FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
TOPICAL DOSAGE FORMS OF LAMOTRIGINE"
We, TORRENT PHARMACEUTICALS LIMITED, of Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad - 380 009, Gujarat, India.

The following specification particularly describes the nature of the invention and the manner in which it is performed:

TOPICAL DOSAGE FORMS OF LAMOTRIGINE
Field of Invention
The present invention relates to a topical dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof for prolonged release. This invention further relates to a process for preparing the said dosage form(s).
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)-1,2,4^ triazine, its molecular formula is C9H7N5C12. It is disclosed in EP-A-0021121.
Lamotrigine has been used to treat over a million patients worldwide, including about 4000 adults and over 1000 children in clinical trials. Extensive experience with lamotrigine has indicated that it may be an effective when other anticonvulsant drugs have failed. It is a valuable broad-spectrum drug that is well tolerated and has few adverse effects apart from skin rash (Besag FMC, CNS Drugs 2000) . Pharmacokinetically, the plasma concentrations of lamotrigine vary linearly with the dose (Ramsay RE, 1991). Over the range 50 to 400mg as a single dose, Cmax increases proportionately from 0.58 to 4.63 |ag/ml, as does the AUC (29.9 to 211.9 mg/L.h). Acute and chronic studies in humans have suggested that lamotrigine levels of 1-3 (ig/ml are effective in controlling seizures (Betts et al, 1991) .
W096/17611 discloses the various powder form formulations of
lamotrigine and their compositions for rapid release of
lamotrigine. Processes of preparing such dosage forms are
also disclosed.
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US patent 5,556,639 discloses a water dispersible tablet comprising lamotrigine, swellable clay and an additional disintegrating agent. The process for preparing the water dispersible tablet is also disclosed.
WO01/80824A2 teaches the art of preparing a timed-release dosage form of low dose drugs in which the drug core contains hydrophilic polymer to form a matrix that is then coated with a water insoluble polymer membrane.
US2004/0043996A1 discloses rapidly disintegrating multiparticulate controlled release formulations of lamotrigine having an improved pharmacokinetic profile and improved patient compliance; and process of preparing the formulations. It provides better control of blood plasma levels then conventional tablet formulations that is administered once or more times a day.
Above prior art discloses many different types of oral dosage forms of lamotrigine but topical dosage forms are not disclosed. Thus, there exists a need for topical dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof.
The oral administration of solid dosage forms, for example tablets, capsules, often presents ingestion problems for the patient, especially in case of children or old people. In order to get around this problem other forms of pharmaceutical formulations are resorted to, for example chewable tablets, dispersible tablets and monodose sachets, the contents of which are to be dissolved or suspended in water and taken orally. But even these dosage forms cannot be given to
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debilitated patients, patients who have difficulty swallowing solids, elderly patients or patients who are not willing to take medication;
This necessitates the need to develop topical dosage form(s) of lamotrigine for prolonged release. Formulations according to the aspect of the- present invention are particularly useful in administration of medications to individuals who cannot or will not chew or swallow, such as debilitated patients, patients who have difficulty swallowing solids, elderly patients or patients who are not willing to take medication.
Summary of the invention
The object of the present invention is to provide topical dosage form of lamotrigine or its pharmaceutically acceptable salts thereof for prolonged release.
Another object of the present invention is to provide a process for preparation of said topical dosage form of lamotrigine or its pharmaceutically acceptable salts thereof.
The general aspect of the present invention relates to a topical dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof for prolonged release.
Another aspect of present invention relates to a process for preparing the said dosage form(s).
Detailed Description
Prolonged release refers to the release of an agent such as a drug from a composition or dosage form in which the agent is released according to a desired profile over an extended period of time. Prolonged release profiles include, for example, sustained release, controlled release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release
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compositions allow delivery of an agent to a subject over an extended period of time according to predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic or diagnostic response as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
Prolonged release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of agents, such as drugs, medicaments, active agents, diagnostic agents, or any substance to be internally administered to an animal, including humans. A prolonged release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bio-availability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as a high initial release rate and, if undesired, uneven blood or tissue levels.
The term 'topical dosage forms' here refers to dosage forms applied over the skin of the mammals for systemic delivery of active ingredients.
The invention provides topical dosage form(s) of lamotrigine or salts of lamotrigine for prolonged release.
The topical dosage form(s) comprises lamotrigine or pharmaceutically acceptable salts thereof along with commonly used water soluble and/or water insoluble and/or water dispersible and/or water disintegrable excipients.
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Further, lamotrigine or its pharmaceutically acceptable salts thereof, where applicable, may be present either in the form of one substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof.
If desired the compositions of this invention may also contain other active ingredient(s) in a form suitable for topical dosage forms.
The topical dosage forms can be in the form of semisolid
dosage forms like gel, lotion, ointment or cream, liquid
dosage forms like spray, patches like transdermal drug
delivery systems.
One of the embodiment as per the instant invention is semisolid dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof for prolonged release. These dosage forms are defined in detail.
An ointment is classified as any semisolid containing fatty material and intended for external application. It may use any of the following ointment bases- hydrocarbon base, absorption base, water removable base or water soluble base.
Gels- The common characteristic of all gels is that they contain continuous structure that provide solid like structure. Depending on the constituents the gel may be clear or opaque, and be polar, hydro alcoholic or nonpolar.
Creams- these are emulsion based formulations. These are two phase preparations in which one phase is finely dispersed in
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other. The dispersed phase can have either a hydrophobic based (oil in water creams), or aqueous based (water in oil creams).
Transdermal patches can be of following types- 1) membrane moderated transdermal drug delivery system, 2) adhesive dispersion transdermal drug delivery system, 3) matrix diffusion controlled transdermal drug delivery system, or 4) microreservoir dissolution controlled transdermal drug delivery system.
Dosage forms as per the instant invention may comprise following pharmaceutical^ acceptable excipients-
Pblymeric thickeners can be selected from but not limited to gums like acacia, alginates, carageenah, chitosan, collagen, tragacahth, or xanthan; celluloses like sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropyimethyl cellulose; acrylic acids like carbomers or polycarbophil; colloidal solids like silica, clays or microcrystallihe cellulose; hydrogels like polyvinyl alcohol, polyvinlpyrrolidone; thermoreversible polymers like poloxamers.
Excipients of oily phase can be selected from but not limited to mineral oil, white soft paraffin, yellow soft paraffin, beeswax, stearyl alcohol, cetyl alcohol, cetosteryl alcohol, stearic acid, oleic acid, isopropyl myristate, isopropyl palmitate, castor oil, canola oil, cottonseed oil, jojoba oil, arachis oil, lanolin and its derivatives, silicone oils.
Surfactants can be selected from but not limited to non-ionic surfactants like sorbitan esters, polysorbates, polyoxyethylene alkyl ethers, polyoxyethylene aryl esters, polyoxyethylene alkyl esters, glycerol esters, cholesterol;
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anionic surfactants like sodium dodecyl sulfate; cationic surfactants like cetrimide, benzalkonium chloride; fatty acid esters and alcohol.
Solvents can be selected from but not limited to polar solvents like water, propylene glycol, glycerol, sorbital, ethanol, industrial methylated spirit, polyethylene glycols, propylene carbonate, triacetin; non-polar solvents like isopropyl alcohol, medium chain triglycerides, acetone; miscellaneous solvents like alkyl methyl sulfoxides, pyrrolidones, laurocapron, tetrahydrofurfuryl alcohol.
Permeability enhancers can be selected from but not limited to solvents and surfactants described above and materials like urea, N,N-dimethyl-m-toluamide, calcium thioglycolate, anticholinergic agents. Permeability through skin of lamotrigine or its salt can also be increased by iontophoresis, which is a process which causes increased penetration of solute molecules into tissues by the use of an applied current through the tissue.
Preservatives can be selected from but not limited to antimicrobial agents like benzalalkoniam chloride, benzoic acid, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, imidazolidinyl urea, paraben esters, phenol, phenoxyethanol, potassium sorbate, sorbic acid; antioxidants like alfa-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydrxytoluene, sodium ascorbate, sodium metabisulphite; chelating agents like citric acid, edetic acid.
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pH adjusters can be selected from but not limited to diethanolamine, lactic acid, monoethanolamine, sodium hydroxide, triethalonamine.
The amount of auxiliary pharmaceutical excipient(s) like polymers, oily phase, surfactants, solvents, Permeability enhancers/ preservatives, pH adjusters to be used be determined based on individual functional category of excipient and can vary from 0.1%w/w to 90 % w/w of total weight of the dosage form.
Transdermal patches have impermeable backing membranes, adhesive layers, and polymeric membranes.
According to present invention dosage form comprises lamotrigine or its pharmaceutically acceptable salts at a concentration of about 0.1%w/w to about 50% w/w.
Semisolid dosage forms as described in the instant invention can be manufactured by using suitable homogenizers, stirrers and melting, colloidal mills and mixing vessels.
Spray dosage forms can be manufactured by use of suitable stirrers and pressurized cans along with suitable propellants and nozzles.
Transdermal patches are manufactured by using suitable layering machines to make layers of uniform thickness and placing the layers in proper order.
The present invention has been described by way of example only, and it is to be recognized that modifications thereto which fall within the scope and spirit of the appended claims,
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and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention.
Examples:
Example-1 Paste Formulation

ingredients Quantity (%w/w)
Lamotrigine (micronized) 10
Starch 20
White soft Paraffin wax 70
Melt the wax i-n jacketed vessel and melt it using minimum heat, slowly add blend of Lamotrigine and starch to molten wax while stirring. Cool the paste slowly while stirring and
transfer the semisolid mass in suitable container.
Example 2 Ointment Formulation

Ingredients Quantity (%w/w)
Lamotrigine (micronized) 5
PEG 4000 40
PEG 400 45
Oleic acid 10
Add PEG 4000, Oleic acid and PEG 400 in jacketed vessel and melt blend using minimum heat, slowly add Lamotrigine to molten material while stirring. Cool the ointment slowly while stirring and transfer the semisolid mass in suitable container.
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I Claim:
1. A pharmaceutical composition for topical delivery comprising a pharmaceutically effective amount of lamotrigine or its pharmaceutically acceptable salts thereof.
2. The pharmaceutical composition according to claim 1 further comprises one or more pharmaceutically acceptable excipient.
3. The pharmaceutical composition according to claim 1, wherein the dosage form is a semisolid dosage form or a liquid dosage form or a txansdermal patch.
4. The pharmaceutical composition according to claim 3, wherein the dosage form is gel, cream, ointment, lotion or spray.
5. The pharmaceutical composition according to claim 1 is a prolonged release dosage form.
6. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable excipient may be selected from the group comprising of water soluble or water insoluble excipient.
7. The pharmaceutical composition according to claim 1, wherein lamotrigine comprises from about 0.1% to about 50% by weight of said composition.
8. A topical pharmaceutical composition as defined herein, substantially described particularly with reference to the foregoing example.

Abstract
Present invention relates to topical dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof for prolonged release; and process of preparing the said topical dosage form(s).
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