FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
STABLE PHARMACEUTICAL COMPOSITION OF LAMOTRIGINE AND PROCESS FOR THEIR PREPARATION"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:
1

ABSTRACT
The technical field of present invention relates to a stable pharmaceutical composition of lamotrigine and process for the preparation thereof, wherein the formulation is essentially devoid of a binder, especially povidone.
The invention has been developed primarily for use as a solid oral dosage form and will be described hereinafter with reference to this application.
BACKGROUND OF THE INVENTION
Lamotrigine, an antiepileptic drug of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is indicated as adjunctive therapy for the treatment of partial seizures in adults with epilepsy. The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. However, one proposed mechanism of action of lamotrigine , the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
2

DESCRIPTION OF THE PRIOR ART:
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
The various compositions of lamotrigine can be known from the prior patents as follows. For example; Pat. No. WO2004/082587A2, Mehta Kamal relates to a stable pharmaceutical composition of lamotrigine and pharmaceutically acceptable acid addition salts thereof. The invention also relates to a process for the preparation of such a composition. The pharmaceutical composition includes: (a) from about 0.1% to about 50 % by weight of lamotrigine or acid addition salt thereof; (b) from about 15.5% to about 70% by weight of microcrystalline cellulose; (c) from about 0.1% to about 14.5% by weight of sodium starch glycolate; and (d) from about 0.1% to about 4.5% by weight of polyvinylpyrrolidone. This formulation includes povidone as a binder, which hardens the tablet after certain period of storage. This may be due to the water gaining ability of povidone at 50% RH up to an extent of 10% weight.
For example; Pat. No. US5698226, Fielden Krystyna Elzbieta relates to a water-dispersible tablet comprises an active compound such as acyclovir or lamotrigine and a dispersing agent. The dispersing agent is swellable clay such as a smectite, e.g. Veegum For bentonite, and is generally present within the granules of the tablet to provide a tablet, which is capable of dispersing in water within 3 minutes to provide a dispersion,
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which will pass through a 710 mu m sieve. The tablet can be optionally film-coated in which case the dispersion time is less than 5 minutes.
While the lamotrigine formulations disclosed in the above patents is suitable for a commercial product, but they suffer from some drawbacks in terms of stability.
A great deal of research has been done in this area to incorporate lamotrigine with other pharmaceutically accepted excipients but it always results in stability problems.
To overcome the problems associated with the prior arts, an intensive and thorough research resulted in providing the most advantageous solid formulation in terms of both stability and processing characteristics. This includes lamotrigine along with pregelatinised starch to overcome the shortcomings of povidone or any binder for that matter which retards disintegration & decrease solubility of drug as well.
OBJECT OF THE INVENTION
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
It is an object of the invention in its preferred form to provide stable solid dosage forms of lamotrigine and process for the preparation thereof, wherein the formulation is essentially devoid of a binder.
4

SUMMARY OF THE INVENTION
The present invention relates to stable solid dosage forms of lamotrigine essentially devoid of a binder.
Another aspect of the invention includes use of pregelatinised starch to improve the processing profile and stability of the formulation.
Pregel starch exhibits a dual functionality in formulation. As a disintegrant, it produces tablet of similar hardness to that of povidone, but, with significantly faster disintegration properties compared to the povidone formulation.
It also exhibits self-lubricating properties.
Thus, with the use of Pregel starch in the formulation of Lamotrigine Tablet, a good hardness, less disintegration time, better dissolution rate are found along with better bioavailability. The in-vitro study also show a similarity with the reference sample under study.
Unlike povidone, storing for a longer period of time, tablet containing pregel starch showed no alteration in hardness, DT & dissolution profile.
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The term "stable" as used herein refers to chemical stability of lamotrigine in solid dosage forms wherein there is no change in assay values, impurities percentages and dissolution data when kept at 40°c /75% RH for 3 months.
The dosage form may include one or more pharmaceutical excipients selected from diluents, desiccants, disintegrants, coloring agents, flavoring agents, surfactants, lubricants/glidants, plasticizers and preservatives.
Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
Exemplary pharmaceutical diluents include monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof, for example, starch, mannitol, lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol, lactitol, fructose, and mixtures thereof dextrates, dextrins, dextrose excipients, fructose, kaolin, and other polyols, starch pregelatinized, sugar compressible sugar confectioners, and the like, dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate or mixtures thereof
Examples of lubricants and glidants include colloidal silicon dioxide, magnesium stearate, and colloidal anhydrous silica, stearic acid, magnesium stearate, and calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, fumarates and the like. Examples of coloring agents include any FDA approved colors for oral use.
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The following example illustrates the invention:

S.N Ingredients %w/w
1 Lamotrigine 31.25
2 Lactose mono -hydrate (milled) 7.5
3 Microcrystalline cellulose 22.5
4 Yellow Ferric oxide 0.125
6 SSG 5
7 Pregel starch 5
8 Purified Water Qs
9 SSG 10
10 Microcrystalline cellulose 17.375
11 Magnesium stearate 1.25
The stable lamotrigine tablets are prepared by a process as follows:
1. Lamotrigine was mixed with microcrystalline cellulose, sodium starch glycolate, yellow ferric oxide, lactose and pregel starch.
2. This premix was then granulated with purified water.
3. The wet mass was then screened to obtain wet granules & then the granules were dried, screened (or directly the wet mass is dried, screened) and mixed with extra granular excipients such as filler, disintegrant, lubricant etc.
4. The resultant blend was then compressed into tablets using appropriate tooling.
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The tablet & granule parameters of Lamotrigine 25mg Tablet are as follows:

S.No Parameters Results
1 Hardness 25-100 N
2 CI of Blend (Flow Index) 22.08%
DISSOLUTION PROFILE:
The dissolution profiles of the tablets in are determined under the following dissolution conditions:

1. Type of Apparatus
2. Rotation speed
3. Dissolution Medium composition
4. Dissolution medium volume
5. Time Points

The Paddle
50rpm
0.l N Hcl
900ml
5,10,15 & 30 minutes

The results are presented below as % of the total lamotrigine in the tablet.

Time Points % Dissolution
Unit-I Unit-H Unit ni Unit-IV Unit-V Unit-VI Mean %RSD
5 mins 98.1 94.2 97.5 97.5 96.7 98.8 97.10% 1.65
10 mins 101.6 97.9 97.9 99.2 98.8 100.1 99.20% 1.44
15 mins 101.1 98.4 98.3 99.5 99.5 100.1 99.50% 1.07
30mins 101.2 99.4 98.0 99.1 100.2 100.5 99.70% 1.14
Dated this the 20th day of 2007

To:

The Controller of Patents, Patent Office, Mumbai 400 037