FORM 2
THE PATENT ACT 1970
(39 of 1970)&The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS OF ENTACAPONE WITH
WETTING AGENT
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising
entacapone or salt thereof along with wetting agent and one or more
pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. Description
The present invention provides a pharmaceutical composition comprising entacapone or salt thereof along with wetting agent and one or more pharmaceutically acceptable excipients.
Entacapone, an inhibitor of catechol-0-methyltransferase (COMT), is a nitro-catechol-structured compound with a molecular weight of 305.3 used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,NHdiethyl-2-propenamide. Its empirical formula is C14H15N3O5, and its structural formula is:

US Patent No 4,963,590 and 5,112,861 provide pharmaceutical composition and method of treatment of Parkinson's disease using entacapone or salt thereof.
US Patent No 6,599,530 provides oral compacted compositions of entacapone or salt thereof with pharmaceutically acceptable excipients.
US Patent No 5,446,194 describe entacapone or pharmaceutically acceptable salts or esters thereof.
US Patent No. 5,135,950 and European equivalent EP 426468B1 provides polymorphic form a of entacapone.
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Entacapone being a BCS (Biopharmaceutics Classification system) class IV drug, It poses problems of low solubility, low dissolution rate and hence \cw bioavailability.
The present inventors while working on the entacapone formulation have noticed that use of a wetting agent reduces the surface tension of water and therefore increases adhesion of water to the entacapone surface. Improved wettability is observed as a lower contact angle between the entacapone and water, which in turn results in increased solubility, significant increase in percent drug release of entacapone and hence improved bioavailability.
One of the aspects of the present invention provides a phamraceutical composition comprising entacapone or salt thereof along with wetting agent and one or more pharmaceutically acceptable excipients.
The pharmaceutical composition of the present invention can be present in the form of tablet, capsule, powder, disc, caplet, granules, pellets and other dosage forms suitable for oral administration.
The "wetting agent" of the present invention may be one or more of anionic, cationic or non-ionic surface-active agents or surfactants. Wetting agent may further include one or more of gum acacia, guar gum, xanthan gum, kaolin, bentonite, hectorite, tragacanth, sodium alginate, pectin and the like.
Suitable anionic surfactants may be one or more of sodium dodecyl sulfate (SDS), sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates, sodium stearate, potassium stearate, sodium oleate and the like.
Suitable cationic surfactants may be one or more of benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, benzethonium chloride, cetrlmide and the like.
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Suitable non-ionic surfactants may be one or more of polyoxyethylene sorbitan fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of ^tty alcohols and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, cholesterol and the like.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include one or more of fillers, lubricants, disintegrants, and glidants.
Suitable filler may be one or more of microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricant may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
Suitable glidant may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
The pharmaceutical composition of the present invention can be prepared by mixing entacapone with wetting agent and other excipients, compacting the pre-mix through compactor, breaking the flakes into granules of desired size. The compacting and breaking can be proceeded one or more times. The granules are then mixed with lubricant, disintegrant, glidant or a mixture thereof, and the mixture is finally compressed.
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While the present invention has been described in temrs 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.
Example-1
Table-1 Composition of Entacapone Tablets (200mg)

S.No. Ingredients Qty/tablet (%w/w)
1 Entacapone 15-50
2 Microcrystalllne cellulose 20-65
3 Mannitol 5-50
4 Sodium dodecyl sulfate 0.5-6
4 Croscarmellose sodium 2-5
5 Colloidal silicon dioxide 0.5-2
6 Sodium starch glycollate 2-12
7 Hydrogenated vegetable oil 0.5-6
8 Talc 0.5-2
9 Magnesium stearate 0.5-2
10 Opadry 0.5-5
Procedure: Entacapone, mannitol and sodium dodecyl sulfate are co-sifted and mixed with microcrystaliine cellulose, croscarmellose sodium and colloidal silicon dioxide in double cone blender. Magnesium stearate is mixed with above pre-mix in double cone blender. Half of this mixture is compacted through roll compactor and sizing is carried out to break flakes in to granules using multi mill. Remaining half of the mixture is also compacted through roll compactor along with fines of first half and sizing is done using multimill to obtain granules of desired size. Granules are mixed with hydrogenated vegetable oil, sodium starch glycollate, colloidal silicon dioxide and talc. Then granules are lubricated with magnesium stearate and final blend is compressed in to tablets using suitable tooling and coated with aqueous dispersion of Opadry.
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WE CLAIM:
1) A pharmaceutical composition comprising entacapone or salt thereof along with wetting agent and one or more pharmaceutically acceptable excipients.
2) The pharmaceutical composition of claim 1, wherein the wetting agent is a surface-active agent.
3) The pharmnaceutical composition of claim 2, wherein the surface-active agent is anionic, cationic, or non-ionic.
4) The surface active agent of claim 3, wherein the anionic surface active agent comprises one or more of sodium dodecyl sulfate, sodium laurate, dialkylsodium sulfosuccinates, sodium stearate, potassium stearate, sodium oleate, and mixtures thereof.
5) The surface active agent of claim 3, wherein the cationic surface active agent comprises one or more of benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, benzethonium chloride, cetrimide, and mixtures thereof.
6) The surface-active agent of claim 3, where in the non-ionic surface-active agent comprises one or more of polyoxyethylene sorbitan fatty acid esters, fatty alcohols, glyceryl esters, and mixtures thereof.
7) The pharmaceutical composition of claim 1, wherein the wetting agent comprises one or more of gum acacia, guar gum, xanthan gum, kaolin,
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bentonite, hectorite, tragacanth, sodium alginate, pectin, and mixtures thereof.
8) The pharmaceutical composition of claim 1 comprises one or more of a tablet, capsules, powder, disc, caplet, granules, pellets and other dosage forms suitable for oral administration.
9) The pharmaceutical composition of claim 1, wherein pharmaceutically acceptable excipients comprises one or more of fillers, lubricants, disintegrants, and glidants.

Dated this 19th day of January, 2007

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