CLIAMS:1. A process for preparing a solid oral modified-release composition of oxcarbazepine or salts thereof comprising steps of:
(a) preparing a core comprising a matrix of oxcarbazepine or salts thereof with one or more rate-controlling excipients optionally with one or more pharmaceutical excipients, wherein the core is devoid of excipients having pH dependent solubility, and
(b) formulating the core matrix of oxcarbazepine in solid oral dosage form.

2. A process for preparing a solid oral modified-release composition of oxcarbazepine or salts thereof comprising steps of:
(a) mixing oxcarbazepine or salts thereof with one or more rate-controlling excipients and optionally with one or more pharmaceutically acceptable excipients to form a homogenous powder blend;
(b) granulating the homogenous powder blend of step (a) with suitable aqueous or non-aqueous solution or dispersion of pharmaceutically acceptable binders to form cores comprising matrix of oxcarbazepine or salts thereof;
(c) compressing the cores formed in step (b) to form a tablet dosage form; and
(d) optionally, coating the tablets formed in step (c) with one or more functional coatings comprising one or more rate-controlling excipients;
wherein the composition is devoid of excipients having pH dependent solubility.

3. A process of claim 1 or 2, wherein the process comprises coating the cores with one or more functional coatings comprising one or more rate-controlling excipients having pH independent solubility.

4. The process of claim 2, in which the granulation step is carried out in rapid mixer granulator or in fluidized bed processor.

5. The process of claim 3, wherein the pH independent polymer is present in the amount of 1% to 50% by weight of the composition.

6. The process of claim 1 or 2, wherein the core comprising matrix of oxcarbazepine or salts thereof is coated with a film forming polymer.
,TagSPECI:DESCRIPTION

The present invention relates to a process of preparing solid oral modified-release composition comprising oxcarbazepine or salts thereof. In particular, the process involves a step of preparation of a matrix core of oxcarbazepine or salts thereof with one or more rate-controlling excipients; wherein the composition is devoid of excipients having pH dependent solubility. The invention further provides a method of treatment of epileptic seizures.

Epilepsy is a common and diverse set of chronic neurological disorders characterized by seizures. Epileptic seizures result from abnormal, excessive or hypersynchronous neuronal activity in the brain. Currently about 50 million people worldwide have epilepsy.

Seizure types are organized according to whether the source of the seizure within the brain is localized (partial or focal onset seizures) or distributed (generalized seizures). The mainstay of treatment of epilepsy is anticonvulsant medications.

The anticonvulsants or antiepileptic drugs are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. In treatment of epilepsy, oxcarbazepine has recently been found to be associated with a greater enhancement in mood and reduction in anxiety symptoms than other drugs employed to treat epilepsy.

Oxcarbazepine is an anticonvulsant and mood-stabilizing drug, used primarily in the treatment of epilepsy. Its chemical name is 10, 11-Dihydro-10-oxo-5H-dibenz [b, f]-azepine-5-carboxamide. Oxcarbazapine has a molecular weight of 252.27 with the following structural formula:

The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite of oxcarbazepine.

Oxcarbazepine extended release tablet is currently marketed in US under brand name Oxtellar XR™, while oxcarbazepine immediate release tablet is currently marketed in US under brand name Trileptal®, where both the dosage forms are approved for treatment of partial 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, 8,017,149 & 8,211,464 disclose controlled-release preparations of oxcarbazepine and derivatives thereof containing 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.

There are several formulations suggested in the arts for sustained-release or controlled-release of oxcarbazepine. But due to poor solubility of oxcarbazepine or salts thereof, their release from a sustained release dosage form is rather incomplete.

However, despite of the known forms of oxcarbazepine, it is highly desirable to provide modified-release formulations oxcarbazepine, particularly which exhibits desired or even improved release profile of oxcarbazepine by avoiding the use of unnecessary excipient load in the formulation. Such formulations are also relatively simple to manufacture. Thus, there still exists an enduring need for an alternate improved formulation of oxcarbazepine.

The inventors of the present invention have surprisingly found that by forming a composition comprising matrix of oxcarbazepine or salts thereof with one or more rate-controlling excipients bioavailability of oxcarbazepine or salts thereof may be improved. The composition according to present invention comprises matrix of oxcarbazepine or salts thereof, wherein the composition is devoid of excipients having pH dependent solubility. Further, the inventors of the present invention have also found that such formulation of oxcarbazepine can exhibit excellent storage stability.

In one general aspect, there is provided a solid oral modified-release composition comprising a core, which core comprises of a matrix of oxcarbazepine or salts thereof with one or more rate-controlling excipients; wherein the composition is devoid of excipients having pH dependent solubility.

In another general aspect, there is provided a solid oral modified-release composition of oxcarbazepine or salts thereof comprising a core of matrix of oxcarbazepine or salts thereof, which core is coated with one or more functional coatings.

In another general aspect, there is provided a solid oral modified-release composition of oxcarbazepine or salts thereof; wherein functional coating comprises of one or more rate-controlling excipients.

In another general aspect, there is provided a solid oral modified-release composition of oxcarbazepine or salts thereof; wherein the rate-controlling excipients in the matrix and functional coatings are polymers.

In another general aspect, there is provided a solid oral modified-release composition of oxcarbazepine or salts thereof; wherein the rate-controlling excipients in the matrix and functional coatings are polymers with pH independent solubility.

In another general aspect, rate-controlling excipients present in the core matrix and functional coating may include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, guar gum, alginates, pectins, polyvinylpyrolidone, polyethylene oxide, stearic acid, sucrose, polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.

In another general aspect, the solid oral modified-release composition of oxcarbazepine or salts thereof; wherein a layer of film forming polymer is present in between core and functional coating.

In another general 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.

In another general aspect, the solid oral modified-release composition comprising one or more pharmaceutically acceptable excipients comprises fillers, glidants, alkalizers, lubricants, anti-adherents, disintegrants, flavours, colours, preservatives, sweeteners, and binders.

In another general aspect, the solid oral modified-release composition is in the form of granules, pellets, tablets, capsules, granules, pellets and/or tablets filled in capsule, multilayer tablet, a bilayer tablet or a tri-layer tablet. Preferably, the composition is in the form of a tablet.

In another general aspect, the solid oral modified-release composition of oxcarbazepine or salts thereof retains at least 90% by weight of the total content of oxcarbazepine or salt thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In another general aspect, there is provided a process of preparing the solid oral modified-release 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 one or more rate-controlling excipients and one or more pharmaceutical excipients, and
(b) formulating the core matrix of oxcarbazepine in solid oral modified-release composition;
wherein the composition is devoid of excipients having pH dependent solubility.

In another general aspect, there is provided a process of preparing the solid oral modified-release 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 one or more rate-controlling excipients and one or more pharmaceutical excipients, and
(b) formulating the core matrix of oxcarbazepine in solid oral dosage form;
(c) optionally, coating the solid oral dosage form of step (b) with one or more functional coatings comprising one or more rate-controlling excipients having pH independent solubility.

In another general aspect, there is provided a process comprising steps of:
(a) mixing oxcarbazepine or salts thereof with one or more rate-controlling substances and optionally with one or more pharmaceutically acceptable excipients to form a homogenous powder blend;
(b) granulating the homogenous powder blend of step (a) with suitable aqueous or non-aqueous solution or dispersion of pharmaceutically acceptable binders to form cores, and
(c) compressing the cores formed in step (b) to form a tablet dosage form; and
(d) optionally, coating the tablets formed in step (c) with one or more functional coatings comprising one or more rate-controlling excipients having pH independent solubility;
wherein the composition is devoid of excipients having pH dependent solubility.

In another general aspect, there is provided a process in which granulation step involved in the process can be carried out in rapid mixer granulator or in fluidized bed processor.

In another general aspect, there is provided a method of treating partial seizures, which method comprises of administering a solid oral modified-release composition comprising a core, which core comprises of a matrix of oxcarbazepine or salts thereof, one or more rate-controlling excipients and one or more pharmaceutical excipients; wherein the composition is devoid of excipients having pH dependent solubility.

The present invention provides a solid oral modified-release composition comprising oxcarbazepine or salts thereof, and one or more pharmaceutically acceptable excipients.

The term “oxcarbazepine” as used herein refers to oxcarbazepine base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.

As used herein the term "functional coating" is a coating that significantly modifies release characteristics of oxcarbazepine or salt thereof from a formulation when administered.

The term "modified release" as used herein means release, which is not immediate release and is taken to encompass all pH independent release systems such as controlled release, sustained release, prolonged release, timed release, retarded release and extended release.

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.

The solid oral modified-release composition in accordance with the present invention comprises a core comprising of a matrix of oxcarbazepine or salts thereof, one or more rate-controlling excipients and one or more pharmaceutical excipients; wherein the composition is devoid of excipient having pH dependent solubility.

In an embodiment, the rate-controlling excipients in the core matrix of the solid oral modified-release composition are polymers.

In another embodiment, the rate-controlling excipients in the core matrix of the solid oral modified-release composition are polymers and having pH independent solubility.

The amount or the type of release-controlling excipients selected 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 another embodiment, the solid oral modified-release composition comprises a core comprising of a matrix of oxcarbazepine or salts thereof, one or more rate-controlling excipients and one or more pharmaceutical excipients; wherein the core is coated with one or more film forming polymers.

In another embodiment, the solid oral modified-release composition comprising a core comprising oxcarbazepine matrix, wherein the core is optionally coated with film forming polymer.

In another embodiment, the solid oral modified-release composition comprises a core comprising oxcarbazepine matrix and a functional coating, wherein a functional coating is surrounded over the core optionally there is present a coating of film forming polymer between core and functional coating.

In an embodiment, the ratio of the amount of oxcarbazepine or salt thereof to rate-controlling excipient in the functional coating of the solid oral modified-release composition ranges from about 30:1 to about 2:1 by weight of the composition.

In another embodiment, the amount of the rate-controlling excipient in the functional coating to that in the core of the solid oral modified-release composition ranges from about 1:1 to about 10:1 by weight of the composition.

In an embodiment, a layer of film forming polymer is provided in between the core matrix and functional coating layer of the composition.

In an embodiment, the solid oral modified-release composition comprises-
(a) about 40% w/w to about 80% w/w of oxcarbazepine or salts thereof;
(b) about 5% w/w to about 30% w/w of rate-controlling substance;
(c) about 1% w/w to about 40% w/w of filler;
(d) about 0.1% w/w to about 20% w/w of surface active agent; and
(e) about 0.001% w/w to about 10% w/w of lubricant,
wherein the composition is devoid of excipient having pH dependent solubility.

In further embodiment, the process of preparing the solid oral modified-release composition of oxcarbazepine or salts thereof comprises steps of:
(a) preparing a core matrix of oxcarbazepine by granulating oxcarbazepine or salts thereof with one or more rate-controlling excipients and one or more pharmaceutical excipients, and
(b) formulating the core matrix of oxcarbazepine in solid oral dosage form.

In further embodiment, the process of preparing the solid oral modified-release composition of oxcarbazepine or salts thereof comprises steps of:
(a) preparing a core matrix of oxcarbazepine by granulating oxcarbazepine or salts thereof with one or more rate-controlling excipients and one or more pharmaceutical excipients;
(b) formulating the core matrix of oxcarbazepine in solid oral dosage form, and
(c) optionally, coating the solid oral dosage form of step (b) with one or more functional coatings comprising one or more rate-controlling excipients having pH independent solubility.

In an embodiment, the solid oral modified-release composition is prepared by a process which comprises steps of:
(a) sifting oxcarbazepine or salts thereof, rate-controlling excipients 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 further embodiment, the process of preparing the solid oral modified-release composition of oxcarbazepine or salts thereof comprises steps of:
(a) mixing oxcarbazepine or salts thereof with one or more rate-controlling excipients and optionally with one or more pharmaceutically acceptable excipients to form a homogenous powder blend;
(b) granulating the homogenous powder blend of step (a) with suitable aqueous or non-aqueous solution or dispersion of pharmaceutically acceptable binders to form cores;
(c) compressing the cores formed in step (b) to form a tablet dosage form, and
(d) optionally, coating the tablets formed in step (c) with one or more functional coatings comprising one or more rate-controlling excipients having pH independent solubility;
wherein the composition is devoid of excipients having pH dependent solubility.

The granulation step involved in the process can be carried out in rapid mixer granulator or in fluidized bed processor.

In another embodiment, oxcarbazepine and pharmaceutically acceptable excipients are sifted either separately or together. Preferably, ingredients are sifted together.

In a further embodiment, the process of preparing the solid oral modified-release composition comprises steps of:
(a) sifting oxcarbazepine, silicified microcrystalline cellulose, microcrystalline cellulose, polyvinyl pyrrolidone & hydroxypropyl methylcellulose;
(b) separately dissolving sodium lauryl sulphate 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 the granules of step (d) with lubricant, and
(f) formulating the lubricated blend of step (e) in to a solid dosage form.

Oxcarbazepine, rate-controlling excipients, 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 tabletted on a tablet press.

The amount of oxcarbazepine in the composition may range from about 10% w/w to about 95% w/w of the composition. Preferably, the amount of oxcarbazepine in the composition ranges from about 40% w/w to about 80% w/w of the composition.

In a further embodiment, the modified release unit dosage form of the present invention retains at least 90% by weight of the total content of oxcarbazepine or salt thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In a further embodiment, there is provided a method of treating partial seizures which method comprises of administering the pharmaceutical composition as substantially described herein throughout the specification.

The solid oral pharmaceutical composition of the invention further may comprise one or more pharmaceutical excipients suitable for oral administration. Such excipients may be selected from one or more binders, fillers, filler-binders, disintegrants, glidants, alkalizers, antiadherents, sweeteners, flavouring and colouring agents. In an embodiment, the composition comprises glidants/lubricants and fillers.

Rate-controlling excipients suitable for use in the composition of the present invention comprise water soluble or water insoluble substances or mixtures thereof. Preferably, rate-controlling excipients are water soluble and/or water insoluble polymers.

The rate-controlling excipients which can be used may be selected from the group consisting of hydrophilic agents (e.g. water-soluble polymers), lipophilic agents (water-insoluble polymers) and inert matrix agents, wherein the hydrophilic agents are selected from the group of pharmaceutical excipients which generate a gel in contact with water, including cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like; sodium carboxymethylcellulose, microcrystalline cellulose, cellulose acetate noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; polyethylene oxide and mixtures thereof; the lipophilic agents are selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable, castor, cottonseed oils, glyceril behenate and the like; ethyl cellulose; and mixtures thereof; and the inert agents are selected from the group consisting of thermoplastic polymers, which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.

Examples of the lubricants/glidants suitable for use in the solid oral modified-release composition of the present invention may be selected from one or more of stearic acid, talc, siliconised talc, sodium stearyl fumarate and magnesium stearate. Preferable lubricant/glidants is magnesium stearate.

Examples of the fillers or filler-binder suitable for use in the solid oral modified-release composition of the present invention may be selected from starches, such as maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, fully pregelatinized starch, cellulose, such as microcrystalline cellulose or silicified microcrystalline 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 and/or filler-binders are selected from microcrystalline cellulose, silicified microcrystalline cellulose or mixtures thereof.

Examples of the binders suitable for use in the solid oral modified-release composition of the present invention may be selected from one or more of polyvinyl pyrrolidone (Povidone), copolymers of vinylpyrrolidone with other vinylderivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum and starch.

The solid oral modified-release composition of the present invention may be formulated in the form of tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, a bilayer tablet or a trilayer tablet or combinations thereof.

The invention further provides a method of treating epileptic seizures, which method comprises of administering the solid oral pharmaceutical composition as substantially described herein throughout the specification.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

Example 1: Oxcarbazepine Tablets
Table 1
Sr. No. Ingredients Quantity (mg/Cap)
A Intragranular
1 Oxcarbazepine 600.00
2 Silicified microcrystalline cellulose 125.00
3 Microcrystalline cellulose 70.00
4 Polyvinylpyrrolidone 50.00
5 Sodium lauryl sulphate 50.00
6 Hydroxypropyl methylcellulose 100.00
7 Purified water q. s.
B Extragranular
8 Magnesium stearate 5.0
Core Tablet Weight 1000.00
C Coating
9 Opadry-II (PVA based) 30.00
10 Water q. s.
Film Coated Tablet Weight 1030.00

Process: Oxcarbazepine, silicified microcrystalline cellulose, microcrystalline cellulose, polyvinylpyrrolidone and hydroxypropyl methylcellulose were sifted through sieve no. 30. Thus formed powder mixture of active ingredient was granulated with aqueous solution of sodium lauryl sulphate in rapid mixer granulator. Granules were then dried and sifted through sieve and lubricated with magnesium stearate. The blend was then compressed to form the tablets. The tablets were then coated using aqueous solution of opadry-II.