FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL DOSAGE FORM OF OXCARBAZEPINE
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 DESCRIPTION
The present invention provides pharmaceutical formulation of oxcarbazepine or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable excipients and a process for preparing the same.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides pharmaceutical formulation of oxcarbazepine or pharmaceutical^ acceptable salt thereof along with pharmaceutically acceptable excipients and a process for preparing the same.
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.


C£>NH2 FORMULA I
US Patent No 7,037,525 discloses a method of treating seizures, which comprises administering a formulation of oxcarbazepine having a maximum residue on a 40um 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 2pm o 12pm.
US Patent No 5,695,782 and US Patent No US 5,472,714 discloses double-layered tablet, comprising a tablet core containing oxcarbazepine, a hydrophilic,
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permeable inner layer consisting of hydroxypropyl methyl cellulose and polyethylene glycol 8000 containing titanium dioxide pigments, and a hydrophilic, permeable outer layer consisting of hydroxypropyl methyl cellulose and polyethylene glycol 8000 containing titanium dioxide pigments in combination with iron(ll)oxide pigments.
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 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 20040197402 disclose dosage form composition for oral administration comprising oxcarbazepine and a wetting agent and a process for the preparation of oxcarbazepine dosage form for oral administration.
PCT Application WO2006046105 discloses a pharmaceutical dosage form for oral administration comprising oxcarbazepine having a median particle size of from about 14pm to about 30pm.
The present inventors while working on the oxcarbazepine formulation have surprisingly found a pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof along with pharmaceutically acceptable excipients wherein the said composition comprises oxcarbazepine and pharmaceutically acceptable salts thereof with a median particle size of 150-210 urn.
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The present invention also provides a process for the preparation of pharmaceutical composition comprising oxcarbazepine and pharmaceutically acceptable salts thereof along with pharmaceutically acceptable excipients wherein the said process comprises the step of compaction followed by wet granulation.
In one of the aspects of present invention there is provided, a pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof, along with pharmaceutically acceptable excipients wherein the said composition comprises oxcarbazepine or pharmaceutically acceptable salts thereof with a median particle size of 150-210 um.
In another aspect of present invention there is provided, a process for preparing a pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof, wherein the said process comprises
a) compacting oxcarbazepine or pharmaceutically acceptable salts thereof along with pharmaceutically acceptable excipients into compact,
b) wet granulating the compacted material,
c) optionally, coating the granules with suitable coating material.
In yet another aspect of present invention there is provided, a pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof, along with pharmaceutically acceptable excipients wherein 60% or more amount of oxcarbazepine is released within 10 min and about 90% or more amount of oxcarbazepine is released in next 90 min when dissolution is measured in a USP Type II apparatus at 60 rpm and using 1% sodium dodecyl sulfate solution in water as dissolution media at 37°C ±2.
The pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof along with pharmaceutically acceptable excipients can be prepared by compaction method. Intragranularly oxcarbazepine and suitable
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pharmaceutically acceptable filler or fillers can be mixed and compacted to get compacts. The compacts can be milled followed by granulating the milled mixture by using a suitable granulating agent dissolved in water. The binder solution may optionally comprise an alkalizing agent. The granules may be dried and mixed with a suitable disintegrant, glidant and lubricant. The lubricated granules can be compressed into tablets and the tablets may optionally be coated.
The pharmaceutical composition comprises oxcarbazepine or pharmaceutically acceptable salts thereof wherein oxcarbazepine has a median particle size of 150 to 210 urn.
The pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof exhibits a dissolution profile wherein 60% or more amount of oxcarbazepine is released within 10 min and about 90% or more amount of oxcarbazepine is released in next 90 min when dissolution is measured in a USP Type II apparatus at 60 rpm and using 1% sodium dodecyl sulfate solution in water as dissolution media at 37°C ±2.
The pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof may optionally comprise an alkalizing agent. An alkalizing agent may be used to achieve an alkaline pH so as to enhance the solubility of oxcarbazepine. A suitable alkalizing agent can be one or more of tromethamine, an alkali metal or alkali earth metal carbonate or bicarbonate and the like.
Pharmaceutically acceptable excipients can be diluent, filler, binder, disintegrant, lubricant, glidant and the like.
Suitable binders may be one or more selected from a group of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose and the like.
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Suitable fillers may be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol and the like.
Suitable lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate and the like.
Suitable glidants may be one or more of microcrystalline cellulose, colloidal silicon dioxide, talc, magnesium stearate and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
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.
Examples- Following formulations are representatives of the preferred
compositions of the present invention.
Example 1
Table 1 - The pharmaceutical composition of oxcarbazepine.

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (Median particle size 150-210 micron) 75.00
2. AvicelPH 101 17.00
3. Hypromellose 2.00
4. Tromethamine 2.00
Extragranular
5. Crosspovidone 3.0
6. Aerosil 200 0.50
7. Magnesium Stearate 0.50
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Procedure:
Oxcarbazepine and Avicel is weighed accurately and mixed in a double cone blender. The blend is compacted in roll compactor to get the compacts. The compacts so obtained are milled and passed though 0.25 mm screen. The milled mass is granulated using the aqueous solution of hypromellose and tromethamine. The granules are dried in fluid bed dryer and passed though 20 mesh (ASTM). The granules are mixed thoroughly with Extragranular material having crospovidone, Aerosil and magnesium stearate. The lubricated granules are compressed to tablets using appropriate tooling. The tablets may optionally be coated with Opadry yellow.
Example 2 and 3
Table 2 - The pharmaceutical composition of oxcarbazepine.

No. Ingredients Example 2% w/w Example 3% w/w
1. Oxcarbazepine ((Median particle size 150-210 micron) 75.00 75.00
2. Avicel PH 101 19.00 17.00
3. Hypromellose 2.00 4.00
4. Crospovidone 3.0 . 3.0
5. Aerosil 200 0.5 0.5
6. Magnesium Stearate 0.5 0.5
Procedure:
Oxcarbazepine and Avicel is weighed accurately and mixed in a double cone blender. The blend is compacted in roll compactor to get the compacts. The compacts so obtained are milled and passes though 0.25 mm mesh. The milled mass is granulated using the aqueous solution of hypromellose. The granules are dried in fluid bed dryer and passed though 20 mesh (ASTM). The dried granules are mixed thoroughly with Extragranular material having crospovidone, Aerosil and magnesium stearate. The lubricated granules are compressed to tablets using appropriate tooling. The tablets may optionally be coated with Opadry yellow.
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Example 4
Table 3 - The pharmaceutical composition of oxcarbazepine.

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (Median particle size 150-210 micron) 75.00
2. Lactose Monohydrate 17.00
3. Hypromellose 2.00
4. Tromethamine 2.00
Extragranular
5. Crospovidone 3.0
6. Aerosil 200 0.5
7. Magnesium Stearate 0.5
Procedure:
Oxcarbazepine and lactose is weighed accurately and mixed in a double cone blender. The blend is compacted in roll compactor to get the compacts. The compacts so obtained are milled and passes though 0.25 mm screen. The milled mass is granulated using the aqueous solution of hypromellose and tromethamine. The granules are dried in fluid bed dryer and passed though 20 mesh (ASTM). The granules are mixed thoroughly with Extragranular material having crospovidone, Aerosil and magnesium stearate. The lubricated granules are compressed to tablets using appropriate tooling. The tablets may optionally be coated with Opadry yellow.
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Example 5
Table 4 - The pharmaceutical composition of oxcarbazepine.

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (Median particle size 150-210 micron) 75.00
2. Lactose monohydrate 19.00
3. Hypromellose 2.0
Extragranular
5. Crospovidone 3.0
6. Aerosil 200 0.5
7. Magnesium Stearate 0.5
Procedure:
Oxcarbazepine and lactose is weighed accurately and mixed in a double cone blender. The blend is compacted in roll compactor to get the compacts. The compacts so obtained are milled and passed though 0.25 mm screen. The milled mass is granulated using the aqueous solution of hypromellose. The granules are dried in fluid bed dryer and passed though 20 mesh (ASTM). The granules are mixed thoroughly with Extragranular material having crospovidone, Aerosil and magnesium stearate. The lubricated granules are compressed to tablets using appropriate tooling. The tablets may optionally be coated with Opadry yellow.
Example 6
Table 5 - The pharmaceutical composition of oxcarbazepine.

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (Median particle size 150-250 micron) 65.00
2. Starch 1500 10.00
3. Povidone 5.0
4. Plasdone S 630 _j 2.0
Extragranular
5. Crospovidone 3.0
6. Microcrystalline Cellulose (Avicel 102) 14.0
7. Magnesium Stearate 1.0
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Procedure:
Oxcarbazepine and starch 1500 are mixed for 5 minutes in the Double cone blender and compacted in roll compactor to get compacts. The compacts so obtained are milled and passed though 0.25 mm screen. The milled mass is granulated using solution of Povidone & Plasdone S630 in purified water. The granules are dried in fluid bed dryer and passed though 20 mesh (ASTM). The material is blended with Crospovidone and Microcrystalline Cellulose and then lubricated with magnesium stearate and compressed into tablets using appropriate tooling. The tablets may optionally be coated with Opadry yellow
Example 7
Examination of in vitro release pattern
Tablet prepared according to Example 1 to 5 containing oxcarbazepine were examined in vitro according to the USP paddle method. The release pattern was studied using 900 ml of 1% w/v aqueous solution of sodium dodecyl sulfate at 60 rpm and 37°C. The release pattern was compared to Trileptal®, the commercially available tablets containing oxcarbazepine. The release pattern of the tablets of present invention and Trileptal® is given in Table 5.
Table 5: The release pattern of the tablets of present invention and Trileptal .

Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Trileptal®
10 63 69 56 66 58 52 70
20 74 84 81 80 81 78 83
30 80 87 87 81 85 86 89
45 85 88 93 84 87 93 91
60 89 90 98 86 93 96 94
90 93 95 99 92 94 100 96
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WE CLAIM:
1. A pharmaceutical composition comprising oxcarbazepine or pharmaceutical^ acceptable salts thereof, along with pharmaceutical^ acceptable excipients wherein the said composition comprises oxcarbazepine and pharmaceutically acceptable salts thereof with a median particle size of 150-210 um.
2. A process for preparing a pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof, wherein the said process comprises
a) compacting oxcarbazepine or pharmaceutically acceptable salts thereof along with pharmaceutically acceptable excipients into compact,
b) wet granulating the compacted material,
c) optionally, coating the granules with suitable coating material.

3. A pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof, along with pharmaceutically acceptable excipients exhibits an in vitro release profile wherein 60% or more amount of oxcarbazepine is released within 10 min and about 90% or more is released in next 90 min when release profile is measured in a USP Type II apparatus at 60 rpm and using 1% sodium dodecyl sulfate solution in water as dissolution media at 37°C ±2.
4. A pharmaceutical composition comprising oxcarbazepine or pharmaceutically acceptable salts thereof and process for preparing according to claim 1 to 3, has 50 to 800 mg of oxcarbazepine or pharmaceutically acceptable salts.
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5. A pharmaceutical composition comprising oxcarbazepine or pharmaceutical^ acceptable salts thereof and process for preparing according to claim 1 to 3, optionally comprises an alkalizing agent.
6. A pharmaceutical composition comprising oxcarbazepine or pharmaceutical^ acceptable salts thereof and process for preparing according to claim 1 to 3, wherein pharmaceutical^ acceptable excipients are diluent, filler, binder, disintegrant, lubricant, glidant and the like.
7. A pharmaceutical composition according to claim 1, wherein the dosage form is oral solid dosage composition.
8. A pharmaceutical composition according to claim 1, wherein the dosage form is tablet.
Dated this 22™ day of September, 2006 For Wockhardt Limited
JL
(Mandar Kodgule) Authorized Signatory
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