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 OR SALT THEREOF
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 pharmaceutical^ acceptable salt thereof as the active pharmaceutical ingredient 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 pharmaceutical formulation of oxcarbazepine or pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient 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 provides a method of treating seizures, which comprises administering a formulation of oxcarbazepine, 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, having a median particle size of approximately 2mm to 12mm.
US Patent No 5,695,782 and US Patent No US 5,472,714 provides double-layered tablet, comprising a tablet core containing oxcarbazepine, a hydrophilic, permeable inner layer consisting of hydroxypropyl methyl cellulose and
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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 (II) oxide pigments.
US Patent No 5,284,662 provides an oral osmotic dosage delivery form 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 20040197402 provides 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.
US Application No 20060111343 provide 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.
PCT Application WO2006046105 provides a pharmaceutical dosage form for oral administration comprising oxcarbazepine having a median particle size of from about 14mm to about 30 mm.
The present inventors while working on the oxcarbazepine formulation surprisingly found that when alkalizing agent other than amide is used in the preparation of dosage form of oxcarbazepine or salt thereof along with other pharmaceutically acceptable excipients, it provides excellent solubility and dissolution profile.
In one of the aspects of the present invention there is provided a pharmaceutical dosage form comprising oxcarbazepine or salt thereof, an alkalizing agent other

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than amide along with other pharmaceutically acceptable excipients, wherein the dosage form having a pH of 7 or greater.
Oxcarbazepine is antiepileptic drug having poor aqueous solubility. The present invention enhance the solubility of oxcarbazepine by adding the alkalizing agent other than amide to the formulation and increasing the pH of the formulation to 7 or greater.
An amide is a derivative of a carboxylic acid in which the hydroxyl group has been replaced by an amine or ammonia. The present invention does not make use of amide in the formulation. Tromethamine may be used in the present invention to achieve an alkaline pH so as to enhance the solubility of oxcarbazepine. Tromethamine should generally be used in an amount, which is sufficient to provide an alkaline medium for solubilisation of the drug. Tromethamine can be present in an amount ranging from about 0.010 w/w % to about 10 w/w % of the dosage form.
The 0.1 molar solution of tromethamine has a pH within the range of 10.4 to 10.6. Use of tromethamine in the formulation provides alkaline pH to the formulation that further increases the solubility. When the formulation containing tromethamine is dispersed in 10 ml aqueous medium, it possesses alkaline pH within the range of 7.0 to 10.0.
In another aspect of the present invention there is provided a pharmaceutical dosage form comprising oxcarbazepine or salt thereof, an alkalizing agent other than amide along with other pharmaceutically acceptable excipients, wherein the dosage form having a pH of 7 or greater, and the dosage form exhibits a dissolution profile such that 70% or more amount of oxcarbazepine is released within first 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
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rpm and using 1% sodium lauryl sulfate solution in water as dissolution media at 37°C ±2.
The pharmaceutical composition comprises oxcarbazepine or pharmaceutically acceptable salts thereof wherein oxcarbazepine has a median particle size of 20 to 30 mm and a maximum residue on a 40 mu.m sieve of greater than 10%.
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.
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, calcium silicate, magnesium silicate, silicon hydrogel and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like and mixtures thereof.
The dosage form according to the present invention may be prepared by wet granulation method. Oxcarbazepine, and other excipients were sifted through 30
# and mixed for 10 minutes in the double cone blender. Tromethamine and
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Hydroxypropyl methylcellulose was dissolved in purified water and this solution was used as binder to granulate the mass. This mass was granulated, the granules were dried using fluidized bed drier at 60°C and sifted through # 30 mesh. Avicel, Polyplasdone and colloidal silicon dioxide were sifted through # 40 mesh and mixed with above granules for 10 min. Granules were lubricated using lubricating agent. This blend was compressed into tablets and further these tablets were coated with Opadry.
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.
Table 1 provides composition of present invention
Table 2 provides the dissolution data of the tablets prepared as per the Formula provided in Table 1. For determination of drug release rate, 1% Sodium dodecyl sulphate in 900 ml of medium using USP Type 2 Apparatus (rpm 60) was used.
Table 1 - Oxcarbazepine Tablets.

No. Ingredients Qty/ tablet (mg) 600 mg Qty/ tablet(mg)300 mg Qty/ tablet(mg)150 mg
Intragranular
1. Oxcarbazepine (d 0.5: 20-30 micron) 600.00 300.00 150.00
2. Microcrystalline cellulose 100.00 50.00 25.00
3. Hydroxypropyl methyl cellulose 8.0 4.0 2.0
4. Tromethamine 4.0 2.0 1.0
Extragranular
5. Avicel 58.00 29.00 14.50
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6. Polyplasdone 40.00 20.00 10.00
7. Colloidal silicon dioxide 4.00 2.00 1.00
8. Magnesium Stearate 6.00 3.00 1.50
TOTAL 820.00 410.00 205.00
COATING
9. Opadry 25.0 mg 12.50 6.00
TOTAL 844.00 422.00 211.00
Procedure -
Oxcarbazepine, Microcrystalline cellulose and Hydroxypropyl methylcellulose were sifted through 30 # and mixed for 10 minutes in the double cone blender. Tromethamine and Hydroxypropyl methylcellulose was dissolved in purified water and this solution was used as binder to granulate the mass. The wet mass was passed through # 30 mesh screen. The granules were dried using fluidized bed drier at 60°C and sifted through # 30 mesh. Avicel, Polyplasdone and colloidal silicon dioxide were sifted through # 40 mesh and mixed with above granules for 10 min. Magnesium stearate was sifted through # 60 mesh screen & mixed with above blend for 2 min. This blend was compressed into tablets and further these tablets were coated with Opadry.
Table 2: The release pattern of the tablets of present invention and Trileotal®.

Time (min) Example Trileptal®
10 77 80
20 88 93
30 90 98
45 94 101
60 95 102
90 98 103
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WE CLAIM:
1. A pharmaceutical dosage form comprising oxcarbazepine or salt thereof, an alkalizing agent other than amide along with other pharmaceutical^ acceptable excipients, wherein the dosage form having a pH of 7 or greater.
2. A pharmaceutical dosage form comprising oxcarbazepine or salt thereof, an alkalizing agent other than amide along with other pharmaceutically acceptable excipients, wherein the dosage form having a pH of 7 or greater, and the dosage form exhibits a dissolution profile such that 70% or more amount of oxcarbazepine is released within first 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 lauryl sulfate solution in water as dissolution media at 37°C ±2.
3. A pharmaceutical dosage form according to claims 1 and 2, wherein the alkalizing agent is tromethamine.
4. A pharmaceutical dosage form according to claims 1 and 2, wherein the one or more pharmaceutically acceptable additives is selected from the group consisting of a diluent, binder, disintegrant, lubricant, glidant, coloring agent, flavoring agent, sweetener and mixtures thereof.
5. A pharmaceutical dosage form according to claims 1 and 2, wherein the one or more pharmaceutically acceptable additives is added intragranularly or extragranularly or both intra and extragranularly.
6. A pharmaceutical dosage form according to claims 1 and 2, has 50 to 800 mg of oxcarbazepine or pharmaceutically acceptable salts.
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7. A pharmaceutical dosage form according to claims 1 and 2, wherein the dosage form is an oral solid dosage composition.
8. A pharmaceutical composition according to claims 1 and 2, wherein the dosage form is tablet.
9. A pharmaceutical composition according to claim 7, wherein the tablet contains a coating thereon.


Dated this 27TH day of December, 2006

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