dry mixing of step (a) in Rapid Mixer Granulator, and
c. granules were prepared by Rapid Mixer Granulator using Hydro-alcoholic solution as the granulating liquid.
d. wet granules of step (c) were dried using fluid bed processor.
e. dry granules of step (d) were screened by suitable mesh and oversized granules were sized using co-mill screened by suitable mesh, and
f. blending the mixture of step (e) with lubricant;
g. formulating the lubricated blend of step (f) in to a solid oral dosage form; and
h. coating the solid oral dosage form of step (g) with one or more rate-controlling excipients having pH-dependent solubility.

In embodiments, the solid oral modified-release pharmaceutical composition of Oxcarbazepine is prepared by a process which comprises steps of:
a. sifting Oxcarbazepine, Hydroxypropylmethyl cellulose and silicified microcrystalline cellulose.
b. separately dissolving Sodium lauryl sulfate and Povidone in water;
c. granulating pre-sifted mixture of step (a) using solution of step (b);
d. drying & sifting the granules of step (c);
e. blending mixture of step (d) with lubricant;
f. formulating the lubricated blend of step (e) in to a solid oral dosage form; and
g. functional coating surrounded the solid oral dosage form of step (f) with one or more rate-controlling excipients having pH-dependent solubility.
h. coating the solid oral dosage form of step (g) with a film forming polymers.

The invention is further exemplified with following examples and is not intended to limit the scope of the invention. Those skilled in the art can determine the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with those known to the industry without undue experimentation.

Examples
Example 1: Pharmaceutical composition without release promoting agent comprising a polymer having pH-dependent solubility
S. No Ingredients Quantity (mg/tablet)
Wet Granulation Examples
Dry Mix 1A 1B 1C 1D 1E
1 Oxcarbazepine USP 600.00 600.00 600.00 600.00 600.00
2 Silicified Microcrystalline cellulose (MICCEL S101) USNF 45.00 50.00 95.00 45.00 40.00
3 Lactose monohydrate (Supertab11SD) 50.00 55.00 - 50.00 45.00
4 Povidone (Kollidon-25) USP 50.00 55.00 50.00 50.00 45.00
5 Pregelatinized starch 20.00 22.00 - - 18.00
6 Hypromellose (Methocel K4MCR) 100.00 83.00 100.00 100.00 67.00
7 Hypromellose (MethocelK100LV) - 55.00 - - 45.00
8 Sodium Lauryl Sulfate (Kolliphor
SLS Fine) USNF 50.00 55.00 50.00 50.00 45.00
9 Fumaric acid 2.00 3.00 - 2.00 1.00
Granulating fluid
10 Purified water USP Q.S. Q.S. Q.S. Q.S. Q.S.
11 Isopropyl Alcohol Q.S. Q.S. Q.S. Q.S. Q.S.
Extra-granular materials
12 Magnesium Stearate (Lubricrest) 5.00 7.00 5.00 5.00 3.00
Total weight of core tablet 922.00 985.00 900.00 902.00 909.00
Film Coating
13 Opadry II brown 85F565331 27.66 32 27 27.06 25.00
14 Purified water USP Q.S. Q.S Q.S Q.S. Q.S.
Total weight of Film coated tablet 949.66 1017.00 927 929.06 934.00
Imprinting
15 Opacode Black S-1-17823 Q.S. Q.S Q.S Q.S Q.S
Total weight of imprinted tablet (mg) 949.66 1017.00 927.00 929.06 934.00

1.0 BRIEF MANUFACTURING PROCESS:
1.1. Sifting: Sifting of all ingredients.
1.2. Dry mixing in RMG: All ingredients, except for magnesium stearate, were charged in to Rapid Mixer Granulator (RMG). The dry powders are blended by running the impeller for 15 minutes.
1.3. Granulation using RMG: Granules were prepared by RMG using Hydro-alcoholic solution as the granulating liquid. Hydro-alcoholic solution poured onto the mixing blend for 3min with slow impeller & slow chopper on. Wet mas kneaded for 2min with slow impeller and fast chopper to obtain the desired granules.
1.4. Drying: Wet granule were dried using fluid bed processor.
1.5. Milling: Dry granules were screened through a 20-mesh screen and oversized granules were sized using co-mill and screened through a 20-mesh screen.
1.6. Lubrication: Screened granules were blended with magnesium stearate.
1.7. Compression: The blend was then tableted on a rotary tablet press.
1.8. Film coating: Suitable film coating was done using coating machine.

Comparison of in-vitro dissolution profile of example 1A and 1B composition with reference product
The Extended-Release tablets of Oxcarbazepine prepared as per the compositions of examples 1A and 1B and reference product OXTELLAR XR ® (Oxcarbazepine) ER tablets were subjected to dissolution studies in deionized water with 1% SLS, 900 ml, Paddle 75 rpm with sinker and Dissolution in pH 6.8 phosphate buffer with 1% SLS, 900ml, Paddle 75 rpm with sinker and the data is shown in below table 1 and table 2.

Table 1:
Dissolution in deionized water with 1% SLS, 900ml, Paddle 75 rpm with sinker:
Time Points [Hrs] Oxtellar XR® 600mg
(Percentage Drug Release) Oxcarbazepine tablets as per example 1A (Percentage Drug Release) Oxcarbazepine tablets as per example 1B (Percentage Drug Release)
1 hr 14 17 14
2 hr 30 35 31
4 hr 69 66 62
6 hr 94 86 86
8 hr 97 97 98
10 hr 97 101 104

Table 2:
Dissolution in pH 6.8 phosphate buffer with 1%SLS, 900ml, Paddle 75rpm with sinker
Time Points [Hrs] Oxtellar XR® 600 mg (Percentage Drug Release) Oxcarbazepine tablets as per example 1A (Percentage Drug Release) Oxcarbazepine tablets as per example 1B (Percentage Drug Release)
1 hr 18 40 20
2 hr 34 55 34
4 hr 63 76 59
6 hr 86 88 79
8 hr 97 97 93
10 hr 99 ND 100

Comparison of example 1A and 1D tablet pH with reference product tablet pH
The Extended-Release tablets of Oxcarbazepine prepared as per the compositions of examples 1A and 1D comprises acidifying agent i.e. Fumaric acid to adjust the tablet pH similar to reference product OXTELLAR XR ® ER tablets pH.

Table 3:
Oxtellar XR® Tablet pH Oxcarbazepine ER Tablets
without Fumaric Acid Example 1A Example 1D
Fumaric acid (mg) - - 2 mg 2 mg
Tablet pH (10% w/w suspension) 6.01 8.22 6.41 6.85

Example 2: Pharmaceutical composition without release promoting agent comprising a polymer having pH-dependent solubility
S. No Ingredients Examples
Wet Granulation Quantity (mg/tablet)
Dry Mix 2A 2B 2C 2D
1 Oxcarbazepine USP 600.00 600.00 600.00 600.00
2 Silicified Microcrystalline cellulose (MICCEL S101) USNF 95.00 95.00 95.00 95.00
3 Povidone (Kollidon-25) USP 50.00 50.00 50.00 50.00
4 Hypromellose (Methocel K4M CR premium) USP 100.00 100.00 100.00 100.00
5 Sodium Lauryl Sulfate (Kolliphor SLS Fine) USNF 50.00 50.00 50.00 50.00
6 Sodium Alginate (Protanal CR) - - - 50.00
Granulating fluid
7 Fumaric acid 2.00 2.00 2.00 2.00
8 Purified water USP Q.S. Q.S. Q.S. Q.S.
9 Isopropyl Alcohol Q.S. Q.S. Q.S. Q.S.
Extra-granular materials
10 Lactose Monohydrate 15.00 - 15.00 15.00
11 Microcrystalline Cellulose 15.00 30.00 -
12 Dicalcium phosphate - - 15.00 15.00
13 Magnesium Stearate (Lubricrest) 5.00 5.00 5.00 5.00
Total weight of core tablet 932.00 932.00 932.00 982.00
Film Coating
14 Opadry II brown 85F565331 27.96 27.96 27.96 29.46
15 Purified water USP Q.S. Q.S. Q.S. Q.S.
Total weight of Film coated tablet 959.96 959.96 959.96 1011.46
Imprinting
16 Opacode Black S-1-17823 Q.S. Q.S Q.S Q.S
Total weight of imprinted tablet (mg) 959.96 959.96 959.96 1011.46

BRIEF MANUFACTURING PROCESS:
1. Co-sift Oxcarbazepine, Silicified microcrystalline cellulose, Povidone, Hypromellose, Sodium lauryl sulfate and sodium alginate (optional).
2. For granulating fluid preparation dissolve Fumaric acid in quantity sufficient purified water and Isopropyl alcohol.
3. Dry mixing of Step 1 material using rapid mixture granulator.
4. Granulation of step 3 dry mix material by step 2 granulating fluid using rapid mixture granulator.
5. Drying, milling and sizing of obtained granules.
6. Sifting of extra-granular material (Lactose monohydrate/ microcrystalline cellulose/ Dicalcium phosphate) with sized granules.
7. Lubrication of step 6 materials using blender.
8. Compression of step 7 granules in to Tablets followed by Film coating.

Example 3: Oxcarbazepine composition without Eudragit by wet Granulation
S. No Ingredients Quantity (mg/tablet)
Intra granulation
1 Oxcarbazepine 600.0
2 Silicified MCC (MICCEL S101) 215.0
3 Povidone K25 50.0
4 Hydroxypropylmethyl cellulose K4M 80.0
5 Sodium lauryl sulfate 50.0
6 Purified water q.s.
Extra granulation
7 Magnesium stearate 5.0
Target weight (core) 1000.0
Coating
8 Opadry Film coating 30.0
9 Purified water q.s.
Coated tablet weight 1030.0

1.0 MANUFACTURING PROCESS:
1.1 Sifting:
1.1.1 Co-sift Oxcarbazepine, Hydroxypropylmethyl cellulose K4M, and Silicified microcrystalline cellulose through 600 µm sieve (ASTM mesh no.# 30).
1.2 Binder Preparation
1.2.1 Add Sodium lauryl sulfate to the Purified water (25% w/w to the dry mix weight) under stirring and continue stirring up to 15 minutes until clear solution is formed.
1.2.2 Add Povidone to the step no.1.2.1 and continue stirring till getting clear solution.
1.3 Wet Granulation
1.3.1 Granulate the sifted material of step 1.1.1 with 25 % w/w binder solution of step 1.2.2 over a period up to 1 minute 30 seconds with impeller at slow speed and chopper off.
1.3.2 Knead the wet mass of step 1.3.1 for not more than 30 seconds with impeller at slow speed and chopper at slow speed.
1.3.3 Unload the material of step 1.3.2 with impeller at slow speed or intermittent inch mode followed by milling through 6 mm screen into FBD bowl at slow speed.
1.4 Drying
1.4.1 Wet granules were dried using fluid bed processor.
1.5 Sifting and Milling
1.5.1 Dry granules were screened through a 20-mesh screen and oversized granules were sized using co-mill and screened through a 20-mesh screen.
1.6 Sifting of extra-granular material
1.6.1 Sift Magnesium stearate through 250 µm sieve (ASTM mesh no # 60).
1.7 Lubrication
1.7.1 Load sifted Magnesium stearate of step 1.6.1 and material of step 1.5.1 in blender and blend for 5 minutes.
1.8 Compression and film coating
1.8.1 Compress the lubricated blend of step 1.7.1 by using rotary compression machine in to tablets followed by film coating.

,CLAIMS:WE CLAIM:

1. A solid oral modified release pharmaceutical composition of Oxcarbazepine comprising a core, which comprises homogeneous matrix comprising Oxcarbazepine or salts thereof, matrix forming polymer, a solubilizer, an acidifying agent and one or more other pharmaceutically acceptable excipients, wherein said composition does not contain pH-dependent soluble polymer.

2. The solid oral modified release pharmaceutical composition of Oxcarbazepine according to claim 1, wherein matrix forming polymer is selected from the group consisting of cellulosic polymers including but are not limited to hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and methylcellulose, alginates, shellac, gums, cross-linked polyacrylic acid, carageenan and polyvinyl pyrrolidone or combinations thereof.

3. The solid oral modified release pharmaceutical composition of Oxcarbazepine according to claim 1, wherein said homogeneous matrix comprising combination of two or more different viscosity hydroxypropylmethylcellulose polymers in different ratios such as 1:20 to 20:1.

4. The solid oral modified release pharmaceutical composition of Oxcarbazepine according to claim 1, wherein a solubilizer is selected from the group comprising sodium docusate, sodium lauryl sulfate, polyethylene oxide (PEO) modified sorbitan monoesters, fatty acid sorbitan esters, low molecular weight polyvinyl pyrrolidone, low molecular weight hydroxypropyl methyl cellulose, cyclodextrins or combinations thereof.

5. The solid oral modified release pharmaceutical composition of Oxcarbazepine according to claim 4, wherein said solubilizer promotes the drug release by forming a porous matrix.

6. The solid oral modified release pharmaceutical composition of Oxcarbazepine according to claim 1, wherein said acidifying agent is selected from the group comprising citric acid, fumaric acid, tartaric acid, succinic acid and aspartic acid or combinations thereof.

7. The solid oral modified release pharmaceutical composition of Oxcarbazepine according to claim 1, wherein said composition further comprising one or more release rate-controlling polymers.

8. A solid oral modified release pharmaceutical composition comprising 40% to 65% by weight of Oxcarbazepine or salts thereof, 10% to 15% by weight of matrix forming polymer, 5% to 10% by weight of solubilizer, 0.1% to 2% by weight of acidifying agent and 20% to 40% by weight of one or more other excipients, wherein said composition does not contain pH-dependent soluble polymer.

9. The solid oral modified release pharmaceutical composition of claim 8, wherein said excipients comprise fillers from about 5% to about 40% by weight, binders from about 2% to about 10% by weight, disintegrants from about 1% to about 10% by weight, glidants and lubricants from about 0.1 % to about 5% by weight of the total weight of the composition.

10. A process of preparing solid oral modified release pharmaceutical composition of Oxcarbazepine or salts thereof, which process comprises steps of (a) preparing a core matrix of Oxcarbazepine by granulating Oxcarbazepine or salts thereof with matrix forming polymer, solubilizer, acidifying agent and one or more other pharmaceutically acceptable excipients (b) coating the homogeneous matrix core with one or more film forming polymers.