FORM 2
THE PATENT ACT 1970
(39 of 1970)&The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS OF ENTACAPONE
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 cyclodextrins or derivatives thereof and one or more pharmaceutically accept excipients

The following specification particularly describes the invention and the mannerin 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 cyclodextrins or derivatives thereof and one or more pharmaceutically acceptable excipients.
Entacapone, an inhibitor of catechol-O-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.N-diethyl-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 low bioavailability.
The present inventors while working on the entacapone formulation have surprisingly found that use of cyclodextrin results in increased solubility, significant increase in percent drug release of entacapone and hence improved bioavailability of entacapone.
One of the aspects of the present invention provides a pharmaceutical composition comprising entacapone or salt thereof along with cyclodextrins or derivatives thereof and one or more pharmaceutically acceptable excipients.
in another aspect of the present invention there is provided a pharmaceutical composition comprising entacapone or salt thereof along with cyclodextrins or derivatives thereof and one or more pharmaceutically acceptable excipients, wherein entacapone is present in admixture with cyclodextrins or derivatives thereof.
In yet another aspect of the present invention there is provided a pharmaceutical composition comprising entacapone or salt thereof along with cyclodextrins or derivatives thereof and one or more pharmaceutically acceptable excipients, wherein entacapone is present in the form of complex with cyclodextrins or derivatives thereof.
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.
Suitable cyclodextrin derivatives may be one or more of hydroxypropyl-P-cyclodextrin, P-cyclodextrin, a-cyclodextrin, hydroxypropyl- a-cyclodextrin and the like.
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The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include 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 cyclodextrin 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.
The complex of entacapone and cyclodextrin can be prepared by various processes including solvent evaporation, kneading, spray drying, colloidal milling, high speed mixing, trituration or simple mixing. The entacapone can be present in an amount relative to the cyclodextrin, such that a molar ratio between the entacapone and the cyclodextrin is from about 1:1 to 1:10. Entacapone or salt thereof may be added to the formulation in the form of complex.
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Exterior portion of cyclodextrin being hydrophilic allows the cyclodextrin to form inclusion complexes with entacapone and which can then be dissolved in water.
While the present invention has been described in terms 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.
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Example-1
Table-1 Composition of Entacapone Tablets (200mg)

S.No. Ingredients Qty/tablet (%w/w)
1 Entacapone 15-50
2 Microcrystalline cellulose 20-65
3 Mannitol 5-50
4 Beta cyclodextrin 20-65
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 beta cyclodextrin are co-sifted and mixed with microcrystalline 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 cyclodextrins or derivatives thereof and one or more pharmaceutically acceptable excipients.
2) A pharmaceutical composition comprising entacapone or salt thereof along with cyclodextrins or derivatives thereof and one or more pharmaceutically acceptable excipients, wherein entacapone is present in admixture with cyclodextrins or derivatives thereof.
3) A pharmaceutical composition comprising entacapone or salt thereof along with cyclodextrins or derivatives thereof and one or more pharmaceutically acceptable excipients, wherein entacapone is present in the form of complex with cyclodextrins or derivatives thereof.
4) The pharmaceutical composition of claim 1, 2 and 3 comprises one or more of a tablet, capsule, powder, disc, caplet, granule, pellet and other dosage forms suitable for oral administration.
5) The pharmaceutical composition of claim 1, 2 and 3, wherein the cyclodextrins comprises one or more of hydroxypropyl-p-cyclodextrin, p-cyclodextrin, a-cyclodextrin, hydroxypropyl- a-cyclodextrin and the like.
6) The pharmaceutical composition of claim 1, 2 and 3, wherein entacapone and cyclodextrin are present in a molar ratio of about 1:1 to 1:10.
7) The pharmaceutical composition of claim 1, 2, and 3, wherein pharmaceutically acceptable excipients comprises one or more of fillers, lubricants, disintegrants, and glidants.
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8) The pharmaceutical composition of claim 7, wherein fillers comprises one or more of microcrystalline cellulose, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
9) The pharmaceutical composition of claim 7, wherein lubricants comprises one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate and the like.
10) The pharmaceutical composition of claim 7, wherein disintegrants comprises one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Dated this 19TH day of January, 2007 For Wockhardt Limited

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