FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - MODIFIED RELEASE TABLET OF LAMOTRIGINE

2. Applicants)
(a) NAME:
(b) NATIONALITY (C) ADDRESS:

ALEMBIC LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

MODIFIED RELEASE TABLET OF LAMOTRIGINE
FIELD OF INVENTION
The present invention relates to modified release tablet of Lamotrigine.
BACKGROUND OF THE INVENTION
Lamotrigine, 3,5-diamino-6-(2,3-dichIorophenyl)-l,2,4-triazine is disclosed in U.S.
Pat. No. 4,602,017. Products comprising lamotrigine are marketed under the trade
name LAMICTAL®
(http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.clm') . Such products are particularly effective for treatment of CNS disorders, particularly epilepsy, pain; oedema; multiple sclerosis and psychiatric indications including bipolar disorder.
The approved tablet formulations of lamotrigine, for instance, conventional compressed instant release (IR) tablets comprising 25 mg, 50mg, 100 mg, 150 mg or 200 mg of active ingredient are administered once, twice or three times daily. Also, recently Lamictal XR® is available as extended-release tablets: 25 mg, 50 mg, 100 mg, and 200 mg indicated for adjunctive therapy for partial onset seizures with or without secondary generalization in patients >13 years of age.
LAMICTAL XR Extended-Release Tablets contain a modified-release eroding formulation as the core. The tablets are coated with a clear enteric coat and have an aperture drilled through the coats on both faces of the tablet (DiffCORE™). Similar formulations are described in US 2004/0192690 Al The combination of this and the modified-release core control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels.

The formulations of the present invention provide simpler and convenient methods to prepare modified release tablet formulations of lamotrigine, which would also be able to achieve gradual increase in serum lamotrigine levels.
SUMMARY OF THE INVENTION
The present invention relates to a modified release tablet of lamotrigine.
According to a first aspect, the invention relates to a modified release tablet of
lamotrigine comprising:
from about 5 to 30 % w/w of lamotrigine;
from about 30 to 50 % w/w of a filler;
from about 1 to 16 % w/w of a first release controlling polymer and
from about 22 to 42 % w/w of a second release controlling polymer.
In a further aspect, the invention relates to, a process for the preparation of modified release tablet of lamotrigine according to the first aspect, comprising the steps of:
(a) mixing lamotrigine, one or more filler, optionally the first release controlling polymer;
(b) granulating the blend of step (a) using either solution of the first release controlling polymer or solvent alone;
(c) drying the product of step (b);
(d) blending the product of step (c) with the second release controlling polymer;
(e) optionally lubricating the product of step (d);
(f) compressing the product of step (d) or (e) to obtain the modified release tablet and
(g) optionally coating the product of step (f).

According to a second aspect, the invention relates to a modified release tablet of
lamotrigine comprising:
from about 5 to 30 % w/w of lamotrigine;
from about 30 to 50 % w/w of a filler;
from about 1 to 16 % w/w of a first release controlling polymer;
from about 22 to 42 % w/w of a second release controlling polymer and
having a dissolution profile such that not more than about 20% of the lamotrigine
dissolves within 2 hours, from about 30 to 50 % of the lamotrigine dissolves within 6
hours, from about 45 to 65 % of the lamotrigine dissolves within 12 hours and not
less than 70 % of the lamotrigine dissolves within 20 hours.
In a further aspect, the invention relates to, a process for the preparation of the modified release tablet of lamotrigine according to the second aspect, comprising the steps of:
(a) mixing lamotrigine, one or more filler, optionally the first release controlling polymer;
(b) granulating the blend of step (a) using either solution of the first release controlling polymer or solvent alone;
(c) drying the product of step (b);
(d) blending the product of step (c) with the second release controlling polymer;
(e) optionally lubricating the product of step (d);
(f) compressing the product of step (d) or (e) to obtain the modified release tablet and
(g) optionally coating the product of step (f).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to modified release tablet of lamotrigine.

The term "modified release" as used herein can be used interchangeably with prolonged release and means release of lamotrigine is modified to achieve therapeutic effect over an extended period of time so that plasma concentrations of lamotrigine are maintained at a therapeutic level to provide therapeutic benefits for a longer period of time.
Unless otherwise indicated herein "%w/w" means percentage by weight of the total weight of the tablet.
The term "tablet" includes without limitation, tablets, pills, minitablets and the like.
The term 'particle' includes particles, granules, beads, crystals, agglomerates and the like.
The term "minitablet" as used herein refers to any tablet with an overall weight in their uncoated form of from about 10-50 mg. The minitablets are preferably cylindrical in shape having a convex upper face and a convex lower face having diameters ranging between 2-4 mm.
The modified release tablet of the present invention, in addition, also contains other excipients necessary for formulation of the dosage form. For example, these excipients include fillers, binders, lubricants, glidants and the like.
Fillers as used herein include but are not limited to calcium salts such as calcium carbonate, dibasic calcium phosphate, calcium phosphate-tribasic, calcium sulfate and the like; cellulose derivatives such as macrocrystalline cellulose, silicified microcrystalline cellulose and the like; saccharides such as lactose, sucrose, starch, pregelatinized starch, mannitol, sorbitol, lactitol, dextrose, fructose and the like and

mixtures thereof. The fillers are present in a suitable amount from about 10 to 90% w/w. More preferably, from about 30 to 50 % w/w.
First release controlling polymers as used herein include but not limited to methacrylic acid copolymers, sodium alginate, chitosan, ethylcellulose, polyethylene, polypropylene, polystyrene, and polyacetal, polyvinyl alcohol and polyvinyl acetate and the like. The first release controlling polymer is present in a suitable amount from about 1 to 40% w/w. More preferably, in an amount from about 1 to 16 % w/w.
Second release controlling polymers as used herein include but not limited to methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and like. Second release controlling polymer is present in a suitable amount from about 10 to 60% w/w. More preferably, in an amount from about 22 to 42 % w/w.
Solvents used as binder or to prepare binder solution may be selected from water, alcohols, ketones, esters and the like. Preferred solvents are water or propanol either alone or in combination thereof.
Examples of lubricants include, but are not limited to talc, stearates such as magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, canola oil, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycols, sodium lauryl sulfate, sodium stearyl fumarate and the like. The lubricant is present in a suitable amount from about 0.5 to 3 % w/w.
Examples of glidants include, but are not limited to talc, starches, stearic acid, anhydrous colloidal silica and magnesium trisilicate. The lubricant is present in a suitable amount from about 0.1 to 1 % w/w.

The modified release tablets of the present invention may be prepared by any of the techniques well known to the person skilled in the art. For example, the tablets of the present invention can be prepared by any of the tabletting techniques such as wet granulation, dry granulation, direct compression and the like.
For example, the modified release tablets of lamotrigine can be prepared by wet granulation technique.
For example, the lamotrigine modified release tablet according to the first aspect, can be prepared by the process mentioned below;
(a) mixing lamotrigine, one or more filler, optionally the first release controlling polymer;
(b) granulating the blend of step (a) using either solution of the first release controlling polymer or solvent alone;
(c) drying the product of step (b);
(d) blending the product of step (c) with the second release controlling polymer;
(e) optionally lubricating the product of step (d);
(f) compressing the product of step (d) or (e) to obtain the modified release tablet and
(g) optionally coating the product of step (f).
Also for example, the lamotrigine modified release tablet according to the second aspect, can be prepared by the process mentioned below;
(a) mixing lamotrigine, one or more filler, optionally the first release controlling polymer;
(b) granulating the blend of step (a) using either solution of the first release controlling polymer or solvent alone;
(c) drying the product of step (b);

(d) blending the product of step (c) with the second release controlling polymer;
(e) optionally lubricating the product of step (d);
(f) compressing the product of step (d) or (e) to obtain the modified release tablet and
(g) optionally coating the product of step (f).
Film coating can be applied using the materials and methods known to the person skilled in the art. In the preferred embodiment, film coating is applied in the range of 2 to 5 % w/w of the tablet. For example, opadry white (Hypromellose, Titanium dioxide, Talc and Polyethylene glycol) can be used as the film coating.
Dissolution studies of the lamotrigine from the modified release tablets are performed using the parameters mentioned below;

Dissolution media First 2 hr in 0. IN HC1 followed by pH 6.8 phosphate buffer up to 20 hours
Volume 900 ml
Apparatus USP Type I
Speed 100 RPM
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

Sr.
No. Ingredients Quantity

nig/tab
Granulation / Intragranular

1 Lamotrigine 50
2 Dibasic calcium phosphate 124
3 EudragitL100 55 20
4 IPA q.s.
5 Hydroxypropyl Methyl cellulose K 4 M CR (4000 cps) 100
6 Colloidal silicon dioxide (Aerosil 200) 3
7 | Magnesium stearate 3
Core weight 300
Film coating
9 Opadry White* 9
10 Purified water q.s.
Total tablet weight 309
* Opadry white contains Hypromellose, Titanium dioxide, Talc and Polyethylene
glycol
Procedure:
1. Sift Lamotrigine, and Dibasic calcium phosphate through 40# sieve and mix.
2. Dissolve Eudragit L 100 55 in Isopropyl alcohol and granulate the Blend of step 1 in Rapid Mixer granulator and dry.
3. Pass the dried granules through 20#
4. Sift Hydroxypropyl Methyl cellulose K 4 M CR (4000 cps) and colloidal silicon dioxide through 40# and mix it with step 3
5. Sift Magnesium stearate through 60# sieve and mix it with blend of step 3.
6. Compress the lubricated blend in to tablets using suitable punches.
7. Add Opadry white in purified water under stirring.

8. Coat step 6 tablets using suitable coating machine with step 7 coating dispersion.
Dissolution Profile

Time (Hr) % Drug Dissolved
2 14
6 38
12 55
20 82
Example 2

Sr.
No. Ingredients Quantity

mg/tab
Granulation / Intragranular
1 Lamotrigine 50
2 Dibasic calcium phosphate 84
3 Sodium alginate 50
4 Magnesium aluminium silicate 10
5 Purified water q.s.
6 Hydroxypropyl Methyl cellulose K 4 M CR (4000 cps) 100
7 Colloidal silicon dioxide (Aerosil 200) 3
8 Magnesium stearate 3
Core weight 300
Film coating
9 Opadry White* 9

10 Purified water q.s.
Total tablet weight 309
* Opadry white contains Hypromellose, Titanium dioxide, Talc and Polyethylene glycol
Procedure:
1. Sift Lamotrigine, Sodium alginate, Magnesium aluminium silicate and Dibasic calcium phosphate through 40# sieve and mix.
2. Granulate the Blend of step 1 in Rapid Mixer granulator using purified water and dry.
3. Pass the dried granules through 20#
4. Sift Hydroxypropyl Methyl cellulose K 4 M CR (4000 cps) and colloidal silicon dioxide through 40# and mix it with step 3
5. Sift Magnesium stearate through 60# sieve and mix it with blend of step 3.
6. Compress the lubricated blend in to tablets using suitable punches.
7. Add Opadry white in purified water under stirring.
8. Coat step 6 tablets using suitable coating machine with step 7 coating dispersion.
Example 3

Sr.
No. Ingredients Quantity

mg/tab
Granulation / Intragranular
1 Lamotrigine 50
2 Dibasic calcium phosphate 84

3 Sodium alginate 50
4 EudragitL 100 55 10
5 IPA q.s.
6 Hydroxypropyl Methyl cellulose K 4 M CR (4000 cps) 100
7 Colloidal silicon dioxide (Aerosil 200) 3
8 Magnesium stearate 3
Core weight 300
Film coating
9 Opadry White* 9
10 Purified water q.s.
Total tablet weight 309
* Opadry white contains Hypromellose, Titanium dioxide, Talc and Polyethylene glycol
Procedure:
1. Sift Lamotrigine, Sodium alginate and Dibasic calcium phosphate through 40# sieve and mix.
2. Dissolve Eudragit L 100 55 in Isopropyl alcohol and granulate the Blend of step 1 in Rapid Mixer granulator and dry.
3. Pass the dried granules through 20#
4. Sift Hydroxypropyl Methyl cellulose K 4 M CR (4000 cps) and colloidal silicon dioxide through 40# and mix it with step 3
5. Sift Magnesium stearate through 60# sieve and mix it with blend of step 3.
6. Compress the lubricated blend in to tablets using suitable punches.
7. Add Opadry white in purified water under stirring.

8. Coat step 6 tablets using suitable coating machine with step 7 coating dispersion.
Example 4

Sr. No. Ingredients Quantity

mg/tab
Granulation / Intragranular
1 Lamotrigine 50
2 Dibasic calcium phosphate 84
3 Sodium alginate 50
4 Chitosan 10
5 Purified water q.s.
6 Hydroxypropyl Methyl cellulose K4M CR (4000 cps) 100
7 Colloidal silicon dioxide (Aerosil 200) 3
8 Magnesium stearate 3
Core weight 300
Film coating
9 Opadry White* 9
10 Purified water q.s.
Total tablet weight 309
* Opadry white contains Hypromellose, Titanium dioxide, Talc and Polyethylene glycol
Procedure:
1. Sift Lamotrigine, Sodium alginate, chitosan and Dibasic calcium
phosphate through 40# sieve and mix.

2. Granulate the Blend of step 1 in Rapid Mixer granulator using purified water and dry.
3. Pass the dried granules through 20#
4. Sift Hydroxy-propyl Methyl celluloseK4MCR(4000 cps) and colloidal silicon dioxide through 40# and mix it with step 3
5. Sift Magnesium stearate through 60# sieve and mix it with blend of step 3.
6. Compress the lubricated blend in to tablets using suitable punches.
7. Add Opadry white in purified water under stirring.
8. Coat step 6 tablets using suitable coating machine with step 7 coating dispersion.

We Claim
1- A modified release tablet of lamotrigine comprising;
from about 5 to 30 % w/w of lamotrigine;
from about 30 to 50 % w/w of a filler;
from about 1 to 16 % w/w of a first release controlling polymer and
from about 22 to 42 % w/w of a second release controlling polymer.
2. The modified release tablet of lamotrigine according to claim 1, wherein the filler is selected from the group consisting of dibasic calcium phosphate, micro crystalline cellulose, lactose, mannitol, starch, sucrose and mixtures thereof.
3. The modified release tablet of lamotrigine according to claim 1, wherein the first release controlling agent is selected from the group consisting of methacrylic acid copolymers, sodium alginate, chitosan, ethylcellulose, polyethylene, polypropylene, polystyrene, polyacetal, polyvinyl alcohol, polyvinyl acetate and mixtures thereof
4. The modified release tablet of lamotrigine according to claim 1, wherein the second release controlling agent is selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and mixtures thereof.
5. The process for the preparation of the modified release tablet of lamotrigine according to claim 1, comprising the steps of:

(a) mixing lamotrigine, one or more filler, optionally the first release controlling polymer;
(b) granulating the blend of step (a) using either solution of the first release controlling polymer or solvent alone;
(c) (frying the product of step (b);

(d) blending the product of step (c) with the second release controlling polymer;
(e) optionally lubricating the product of step (d);
(f) compressing the product of step (d) or (e) to obtain the modified release tablet and
(g) optionally coating the product of step (i).
6. A modified release tablet of lamotrigine comprising:
from about 5 to 30 % w/w of lamotrigine;
from about 30 to 50 % w/w of a filler;
from about 1 to 16 % w/w of a first release controlling polymer;
from about 22 to 42 % w/w of a second release controlling polymer and
having a dissolution profile such that not more than about 20% of the lamotrigine
dissolves within 2 hours, from about 30 to 50 % of the lamotrigine dissolves within 6
hours, from about 45 to 65 % of the lamotrigine dissolves within 12 hours and not
less than 70 % of the lamotrigine dissolves within 20 hours.
7. The modified release tablet of lamotrigine according to claim 6, wherein the filler is selected from the group consisting of dibasic calcium phosphate, microcrystalline cellulose, lactose, mannitol, starch, sucrose and mixtures thereof.
8. The modified release tablet of lamotrigine according to claim 6, wherein the first release controlling agent is selected from the group consisting of methacrylic acid copolymers, sodium alginate, chitosan, ethylcellulose, polyethylene, polypropylene, polystyrene, polyacetal, polyvinyl alcohol, polyvinyl acetate and mixtures thereof.
9. The modified release tablet of lamotrigine according to claim 6, wherein the second release controlling agent is selected from the group consisting of methylcellulose, hydroxypropy I cellulose, hydroxypropylmethyl cellulose and mixtures thereof.

10. The process for the preparation of the modified release tablet of lamotrigine according to claim 6, comprising the steps of:
(a) mixing lamotrigine, one or more filler, optionally the first release controlling polymer;
(b) granulating the blend of step (a) using either solution of the first release controlling polymer or solvent alone;
(c) drying the product of step (b);
(d) blending the product of step (c) with the second release controlling polymer;
(e) optionally lubricating the product of step (d);
(f) compressing the product of step (d) or (e) to obtain the modified release tablet and
(g) optionally coating the product of step (f).