FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTION: OXCARBAZEPINE ORAL FORMULATION
2. APPLICANT (S)(a) NAME: WOCKHARDT LTD.(b) NATIONALITY: INDIAN(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTIONThe present invention provides aqueous suspension of oxcarbazepine or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable excipients for oral administration.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides aqueous suspension of oxcarbazepine or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable excipients for oral administration.
Oxcarbazepine is a widely used antiepileptic drug with poor aqueous solubility. Chemically it is 10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide of formula 1. Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children ages 4-16 with epilepsy. Oxcarbazepine is converted in the body into monohydroxydihydrocarbamazepine (MHD), which is the actual active compound.

US Patent No 7,037,525 discloses a method of treating seizures, which comprises administering a formulation of oxcarbazepine having improved bioavailability, wherein said oxcarbazepine consists essentially of oxcarbazepine having a maximum residue on a 40pm sieve of less than or equal to 5% and method of treating seizures, comprising oral administration of a formulation of oxcarbazepine, wherein said formulation comprises a therapeutically effective dose of oxcarbazepine and wherein said oxcarbazepine has a median particle size of approximately 2µm o 12µm.
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US Patent No 5,284,662 discloses an oral osmotic dosage delivery form adapted to deliver carbamazepine comprising carbamazepine in an amount sufficient to deliver an effective amount thereof over the intended delivery time, an effective amount of a crystal habit modifier, an effective amount of a tabletting lubricant; and an effective amount of a wetting agent.
US Application No 2003004155 discloses a pharmaceutical composition in the form of a suspension comprising oxcarbazepine and having, when shaken, a viscosity in the range of 5 to 52 mPa.s.
US Application No 20060111343 disclose an oral dosage composition comprising a prophylactically or therapeutically effective amount of oxcarbazepine or a pharmaceutically acceptable salt thereof and a pH modifier comprising an amide.
US Application No 20040157797 discloses a pharmaceutical composition comprising a solubilizing agent selected from crystalline methylated α-, β-, γ-cyclodextrin, or mixtures thereof along with pharmaceutically active agent selected from carbamazepine, fenofibrate, oxcarbazepine, or glipizide.
PCT Application WO2006046105 discloses a pharmaceutical dosage form for oral administration comprising oxcarbazepine having a median particle size of from about 14µm to about 30µm.
The present invention now provides an aqueous suspension for oral administration comprising oxcarbazepine or pharmaceutically acceptable salt thereof, hydroxypropyl beta cyclodextrin (HP-β-CD), along with pharmaceutically acceptable excipients. Oxcarbazepine is used in the form of complex with hydroxypropyl beta cyclodextrin, which helps to increase its aqueous solubility.
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In one of the aspects of the present invention there is provided an aqueous dosage form comprising therapeutically effective amount of oxcarbazepine or salt thereof and cyclodextrins or derivatives thereof along with pharmaceutically acceptable excipients.
In another aspect of the present invention there is provided a pharmaceutical dosage form in the form of aqueous suspension comprising therapeutically effective amount of oxcarbazepine or salt thereof along with pharmaceutically acceptable excipients, wherein the oxcarbazepine is present in the form of complex with cyclodextrins or derivatives thereof.
Oxcarbazepine-cyclodextrin complex helps to improve aqueous solubility of the oxcarbazepine. The interior of the cyclodextrin molecule is hydrophobic while the exterior is sufficiently hydrophilic to allow the cyclodextrin to be dissolved in water. This difference between the interior and exterior faces allows the cyclodextrin to act as a host molecule and to form inclusion complexes with oxcarbazepine. The cyclodextrin-oxcarbazepine inclusion complex can then be dissolved in water thereby providing for the introduction of oxcarbazepine that has little or no aqueous solubility into an aqueous environment.
Cyclodextrins are cyclic (α-1,4)-linked oligosaccharides of a-D-gluco-pyranose containing a relatively hydrophobic central cavity and hydrophilic outer surface. In the pharmaceutical industry, cyclodextrins have mainly been used as complexing agents to increase the aqueous solubility of poorly water-soluble drugs, and to increase their bioavailability and stability. Light, thermal and oxidative stability of actives may be improved through the formation of cyclodextrin complexes. In addition, cyclodextrins are used to reduce or prevent gastrointestinal or ocular irritation, reduce or eliminate unpleasant smells or tastes, prevent drug-drug or drug-additive interactions, or even to convert oils and liquid drugs into microcrystalline or amorphous powders. Suitable cyclodextrin derivatives may be
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selected from hydroxypropyl-β-cyclodextrin, β-cyclodextrin, α-cyclodextrin, hydroxypropyl- α-cyclodextrin and the like.
Hydroxypropyl-β-cyclodextrin, a chemically modified β-cyclodextrin is highly water soluble, stable and its safety and tolerance has been well documented. Its ability to improve aqueous solubility has been attributed to the formation of inclusion complex between cyclodextrins and 'guest' drug molecule. The prepared HP-β-CD complex is stable increases aqueous solubility and reduces oxidation of oxcarbazepine in the suspension, which further prevents discoloration of suspension due to oxidation of oxcarbazepine.
Therapeutically effective amount of oxcarbazepine or salt thereof was added to the suspension in the form of complex. The complex of oxcarbazepine and HP-β-CD was prepared by various processes including solvent evaporation, kneading, spray drying, colloidal milling, high speed mixing, trituration or simple mixing. The oxcarbazepine is in an amount relative to the cyclodextrin such that a molar ratio between the oxcarbazepine and the cyclodextrin is from about 1:1 to 1:10.
The suspension for oral administration is usually aqueous based and includes suspensions comprising water or one or more water-miscible solvents. Suitable water-miscible solvents include propylene glycol, polyethylene glycol, ethanol and the like.
The suspension may further include one or more pharmaceutically acceptable additives. The one or more pharmaceutically acceptable additives comprise additives known in the art of formulation such as sweetening agents, flavouring substances, solubility enhancers, viscosity regulating agents, thickening agent, preservatives, buffering agents and the like additives. The preservatives prevent the growth of micro-organisms in the formulation and may be one or more of methylparaben or salt thereof, propylparaben or salt thereof, benzoic acid, sorbic acid, benzylalkonium chloride, and the like. The buffering agent may be an acid-
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base combination or base alone. The acid may be one or more of sorbic, succinic, tartaric, lactic or citric acid and base is potassium hydroxide, sodium hydroxide or disodium hydrogen phosphate. The unpleasant taste of oxcarbazepine may be masked by the presence of one or more sweetening agents such as sodium saccharin, potassium saccharin, calcium saccharin, sorbitol, neotame, acesulfame potassium or sodium cyclamate. The flavours may be one or more of vanilla, cherry, raspberry, strawberry and the like. The thickening agent may be sodium carboxymethyl cellulose, carboxymethyl cellulose, methylcellulose, microcrystalline cellulose and the like. The viscosity of the suspension is from 60-400mPas.
The oxcarbazepine oral suspension may be prepared by the processes for preparation of oral suspension known in the art and may prepared by using purified water. Oxcarbazepine and HP-β-CD were mixed together in suitable solvent for specified period of time, and thus complex was prepared. This prepared complex was suspended in water to form a paste. Ascorbic acid was added to the above paste. Methyl paraben, propyl paraben and sorbic acid were dissolved in hot propylene glycol, allowed to cool and added to paste. Sodium carboxymethylcellulose was dispersed in propylene glycol and added to paste. Sodium saccharine was dissolved in water and added to he paste Sorbitol solution was added to above mix. Colloidal silicon dioxide was dispersed in above suspension under stirring. Further suspension was homogenized at 16,000 rpm for 5 minutes to 30 minutes and continued till bottle filling. Suspension was filled in amber glass bottle, capped.
While the present invention has been described in terms of its specific embodiments, 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.
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EXAMPLES
The composition of the batches is provided in example 1, example 2 an< example 3.
Example 1 -

Sr.No. Ingredients % Composition w/w
1 Oxcarbazepine 6%
2 Hydroxypropyl betacyclodextrin 30% - 70%
3 Ascorbic acid 0.1%-1.0%
4 Propylene glycol 1.0%-20.0%
5 Methyl Paraben 0.05 % - 0.5%
6 Propyl Paraben 0.001%-0.1%
7 Sorbic acid 0.005% - 0.05%
8 Sodium saccharine 0.015%-0.15%
9 Colloidal silicon dioxide (Aerosil - 200) 0.2% - 8%
10 Sorbitol solution 70% 10%-50%
11 Sodium Carboxymethyl cellulose 0.1%-5%
12 Purified Water q.s.
Procedure -
Oxcarbazepine and HP-β-CD were mixed together in suitable solvent and thus complex was prepared. Preparation of complex is tested with the help of IR, NMR and XRD techniques. This prepared complex was suspended in water to form a paste. All the other ingredients are added in the above prepared paste and mixed well to form a suspension. Further suspension was homogenized at 16,000 rpm for specific time period and further filled in amber glass bottle and capped.
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Example 2 -

Sr.No. Ingredients %Composition w/w
1 Oxcarbazepine 6%
2 Hydroxypropyl betacyclodextrin 30% - 70%
3 Ascorbic acid 0.1%-1.0%
4 Propylene glycol 1.0 % - 20.0%
5 Methyl Paraben 0.05 % - 0.5%
6 Propyl Paraben 0.001%-0.1%
7 Sorbic acid 0.005% - 0.05%
8 Sodium saccharine 0.015%-0.15%
9 Colloidal silicon dioxide (Aerosil - 200) 0.2% - 8%
10 Sorbitol solution 70% 10%-50%
11 Sodium Carboxymethyl cellulose 0.1%-5%
12 Citric acid monohydrate 0.05%-1%
13 Flavour q.s.
14 Purified Water q.s.
Procedure -
Oxcarbazepine and HP-β-CD were mixed together in suitable solvent and thus complex was prepared. Preparation of complex is tested with the help of IR, NMR and XRD techniques. This prepared complex was suspended in water to form a paste. All the other ingredients are added in the above prepared paste and mixed well to form a suspension. Further suspension was homogenized at 16,000 rpm for specific time period and further filled in amber glass bottle and capped.
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Example 3 -

Sr.No. Ingredients % Composition w/w
1 Oxcarbazepine 6%
2 Hydroxypropyl betacyclodextrin 30% - 70%
3 Ascorbic acid 0.1%-1.0%
4 Propylene glycol 1.0%-20.0%
5 Methyl Paraben 0.05 % - 0.5%
6 Propyl Paraben 0.001%-0.1%
7 Sorbic acid 0.005% - 0.05%
8 Sodium saccharine 0.015%-0.15%
9 Colloidal silicon dioxide (Aerosil - 200) 0.2% - 8%
10 Sorbitol solution 70% 10%-50%
11 Carboxymethyl cellulose 0.1%-5%
12 Flavour q.s.
13 Purified Water q.s.
Procedure -
Oxcarbazepine and HP-β-CD were mixed together in suitable solvent and thus complex was prepared. Preparation of complex is tested with the help of IR, NMR and XRD techniques. This prepared complex was suspended in water to form a paste. All the other ingredients are added in the above prepared paste and mixed well to form a suspension. Further suspension was homogenized at 16,000 rpm for specific time period and further filled in amber glass bottle and capped.
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WE CLAIM:
1. An aqueous pharmaceutical dosage form comprising therapeutically effective amount of oxcarbazepine or salt thereof and cyclodextrins or derivatives thereof along with pharmaceutically acceptable excipients.
2. A pharmaceutical dosage form in the form of aqueous suspension comprising therapeutically effective amount of oxcarbazepine or salt thereof along with pharmaceutically acceptable excipients, wherein the oxcarbazepine is present in the form of complex with cyclodextrins or derivatives thereof.
3. A pharmaceutical dosage form according to claim 1, wherein the cyclodextrin is hydroxypropyl-P-cyclodextrin.
4. An inclusion complex according to claim 1, wherein the oxcarbazepine is in an amount relative to the cyclodextrin such that a molar ratio between the oxcarbazepine and the cyclodextrin is from about 1:1 to 1:10.
5. A pharmaceutical dosage form according to claim 1 and 2, having a viscosity in the range of 60 to 400 mPa.s.
6. A pharmaceutical dosage form according to claim 1, wherein the dosage form further comprises one or more pharmaceutically acceptable additives.
7. A pharmaceutical dosage form according to claim 1, wherein the
pharmaceutically acceptable excipients comprise one or more of preservatives,
solubilizers, viscosity enhancing agents, buffers, sweeteners, colors and flavors.
8. A pharmaceutical dosage form according to claim 1, wherein the preservative
comprises one or more of benzoic acid, sorbic acid, methyl paraben or salts
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thereof, propyl paraben or salts thereof, benzyl alcohol and benzylalkonium chloride and the like.
9. A pharmaceutical dosage form according to claim 1, wherein the sweetening
agents comprises one or more such as sodium saccharin, potassium saccharin,
calcium saccharin, neotame, acesulfame potassium or sodium cyclamate.
10. A pharmaceutical dosage form according to claim 1, wherein the thickening
agent comprises of sodium carboxymethyl cellulose, carboxymethyl cellulose,
methylcellulose, microcrystalline cellulose and the like.

Dated this 29TH . day of September, 2006 For Wockhardt Limited

(Mandar Qodgule) Authorized Signatory
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