COMPLATE AFTER PROVISIONAL
LEFT ON 28 MAR 2006

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
"INJECTABLE 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:

INJECTABLE DOSAGE FORMS OF LAMOTRIGINE
Field of Invention
The present invention relates to ah Injectable dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof for immediate and/or 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 C9H7N5Cl2. 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 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
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and chronic studies in humans have suggested that lamotrigine levels of 1-3 jig/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.
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.
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EP247892 discloses salts of lamotrigine and also its sterile aqueous pharmaceutical composition but it essentially requires specialized salt i.e. isethionate salt of lamotrigine to prepare this formulation.
Above prior art primarily discloses different types of oral dosage forms of lamotrigine. But there remains a need for Injectable dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof for immediate and/or prolonged release, which avoids any complex procedures.
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 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 injectable dosage form(s) of lamotrigine either for immediate release or prolonged release. Immediate release injectable dosage
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form(s) can be administered once or twice daily to improve the patient compliance and prolonged release dosage forms can be administered for longer duration like for seven days or more.
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 an injectable dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide an injectable dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof, which is an immediate release dosage form.
Yet another object of the present invention is to provide an injectable dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof, which is a prolonged release dosage form.
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Further object of the present invention is to provide a process for preparing an injectable dosage forih(s) of lamotrigine or its pharmaceutically acceptable salts thereof.
The present invention relates to an Injectable dosage form(s) of lamotrigine or its pharmaceutically acceptable salts thereof for immediate and/or prolonged release. This invention further 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 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
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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 bioavailability, 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 'injectable dosage forms' here refers to dosage forms administered into mammals through intramuscular route, intravenous route, intraperitonial route, subcutaneous route or surgery.
The invention provides an injectable dosage form(s) Of lamotrigine or pharmaceutically acceptable salts of lamotrigine for immediate and/or prolonged release
The injectable dosage form(s) comprises lamotrigine or its pharmaceutically acceptable salts thereof along with
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commonly used water soluble and/or water insoluble and/or water dispersible and/or water disintegrable excipients.
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 injection.
The immediate release injectable dosage forms can be in the form of solution containing vehicle, it can also be in the form of powder which is dissolved in vehicle prior to use. Alternatively it can be in the form of emulsion or suspension.
The immediate release injectable dosage forms can be a small volume parentral formulation filled in vial or ampule or it can be a large volume parentral formulation filled in infusion bottles.
When used herein the term "vehicle" means a pharmaceutically acceptable liquid which consists of water or other solvent and/or combination thereof to which has been added small amounts of conventional materials such as (a) ionic salts to adjust the tonicity
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of the final solution, (b) buffers, (c) preservatives or (d) other conventional materials used in injectable compositions. Particularly suitable vehicles for addition to compositions of this invention are water and saline solutions. A preferred vehicle for addition to the compositions of this invention is water for injection.
The prolonged release injectable dosage forms can be in the form of solution, suspension, gel, emulsion, microsphere, microcapsule, liposomes, nanoparticles or an implantable device.
The prolonged release dosage form of lamotrigine or its pharmaceutically acceptable salts thereof may comprise biocompatible materials selected from the following but not limited to suspending medium, oils, gelling agents, polymers and/or combination thereof.
The prolonged release dosage forms may also comprise other pharmaceutically acceptable excipients.
The suspending media for prolonged release formulations can be selected from but not limited to triglycerides with monocarboxylic and dicarboxylic acids of chain lengths C6 to C2o in saturated or unsaturated, optionally also hydroxylated, form (especially oily triglycerides, such as viscoleo, and cottonseed, groundnut, maize germs, almond, olive, castor and sesame oil). Also suitable are
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esters of monohydric or polyhydric alcohols, ' for example propylene glycol, butanediols and higher alkanols, alkanediols, of chain length C2-C30 with the abovementioned acid components (the following may be mentioned as examples: ethyl oleate, isopropyl myristate and isopropyl stearate) and furthermore benzylbenzoate and glycofurate.
In place of or in addition to suitable esters, the suspending medium can also contain ethers, alcohols and amides (.saturated and unsaturated, aliphatic or aromatic), and the amides can also be cyclised, for example 2-pyrrolidone (as a monomer or polymer) which are toxicologically innocuous.
Few examples of suspending agents are viscoleo, isopropyl myristate, ethyl oleate, castor oil, sesame oil, arachis oil, cottonseed oil, almond oil, olive oil, neatsfoot oil, neutral oil and maize oil.
The sterile solutions or suspensions for injection purposes can also contain gelling agents, for example aluminum mono-fatty acid esters, for example, aluminum monostearate, aluminum mono-oleate, aluminum monolaurate, aluminum monomyristate, aluminum monopalmitate, and the like.
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Where appropriate, one or more preservatives can be used, for example benzyl alcohol, phenylethyl alcohol, chlorobutanol and chlorocresol. Where appropriate, one or more antioxidants are added to the suspending medium, for example, tocopherols, noridhydroguaiaretic acid, 2- and S'-tert butyl-4-hydroxy-amide, ascorbic acid, propyl, octyl, dodecyl-gallate and butylhydroxytoluene.
Where appropriate, it is also possible for the prolonged release dosage forms to exist initially in a separated form (active compound/dissolving or suspending medium) and to be mixed before use (for example dry ampoules).
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.
The preparation of the formulations described above is carried out by vigorously mixing the active compound with the suspending medium.
Solutions are normally prepared by dissolving the active compounds and auxiliaries, which are sterile or have a low organism count in the sterilised solvent. The solution is then sterilised by filtration and filled into ampoules.
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The suspensions are prepared from sterile active compounds and auxiliaries under aseptic conditions. Where appropriate, these operations (with solution and suspension) are carried out under protective gas^ and heat sterilisation is possible in particular cases.
Liposomes can be oligolamellar, unilamellar or multilamellar vesicles and can be manufactured by various methods like dehydration or rehydration, removal of lipid solubilization agent or reverse phase evaporation.
Nanoparticles can be manufactured by various methods like insitu polymerization, emulsification polymerization or dispersion polymerization.
Microspheres and microcapsules can be manufactured by various methods like spray drying, fluid bed coating, phase separation, solvent evaporation, solvent extraction or cryogenic solvent extraction.
The pharmaceutical dosage form(s) of the present invention may conveniently be prepared and sterilized by any of the methods well known in the pharmaceutical art, for example, as described in Remmington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 1970.
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The amount of auxiliary pharmaceutical excipient(s) 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.
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, and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention.
Examples 1:

Ingredient Quantity/ml
Lamotrigine (micronized) 5 mg
Absolute ethanal q.s.to 1 ml
PEG 400 . 5 %w/v
pH modifier solution q; s.
Mix PEG 400 and absolute ethanol in 1:2 %w/w ratio, add Lamotrigine into it and dissolve with the help of pH modifier solution. Adjust the volume with absolute alcohol. Filter the solution through 0.2 micron filter and fill in 2 ml clear glass ampoules.
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I Claim:
1. An injectable pharmaceutical dosage form comprising a pharmaceutically effective amount of lamotrigine or its pharmaceutically acceptable salts thereof.
2. The dosage form according to claim 1 further comprises one or more pharmaceutically acceptable excipient.
3. The dosage form according to claim 1 is an immediate release dosage form.
4. The dosage form according to claim 1 is a prolonged release dosage form.
5. The dosage form according to claim 1 is in a form of solution, suspension, gel, emulsion, microsphere, microcapsule, liposomes, nanoparticles or an implantable device
6. The dosage form according to claim 1, wherein the dosage form is administered intramuscularly, intravenously, intraperitonially, subcutaneously or by surgery.
7. The dosage form according to claim 1, wherein the concentration of lamotrigine comprises about 0.1%w/w to about 50% w/w.
8. The dosage form according to claim 2 wherein one or more pharmaceutically acceptable excipient is selected from the group comprising vehicles, diluents, gelling agents, suspending agents,
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surfactants, solubilizers, preservatives or antioxidants.
9. An injectable composition as defined herein, substantially described particularly with reference to the foregoing example.

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Abstract
Injectable dosage form(s) of lamotrigine or its
pharmaceutically acceptable salts thereof for immediate and/or prolonged release; and process of preparing the said injectable dosage form(s).
2 8 MAR 2006
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