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:
OXCARBAZEPINE ORAL DOSAGE 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 DESCRIPTION
The present invention provides formulation of oxcarbazepine or pharmaceutically acceptable salt thereof, cyclodextrin or derivative thereof along with pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides formulation of oxcarbazepine or pharmaceutical^ acceptable salt thereof, cyclodextrin or derivative thereof along with pharmaceutically acceptable excipients.
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.

C0NH2 FORMULA I
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 2um 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,
2

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 14um to about 30pm.
US Application No 20040157797 discloses a pharmaceutical composition comprising a solubilizing agent selected from crystalline methylated a-, (5-, y-cyclodextrin, or mixtures thereof along with pharmaceutically active agent selected from carbamazepine, fenofibrate, oxcarbazepine, or glipizide.
3

Oxcarbazepine, 10,11-dihydro-10-oxo-5H-dibenzo[b,]azepine-5-carboxamide, is a widely used antiepileptic drug which is practically insoluble in water. Developing pharmaceutical composition comprising oxcarbazepine having immediate release is one of the major challenges. The present invention now provides composition for oral administration comprising oxcarbazepine or pharmaceutically acceptable salt thereof, beta cyclodextrin or derivative thereof, along with pharmaceutically acceptable excipients. Cyclodextrin or derivative thereof is used Intragranularly or extra granularly or both intra and extra granularly. Oxcarbazepine can also present in the form of complex with cyclodextrin.
In one of the aspects of the present invention there is provided a solid dosage form comprising oxcarbazepine or pharmaceutically acceptable salt thereof wherein oxcarbazepine is present in admixture with cyclodextrin or derivatives thereof and pharmaceutically acceptable additives.
In another aspect of the invention there is provided a solid dosage form comprising oxcarbazepine or pharmaceutically acceptable salt thereof wherein oxcarbazepine is present in the form of complex with cyclodextrin or derivatives thereof.
In yet another aspect of the present invention there is provided a solid dosage form comprising oxcarbazepine or pharmaceutically acceptable salt thereof wherein oxcarbazepine is present in admixture with cyclodextrin or derivatives thereof and pharmaceutically acceptable additives, wherein the dosage form exhibits a dissolution profile such that 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.
4

In yet another aspect of the invention there is provided a solid dosage form comprising oxcarbazepine or pharmaceutical^ acceptable salt thereof wherein oxcarbazepine is present in the form of complex with cyclodextrin or derivatives thereof, wherein the dosage form exhibits a dissolution profile such that 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.
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.
Cyclodextrin are cyclic (a-1,4)-linked oligosaccharides of a-D-gluco-pyranose containing a relatively hydrophobic central cavity and hydrophilic outer surface. In the pharmaceutical industry, cyclodextrin 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, cyclodextrin 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 selected from hydroxypropyl-p-cyclodextrin, p-cyclodextrin, a-cyclodextrin, hydroxypropyl- a-cyclodextrin and the like.
5

Hydroxypropyl-P-cyclodextrin, a chemically modified p-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 cyclodextrin and 'guest' drug molecule. The prepared HP-P-CD complex is stable and reduces oxidation of oxcarbazepine in the dosage form, which further increases dissolution rate of the formulation. Incorporation of cyclodextrin in the composition also prevents discoloration of the dosage form.
Therapeutically effective amount of oxcarbazepine is used for preparation of the dosage form. Pharmaceutically acceptable carrier can be a diluent, binder, disintegrant, lubricant, glidant, coloring agent, flavoring agent, sweetener and mixtures thereof. The filler may be one or more of Avicel PH 101, Avicel PH 102, lactose, dibasic dicalcium phosphate dehydrate and dicalcium phosphate monohydrate. The lubricants may be one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. The glidant may be one or both of colloidal silicon dioxide and talc or magnesium stearate. The disintegrant may be one or more of croscarmellose sodium, crospovidone and sodium starch glycolate.
The pharmaceutical composition comprises oxcarbazepine or pharmaceutically acceptable salts thereof wherein oxcarbazepine has a median particle size of 150 to 210 urn.
Therapeutically effective amount of oxcarbazepine or salt thereof was added to the formulation in the form of complex. The complex of oxcarbazepine and HP-P-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.
6

The oxcarbazepine oral formulation may be prepared by the processes for preparation of oral dosage forms known in the art. Oxcarbazepine along with other excipients were weighed accurately and mixed in the Double cone blender. The blend is granulated using Oxcarbazepine and Hydroxypropyl beta cyclodextrin in water. The granules are dried in fluid bed drier and passed through # 20 mesh. The above material is blended with Crospovidone and Aerosil 200. These blended granules are lubricated with magnesium stearate and compressed into tablets. The compressed tablets of are coated using Opadry yellow.
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.
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
Table 1-4 provides composition of present invention.
Table 5 provides the dissolution data of the tablets prepared as per the Formula provided in Table 1-4. For determination of drug release rate, 1% Sodium dodecyl sulphate in 900 ml of medium using USP Type 2 Apparatus (rpm 60) was used.
7

Example 1
Table 1 - The pharmaceutical composition of oxcarbazepine

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (median particle size 30-40micron) 52.00%
2. Oxcarbazepine (median particle size 150-250micron) 13.00%
3. Avicel PH 101 15.00
4. Hypromellose 2.00
5. Hydroxypropyl beta cyclodextrin 14.00
Extragranular
6. Crospovidone 3.0
7. Aerosil 200 0.5
8. Magnesium Stearate 0.5
Procedure:
80 % oxcarbazepine having median particle size 30-40 micron and 20 % having 150-250 micron, Avicel PH 101 and Hypromellose were weighed accurately and mixed in the Double cone blender. The blend is granulated using Oxcarbazepine and Hydroxypropyl beta cyclodextrin in water. The granules are dried in fluid bed drier and passed through # 20 mesh. The above material is blended with Crospovidone and Aerosil 200. These blended granules are lubricated with magnesium stearate and compressed into tablets using suitable tooling. The compressed tablets of are coated using Opadry yellow.
8

Example 2
Table 2 - The pharmaceutical composition of oxcarbazepine

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (Median particle size 150-210 micron) 65.00
2. Avicel PH 101 15.00
3. Hypromellose 2.00
Extragranular
4. Hydroxypropyl beta cyclodextrin 14.00
5. Crospovidone 3.00
6. Aerosil 200 0.5
7. Magnesium Stearate 0.5
Procedure:

65
Oxcarbazepine and Avicel PH 101 are passed through # 30 mesh (ASTM) and mixed in the Double cone blender. The blend is compacted in roll compactor to get compacts/slugs. The compacts/slugs are milled in multimiil using 0.5 mm screen and then passed through 0.25 mm screen. The milled mass is granulated using solution Hypromellose in water. The granules are dried in fluid bed drier. The dried granules passed through # 20 mesh and further blended with Hydroxypropyl beta cyclodextrin, Crospovidone and Aerosil 200. The blended granules are lubricated with magnesium stearate and compressed into tablets using suitable tooling. The compressed tablets were coated using Opadry yellow.
9

Example 3
Table 3 - The pharmaceutical composition of oxcarbazepine

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (Median particle size 150-210) 65.00
2. Avicel PH 101 15.00
3. Hypromellose 2.00
Extragranular
4. Beta cyclodextrin 14.00
5. Crospovidone 3.00
6. Aerosil 200 0.5
7. Magnesium Stearate 0.5
Procedure:
Oxcarbazepine and Avicel PH 101 are passed through # 30 mesh (ASTM) and mixed in the Double cone blender. The blend is compacted in roll compactor to get compacts/slugs. The compacts/slugs are milled in multimill using 0.5 mm screen and then passed through 0.25 mm screen. The milled mass is granulated using solution Hypromellose in water. The granules are dried in fluid bed drier. The dried granules passed through # 20 mesh and further blended with beta cyclodextrin, Crospovidone and Aerosil 200. The blended granules are lubricated with magnesium stearate and compressed into tablets using suitable tooling. The compressed tablets were coated using Opadry yellow.
10

Example 4
Table 4 - The pharmaceutical composition of oxcarbazepine

No. Ingredients % w/w
Intragranular
1. Oxcarbazepine (Median particle size 150-210 micron) 65.00
2. Beta cyclodextrin 29.00
3. Hypromellose 2.00
Extragranular
4. Crospovidone 3.00
5. Aerosil 200 0.5
6. Magnesium Stearate 0.5
Procedure:
Oxcarbazepine and beta cyclodextrin is weighed accurately and mixed in a double cone blender. The blend is compacted in roll compactor to get compacts/slugs. The compacts/slugs are milled in multimill using 0.5 mm screen and then passed through 0.25 mm screen. The milled mass is granulated using Hypromellose in water. The granules are dried in fluid bed drier. The dried granules further passed through # 20 mesh and blended with other excipients. The blended granules further lubricated with magnesium stearate and compressed into tablets using suitable tooling. The compressed tablets are coated using Opadry yellow.
11

Table 5: The release pattern of the tablets of present invention and Trileptal'

Time (min) Example 1 Example 2 Example 3 Example 4 Trileptal®
Cumulative percent release
10 64 63 60 66 70
20 79 82 81 80 83
30 85 86 87 84 89
45 89 92 89 88 91
60 93 94 92 0 93
90 95 99 95 93 96

WE CLAIM:
1. A solid dosage form comprising oxcarbazepine or pharmaceutical^ acceptable salt thereof wherein oxcarbazepine is present in admixture with cyclodextrin or derivatives thereof and pharmaceutically acceptable additives.
2. A solid dosage form comprising oxcarbazepine or pharmaceutically acceptable salt thereof wherein oxcarbazepine is present in the form of complex with cyclodextrin or derivatives thereof.
3. A solid dosage form comprising oxcarbazepine or pharmaceutically acceptable salt thereof wherein oxcarbazepine is present in admixture with cyclodextrin or derivatives thereof and pharmaceutically acceptable additives, wherein the dosage form exhibits a dissolution profile such that 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.
4. A solid dosage form comprising oxcarbazepine or pharmaceutically acceptable salt thereof wherein oxcarbazepine is present in the form of complex with cyclodextrin or derivatives thereof, wherein the dosage form exhibits a dissolution profile such that 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.
5. A solid dosage form according to claims 1 and 2, wherein the cyclodextrin is hydroxypropyl-p-cyclodextrin.
13

6. A solid dosage form according to claim 2, 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.
7. A solid dosage form according to claim 1, wherein the cyclodextrin or derivative thereof is used Intragranularly or extra granularly or both intra and extra granularly.
8. A solid 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.
9. A solid dosage form according to claims 1 and 2, wherein the binder comprises acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, povidone and. pregelatinized starch, combinations thereof and the like.
10. A solid dosage form according to claims 1 and 2, wherein the dosage form is
an oral solid dosage composition.
Dated this 25th day of September, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
14