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:
SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING LAMOTRIGINE AND HYDROPHOBIC POLYMER
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS : Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a sustained release pharmaceutical composition comprising lamotrigine or salts thereof and pharmaceutically acceptable hydrophobic polymer 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 a sustained release pharmaceutical composition comprising lamotrigine or salts thereof and pharmaceutically acceptable hydrophobic polymer along with pharmaceutically acceptable excipients.
Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine of Formula I. Lamotrigine, is commercially available as Lamictal ® Tablets and oral Chewable Tablet. It is indicated as adjunctive therapy for partial seizures, generalized seizures of Lennox-Gastaut syndrome in adults and pediatric patients. It is also indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.

FORMULA 1
US Patent No 4,602,017 (the '017 Patent) discloses the compound lamotrigine specifically, its pharmaceutical compositions and method of use.
US patent No 5,863,558 (the '558 patent) discloses the method of administering the antiepileptic drug from a controlled-release dosage form.
US patent number 5,906,832 and 5,660,861; US Patent Application 2004191314 disclose the osmotic drug delivery devices to deliver antiepileptic drugs.

US Patent Application 2004043996 disclose a multiparticulate controlled release dosage formulation of lamotrigine.
US patent applications 2005032799 and 2004192690 disclose method of treating a CNS disorder using sustained release formulation of lamotigine.
The present inventors while working on sustained release pharmaceutical composition of lamotrigine have surprisingly found a pharmaceutical composition comprising lamotrigine or salts thereof comprising pharmaceutically acceptable hydrophobic polymers. The sustained release pharmaceutical composition of lamotrigine releases the therapeutically active amount of lamotrigine over an extended period of time.
In one of the aspects of the present invention there is provided, a sustained release pharmaceutical composition comprising lamotrigine or salts thereof and pharmaceutically acceptable hydrophobic polymer.
In yet another aspect of present invention, there is provided, a sustained release pharmaceutical composition comprising lamotrigine or salts thereof and a pharmaceutically acceptable hydrophobic polymer wherein the in-vitro dissolution rate of the said pharmaceutical composition, when measured by the USP Paddle method at 50 rpm in 900 ml 0.1N HCI: between 0% and 30% (by weight) lamotrigine released by 1 hour; between 10% and 60% (by weight) lamotrigine released by 4 hours; between 20% and 70% (by weight) lamotrigine is released by 8 hours; between 30% and 90% (by weight) lamotrigine is released by 12 hours; between 35% and 90% (by weight) lamotrigine is released by 16 hours; and not less than 80% (by weight) lamotrigine released by 24 hours.
In yet another aspect of the present invention, there is provided a method of treating epilepsy by administering a patient in need thereof, a pharmaceutical

composition comprising Lamotrigine or salts thereof and pharmaceutical^ acceptable hydrophobic polymer.
The sustained release pharmaceutical composition comprising lamotrigine or salts thereof and pharmaceutically acceptable hydrophobic polymer may further comprise pharmaceutically acceptable excipients. The excipients comprise one or more of fillers, binders, disintegrants, lubricants, glidants, plastisizer, aqueous or non-aqueous solvents, polymers and the like.
The sustained release pharmaceutical composition comprising lamotrigine or salts thereof wherein the said composition comprises 5 to 500 mg of lamotrigine or salts thereof.
The sustained release pharmaceutical composition comprising lamotrigine or salts thereof wherein the lamotrigine or salts thereof comprises lamotrigine.
The sustained release pharmaceutical composition comprising lamotrigine or salts thereof and pharmaceutically acceptable hydrophobic polymer wherein the said composition comprises 0.001% to 95% of the total polymer content. In one of the embodiments of the present invention, the said polymer is capable of sustaining the release of lamotrigine or salts thereof.
The sustained release pharmaceutical compositions comprising lamotrigine or salts thereof may be matrix formulation prepared by compression of powder or granular mixtures, for example by blending the drug, polymer and excipients followed by dry compression or wet granulation followed by compression. The drug along with a pharmaceutically acceptable hydrophobic polymer and suitable pharmaceutical excipients may be blended to form a powder mixture followed by dry compression of this blend. Also the drug along with a pharmaceutically acceptable hydrophobic polymer and suitable pharmaceutical excipients may be granulated using a suitable pharmaceutical vehicle to for granular mixture. This

granular mixture may be compressed to form tablets or its may be formulated in the desired dosage form like powder, sachets, minitablets, pellets, granules, capsules, monolayer tablets, bilayer tablet and the like. In addition a covering may be applied to the said finished dosage form by a coating process and/or any other process well known in the art. The coating may be a functional or non¬functional coating.
The sustained release formulation of lamotrigine or salts thereof may release between 0% and 30% (by weight) lamotrigine released by 1 hour; between 10% and 60% (by weight) lamotrigine released by 4 hours; between 20% and 70% (by weight) lamotrigine is released by 8 hours; between 30% and 90% (by weight) lamotrigine is released by 12 hours; between 35% and 90% (by weight) lamotrigine is released by 16 hours; and not less than 80% (by weight) lamotrigine released by 24 hours when the dissolution is measured using USP Paddle method at 50 rpm in 900 ml 0.1 N HCI at 37°C±2.
In one of the embodiments of the invention, the sustained release pharmaceutical composition comprising lamotrigine or salts thereof and a pharmaceutically acceptable hydrophobic polymer may be formulated as a multilayer tablet. The said multilayer tablet may comprise one or more layers comprising lamotrigine or salts thereof and a pharmaceutically acceptable hydrophobic polymer.
In one of the embodiments of the invention, the sustained release pharmaceutical composition comprising lamotrigine or salts thereof, may be used to treat epilepsy by administering the said composition either once or twice a daily.
The pharmaceutically acceptable hydrophobic polymers can be one or more selected from a group comprising of acrylic polymer, alkylcelluloses, aliphatic alcohol, natural or synthetic wax or oil and the like. The acrylic acid polymers

may include one or more selected from a group of methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. The alkylcellulose include Ci -C6 alkyl cellulose, like ethyl cellulose, methylcellulose and the like. The aliphatic alcohol may include one or more selected from a group of lauryl alcohol, myristyl alcohol or stearyl alcohol but is preferably cetyl alcohol or more preferably cetostearyl alcohol. Suitable natural or synthetic wax or oil, may include one or more selected from a group of hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax, Carnauba wax or glyceryl monostearate and the like.
The film coating may suitably comprise a polymer. Suitable polymers may include one or more selected from cellulose ethers, for example hydroxypropylmethyl cellulose, hydroxypropyl cellulose or methylcellulose, and copolymers of methacrylic acid and methyl methacrylate.
Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, glidant and the like. Suitable binders may be one or more selected from a group of starch, sugars, gums, low molecular weight, polyvinylpyrrolidone 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, 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.

The sustained release pharmaceutical composition comprising lamotrigine or salts thereof comprises a pharmaceutical^ acceptable vehicle wherein the vehicle may be one or more selected from a group comprising water, isopropyl alcohol, dichloromethane, acetone, chloroform 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 Example 1
The sustained release pharmaceutical composition of lamotrigine is provided in Table 1.

Example 1
Sr. No. Ingredient mg/tab Qty %w/w
1 Lamotrigine 300.00 37.50
2 Eudragit RS PO 200.00 25.00
3 Ethyl cellulose 160.00 20.00
4 DCP 88.00 11.00
5 Povidone 40.00 5.00
6 I PA q.s. -
7 Purified water q.s. -
8 Colloidal silicon dioxide 4.00
9 Talc 4.00 0.50
10 Magnesium stearate 4.00 0.50
Total weight 800.00 100.00
Table 1 Procedure:
Weigh accurately lamotrigine, Eudragit, ethylcellulose and DCP and sift these chemicals through #40 sieve. Dissolve accurately weighed amount of povidone in

a mixture of isopropyl alcohol and water. Granulate the blend of lamotrigine, HPMC and MCC with solution of povidone. Dry the granules and pass them through #25 sieve. Lubricate these granules by adding accurately weighed amount of magnesium stearate, Talc and colloidal silicon dioxide followed by compressing these granules into tablets.
Table 2 provides the dissolution data of the tablets prepared as per the Formula provided in Table 1. For determination of drug release rate, 0.1M hydrochloric acid in 900 ml of medium using USP Type 2 Apparatus (rpm 50) was used.

Lamotrigine XR tablets 300 mg - Dissolution Data
Medium: 0.1 N HCI, 900 ml, USP 2 (Paddle), 50 rpm
Time (Hour) Example 2
1 10
2 15
4 21
6 25
8 29
10 32
12 35
16 39
20 43
24 46
Table 2
Figure 1 provides in vitro drug release profile of the tablets prepared as per the Formula provided in Example 1, in 0.1 M hydrochloric acid in 900 ml of medium using USP Type 2 Apparatus (rpm 50).
Example 2

The sustained release pharmaceutical composition of lamotrigine is provided in Table 3.

Sr. No. Ingredient mg/tab Qty %w/w
1 Lamotrigine 300.00 37.50
2 Eudragit RL PO 200.00 25.00
3 Ethyl cellulose 160.00 20.00
4 Di-Calcium phosphate Dihydrate 88.00 11.00
5 Povidone 40.00 5.00
6 I PA q.s. -
7 P.water q.s. -
8 Colloidal silicon dioxide 4.00
9 Talc 4.00 0.50
10 Magnesium stearate 4.00 0.50
Total weight 800.00 100.00
Table 3
Procedure:
Weigh accurately lamotrigine, Eudragit, ethyl cellulose and DCP and sift these chemicals through 40 sieve. Dissolve accurately weighed amount of povidone in a mixture of isopropyl alcohol and water. Granulate the blend of lamotrigine, HPMC and MCC with solution of povidone. Dry the granules and pass them through 25 sieve. Lubricate these granules by adding accurately weighed amount of magnesium stearate, talc and colloidal silicon dioxide followed by compressing these granules into tablets.
Example 3
The sustained release pharmaceutical composition of lamotrigine is provided in Table 4.

Sr. No. Ingredient mg/tab Qty %w/w
1 Lamotrigine 300.00 37.50


2 Eudragit NE 30D* 200.00 25.00
3 Ethyl cellulose 160.00 20.00
4 Di-Calcium phosphate Dihydrate 128.00 16.00
5 Purified water q.s. -
6 Colloidal silicon dioxide 4.00 0.50
7 Talc 4.00 0.50
8 Magnesium stearate 4.00 0.50
Total weight 800.00 100.00
Table 4
Procedure:
Weigh accurately lamotrigine, Eudragit, ethyl cellulose and DCP and sift these chemicals through 40 sieve. Dissolve accurately weighed amount of povidone in a mixture of isopropyl alcohol and water. Granulate the blend of lamotrigine, HPMC and MCC with solution of povidone. Dry the granules and pass them through 25 sieve. Lubricate these granules by adding accurately weighed amount of magnesium stearate, talc and colloidal silicon dioxide followed by compressing these granules into tablets.


WE CLAIM:
1. A sustained release pharmaceutical composition comprising lamotrigine or salts thereof and pharmaceutical^ acceptable hydrophobic polymer.
2. A sustained release pharmaceutical composition comprising lamotrigine or salts thereof and a pharmaceutically acceptable hydrophobic polymer wherein the in-vitro dissolution rate of the said pharmaceutical composition, when measured by the USP Paddle method at 50 rpm in 900 ml 0.1N HCI: between 0% and 30% (by weight) lamotrigine released by 1 hour; between 10% and 60% (by weight) lamotrigine released by 4 hours; between 20% and 70% (by weight) lamotrigine is released by 8 hours; between 30% and 90% (by weight) lamotrigine is released by 12 hours; between 35% and 90% (by weight) lamotrigine is released by 16 hours; and not less than 80% (by weight) lamotrigine is released by 24 hours.
3. A method of treating epilepsy by administering a patient in need thereof, a pharmaceutical composition comprising Lamotrigine or salts thereof and a pharmaceutically acceptable hydrophobic polymer.
4. The sustained release composition according to claims 1 to 3 wherein about 5 mg to 500 mg of lamotrigine or salt thereof is present.
5. The sustained release composition according to claims 1 to 3 wherein lamotrigine or salt thereof comprises lamotigine.
6. The sustained release composition according to claims 1 to 3 wherein hydrophobic polymer comprises one or more of acrylic polymer, alkylcelluloses, aliphatic alcohol, natural or synthetic wax or oil and mixtures thereof.
7. The sustained release composition according to claims 1 to 3 wherein hydrophobic polymer comprises ethylcellulose.


8. The sustained release composition according to claims 1 to 3 wherein the said composition comprises pharmaceutically acceptable excipients.
9. The sustained release composition according to claims 1 to 3 wherein the pharmaceutically acceptable excipients are fillers, binders, disintegrants, lubricants, glidants, plastisizer, aqueous or non-aqueous solvents, polymers and the like.
10. The sustained release composition according to claims 1 to 3 wherein the said pharmaceutical composition is in the form of powder, sachets, minitablets, pellets, granules, capsules, tablets meant for oral administration.

Abstract
A sustained release formulation of lamotrigine or salts thereof and methods of treatment and uses thereof. One of the embodiments of the present invention provides sustained release pharmaceutical composition comprising lamotrigine or salts thereof and a pharmaceutically acceptable hydrophobic polymer and the method of treatment.