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 HYDROPHILIC 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 hydrophilic 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 hydrophilic 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.

H2N N NH2
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 hydrophilic 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 hydrophilic polymer.
In yet another aspect of present invention, there is provided, a sustained release pharmaceutical composition comprising lamotrigine or salts thereof and hydrophilic 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 hydrophilic polymer.


The sustained release pharmaceutical composition comprising lamotrigine or salts thereof and hydrophilic polymer may comprise pharmaceutical^ 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 a hydrophilic polymer wherein the said composition comprises 0.001% to 95% of the hydrophilic polymer. In one of the embodiments of the present invention, the said hydrophilic 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 formulations prepared by compression of powder or granular mixtures, for example by blending followed by dry compression or wet granulation followed by compression. The drug along with hydrophilic polymer/s and suitable pharmaceutical excipients may be blended to form a powder mixture followed by dry compression of this blend. Also the drug along with hydrophilic polymer/s 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 hydrophilic 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 hydrophilic polymers can be one or more selected from a group comprising of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures, thereof. . Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum, ghatti gum, agar, gum arabic, galactomannan, irish moss, carrageenan xylogalactan, glucomannan and other


carbohydrate gums having similar properties. Suitable polyuronic acid salts
include one or more of alkali metal salts of alginic acid or pectic acid and
mixtures thereof. Suitable alkali metal salts of alginic acid that may be used
include one or more of sodium alginate, potassium alginate, ammonium alginate,
propylene glycol alginate and other suitable alkali metal salts of alginic acid.
Suitable cellulose ethers include one or more of methylhydroxypropylcelluloses,
hydroxyethylcelluloses, hydroxypropylcelluloses, methylcelluloses,
ethylcelluloses, and carboxymethylcelluloses and other suitable cellulose ethers.
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 pharmaceutically 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.
Table 1

Example 1
Sr. No. Ingredient mg/tab Qty %w/w
1 Lamotrigine 300.00 41.38
2 Hydroxypropyl methylcellulose (HPMC) 300.00 41.38
3 Microcrystalline cellulose (MCC) 100.00 13.79
5 Povidone 20.00 2.76
6 Isopropyl alcohol (IPA) q.s. —
7 Purified water q.s. -
8 Magnesium stearate 5.00 0.69
Total weight 725.00 100.00
Procedure:
Weigh accurately lamotrigine, hydroxypropyl methylcellulose (HPMC) and microcrystalline cellulose (MCC) 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 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, 0.1 M hydrochloric acid in 900 ml of medium using USP Type 2 Apparatus (rpm 50) was used.

Lamotrigine XR tablets 300 mg - Dissolution Data
Medium: 0.1N HCI, 900 ml, USP 2 (Paddle), 50rpm
Time (Hour) Example 1
1 9
2 12
4 17
6 21
8 24
10 29
12 32
16 39
20 47
24 53
Table 2
Figure 1 provides in vitro drug release profile of the tablets prepared as per the Formula provided in Example 1, in 0.1M 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.

Example 2
Sr. No. Ingredient mg/tab Qty %w/w
1 Lamotrigine 300.00 38.71
2 HPMC 250.00 32.26
3 Xanthan gum 100.00 12.90

5 MCC 100.00 12.90
6 Povidone 20.00 2.58
7 IPA q.s. —
8 Purified water q.s. —
9 Magnesium stearate 5.00 0.65
Total weight 775.00 100.00
Table 3 Procedure:
Weigh accurately lamotrigine, HPMC, Xanthan Gum and MCC 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 followed by compressing these granules into tablets.
Table 4 provides the dissolution data of the tablets prepared as per the Formula provided in Table 3. For determination of drug release rate, 0.1 M 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 7
2 9
4 12
6 17
8 21
10 24
12 27
16 34
20 41

Figure 2 provides in vitro drug release profile of the tablets prepared as per the Formula provided in Example 2, in 0.1M hydrochloric acid in 900 ml of medium using USP Type 2 Apparatus (rpm 50).
Example 3 and 4
The sustained release pharmaceutical composition of lamotrigine is provided in Table 5.

Sr. No. Ingredient Example 3 Example 4
mg/tab Qty %w/w mg/tab Qty %w/w
1 Lamotrigine 400.00 50.00 400.00 50.00
2 HPMC 160.00 20.00 240.00 30.00
3 MCC 97.00 12.13 57.00 7.13
4 Di-Calcium phosphateDi hydrate(DCP) 100.00 12.50 60.00 7.50
5 Povidone 40.00 5.00 40.00 5.00
6 Purified Water q.s. q.s.
7 I PA q.s. q.s.
9 Magnesium stearate 3.00 0.38 3.00 0.38
Total weight 800.00 800.00
Table 5 Procedure:
Weigh accurately lamotrigine, HPMC, DCP and MCC 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 followed by compressing these granules into tablets.

WE CLAIM:
1. A sustained release pharmaceutical composition comprising lamotrigine or salts thereof and a pharmaceutical^ acceptable hydrophilic polymer.
2. A sustained release pharmaceutical composition comprising lamotrigine or salts thereof and a pharmaceutical^ acceptable hydrophilic 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 0.1 N 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 hydrophilic 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 a pharmaceutically acceptable hydrophilic polymer comprises one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures, thereof.
7. The sustained release composition according to claims 1 to 3 wherein a pharmaceutically acceptable hydrophilic polymer comprises hydroxypropyl methylcellulose.

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 pharmaceutically acceptable hydrophilic polymer and the method of treatment.