FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention.- NOVEL COATED EXTENDED RELEASE
PHARMACEUTICAL COMPOSITIONS OF LEVETIRACETAM

2. Applicant(s)
(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 describes the invention

FIELD OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition comprising levetiracetam. In particular, the present invention relates to a novel coated extended release pharmaceutical composition comprising levetiracetam.
BACKGROUND OF THE INVENTION
Levetiracetam is chemically (-)-(S)-o>ethyl-2-oxo-1 -pyrrolidine acetamide having molecular formula C8H14N2O2 and molecular weight of 170.21. It is a white to off white crystalline powder and has an aqueous solubility of 1.04 g/mL. Levetiracetam is indicated as adjunctive therapy in the treatment of 1) partial onset seizures in adults and children 4 years of age and older with epilepsy, 2) myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy and 3) primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy. It is marketed in the United States under the brand name Keppra®as 250 mg, 500 mg, 750 mg and 1000 mg tablets for oral administration. Levetiracetam is a Class I molecule as per the Biopharmaceutics Classification System, since it is highly soluble (1.04 g/ml), highly permeable (F>90%) and more than 85% of the drug is released in 15 minutes in three different pH media. It is not a narrow therapeutic class drug because it has a relatively low order of toxicity and a relatively high therapeutic index. The twice daily dosing regimen for immediate-release levetiracetam tablets is well tolerated but with few incidences of neuropsychiatric adverse events like somnolence, fatigue, coordination difficulties and behavioral abnormalities. These adverse events are proportionate to the drug plasma level and therefore there is a need in the art for an extended release once-daily regimen of levetiracetam. However, the high dose of levetiracetam requires a high amount of rate controlling excipients to be used in the formulation which increases the size of the dosage form thereby affecting patient comfort while swallowing it. Also levetiracetam is a freely water soluble drug and it is known in the art that, it is very difficult to develop a pharmaceutical composition with a sufficiently slow dissolution rate for freely soluble drugs.
Hence there is a need in the art for an extended release pharmaceutical composition of levetiracetam which overcomes these problems. The present
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inventors have now found a novel coated extended release pharmaceutical composition comprising levetiracetam.
OBJECT OF THE INVENTION
An object of the present invention is to provide a novel coated extended release pharmaceutical composition comprising levetiracetam.
SUMMARY OF THE INVENTION
The present invention provides a novel coated extended release pharmaceutical composition comprising levetiracetam.
DETAILED DESCRIPTION OF THE INVENTION
Levetiracetam is a freely soluble drug which makes it difficult to formulate an extended release pharmaceutical composition. The present invention provides a novel coated extended release pharmaceutical composition comprising levetiracetam which uses minimal amount of excipients in the core thereby minimizing the size of the dosage form. The coating exhibits excellent elastic properties thereby avoiding dose dumping and also prevents the burst effect that is normally observed when formulating matrix extended release pharmaceutical compositions of highly soluble drugs like levetiracetam.
The pharmaceutical compositions of the present invention can be any solid coated dosage form for example, but not limited to, granules, pellets and tablets. The core dosage forms can be prepared by any of the means and using excipients well known to the person skilled in the art.
In a preferred embodiment, the novel coated extended release pharmaceutical composition comprising levetiracetam is in the form of a tablet. The core of the coated extended release tablet composition comprising levetiracetam is a conventional core wherein it comprises of levetiracetam and one or more conventional excipients.
The conventional excipients according to present invention are those excipients which are commonly used in the art and known to any person skilled in the art.
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These include, but are not limited to, fillers, binders, lubricants, glidants and the
like. Examples of fillers or diluents include, but are not limited to, corn starch,
lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dextrose, lactose,
sorbitol, dicalcium phosphate, calcium carbonate, sodium chloride, maltitol, xylitol
and the like. Examples of binders include, but are not limited to, methylcellulose,
hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,
sodium carboxymethylcellulose, polyvinylpyrrolidone, sucrose, starch,
ethylcellulose, acacia, gelatin, gum arabic, copovidone, polyvinyl alcohol, pullulan, agar, tragacanth, sodium alginate, alginic acid and the like. Examples of lubricants and glidants include, but are not limited, to stearates and stearic acid, silicone fluid, talc, waxes, oils, colloidal silicon dioxide, sodium stearyl fumarate, polyethylene glycols, hydrogenated vegetable oil, glyceryl behenate, magnesium trisilicate, microcrystalline wax, yellow beeswax, white beeswax and the like.
It should be appreciated that there is considerable overlap between the above-
listed additives in common usage, since a given additive is often classified
differently by different practitioners in the field, or is commonly used for any of
several different functions. Thus, the above-listed additives should be taken as
merely exemplary, and not
limiting, of the types of additives that can be included in compositions of the present invention. One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden. The amount of each type of additive employed may vary within ranges conventional in the art.
In a preferred embodiment, the core of the present invention is formulated with levetiracetam, a binder and a lubricant. In a more preferred embodiment, the core of the present invention is formulated with levetiracetam, polyvinyl pyrrolidone as the binder and magnesium stearate as the lubricant.
The core tablets comprising levetiracetam can be prepared by processes well known to those of skill in the art. For example, core tablets can be prepared by wet granulation or dry granulation. In a preferred embodiment, the core tablets comprising levetiracetam are prepared by the process of aqueous wet granulation.
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The core dosage forms comprising levetiracetam are then coated with a suitable rate controlling composition to control the release rate of levetiracetam.
In a preferred embodiment, core tablets comprising levetiracetam are subsequently coated with a coating composition which controls the release of levetiracetam.
In a preferred embodiment, the coating composition comprises a water insoluble polymer. Examples of water insoluble polymers include, but are not limited to cellulose acetate, ethylcellulose, ammoniomethacrylate copolymers for example marketed under the brand name of Eudragit® RL, aminoalkyl methacrylate copolymers, for example, marketed under the brand name of Eudragit® RS, polyvinyl acetate for example marketed under the brand name Kollicoat® SR and the like. In a still preferred embodiment, the water insoluble polymer used in the present invention is ethyl cellulose.
In another preferred embodiment, the coating composition comprises a water insoluble polymer along with a water soluble polymer. Examples of water-soluble polymers include, but are not limited to sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose, vinylpyrrolidone / vinyl acetate copolymer for example marketed as Plasdone® S-630, polyvinyl alcohol and the like.
In yet another preferred embodiment, the coating composition comprises water insoluble polymer along with a pore forming agent. Examples of pore forming agent include, but are not limited to sucrose, xylitol, mannitol, sorbitol, glucose, fructose, galactose, maititol, lactose, maltodextrin, citric acid or salts, aminoacids or salt thereof, inorganic salts such as sodium carbonate, sodium bicarbonate, potassium chloride and sodium chloride, polyvinyl alcohol, sodium carboxymethyl cellulose, crospovidone and the like.
The coating composition may optionally contain other excipients which include, but are not limited to plasticizers, opacifiers, coloring agents and antifoaming agents. Examples of plasticizers used include, but are not limited to citrates such
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as triethyl citrate, acetyl tributyl citrate, phthalates, dibutyl sebacate, triacetin, polyethylene glycol and the like. Examples of opacifying agents and coloring agents include, but are not limited to titanium dioxide, talc, aluminum lake dyes, insoluble pigments, water-soluble dyes and the like. Antifoaming agents include, but are not limited to silicone, simethicone and the like.
The core tablets can be coated using any of the techniques well known to the persons skilled in the art. In a preferred embodiment, coating of core tablets of levetiracetam is carried out by spraying a non - aqueous dispersion of the coating composition excipients onto a core tablet bed in a perforated coating pan.
The following is a representative of the present invention, but should not be considered as limiting the invention.
Example 1

Ingredients Weight (mg)
Levetiracetam 500.0
Polyvinyl pyrrolidone K 30 10.0
Purified water q.s
Magnesium stearate 5.1
Total 515.1
Procedure:
Levetiracetam is granulated with aqueous solution of polyvinyl pyrrolidone and dried. The granules obtained are sifted, lubricated with magnesium stearate and compressed into tablets using 16.5x8 mm capsule shape punches to give a tablet of 515.1 mg.
The core is then coated with the following coating solution

Ingredients %
Ethyl cellulose (Ethocel, 7cps) 65
Polyethylene glycol 35
Total 100
Procedure:
Ethyl cellulose is dispersed in isopropyl alcohol and kept for stirring for one hour. Dichloro methane is then added to this dispersion. Polyethylene glycol is
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dissolved in water and added to the ethyl cellulose dispersion to make the coating solution which is then sprayed onto the tablets upto a weight build up of the dry coating up to 6% w/w of the tablet weight.
The coated tablets were subjected to dissolution in 900ml_ of pH 6.8 buffer in USP type I (basket) apparatus at 100 rpm. The results are tabulated as follows.

Time (hrs) Example 1
1 9
2 19
4 39
6 55
8 69
10 81
12 88
The above data shows that the coated tablets of the present invention shows satisfactory dissolution profile thereby improving patient compliance.
Dated this 21st day of September 2007

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