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: ENTACAPONE COMPOSITIONS
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 having mean particle diameter of 40 microns or less along with pharmaceutical^ 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 having mean particle diameter of 40 microns or less along with 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 entacapone formulation have noticed that when entacapone having mean particle diameter of more than 40 microns is used, it leads to decreased percent release of entacapone and hence low bioavailability. Surprisingly it was found that when entacapone having mean particle diameter of 40 microns or less is used it results in increased solubility, significant increase in percent drug release of entacapone and hence improved bioavailability.
For the present invention, the term entacapone as used herein is referred to as (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide or salt thereof.
One of the aspects of the present invention provides entacapone having mean particle diameter of 40 microns or less.
Another aspect of the present invention provides a pharmaceutical composition comprising entacapone having mean particle diameter of 40 microns or less along with pharmaceutically acceptable excipients.
In another aspect of the invention there is provided a pharmaceutical composition, which comprises of granules of entacapone having size of 900 microns or less along with pharmaceutically acceptable excipients.
In yet another aspect of the present invention there is provided a pharmaceutical composition, which comprises of entacapone having mean particle diameter of 40 microns or less along with pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 80% of entacapone or salt thereof is released, wherein the release
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rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C.
The pharmaceutical composition of the present invention can be present in the form of tablet, capsule, powder, disc, caplet, granules and pellets.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include fillers, lubricants, disintegrants, and glidants.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricant may be selected from a group comprising 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, crospovidone, sodium starch glycolate and the like.
Entacapone having mean particle diameter of 40 microns or less can be prepared by chemical methods and/or mechanical methods.
Chemical methods involve solvent crystallization, chemical synthesis, modified crystal engineering, freeze-drying or other suitable means.
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Mechanical methods involve milling, ultrasonication or other suitable techniques. Milling further involves conventional techniques like ball mill, fluid energy attrition mills, jet mills or other suitable means.
Alternatively, size reduction of entacapone of bigger size can be carried out by dissolving entacapone of bigger size in suitable solvent such as dimethyl formamide optionally with above said pharmaceutically acceptable excipients and the resultant mass is spray dried to get desired size of entacapone. Further, the resultant mass may optionally be spray dried over other excipients to form film.
Further, entacapone of bigger size can be reduced to desired size by co-melting entacapone of bigger size with other pharmaceutically acceptable excipients and resultant mass is cooled to get solid-solid dispersion.
The pharmaceutical composition of the present invention can be prepared by mixing entacapone (mean particle diameter of 40 microns or less) with 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.
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(mean particle diameterof 40 microns or less) 15-50
2 Microcrystalline cellulose 20-65
3 Mannitol 5-50
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 (mean particle diameter of 40 microns or less), microcrystalline cellulose, mannitol, croscarmellose sodium and colloidal silicon dioxide are sieved and mixed together 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 milling 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 again milling 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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Table 2: Comparative dissolution data of entacapone tablets 200mg (Entacapone with mean particle diameter more than 40 microns vis-a-vis Entacapone with mean particle diameter of 40 microns or less)

Time (min) Entacapone tablets(Entacapone with mean particlediameter more than 40 microns)% drug released Entacapone tablets(Entacapone with mean particlediameter of 40 microns or less)% drug released
20 61 68
30 66 83
45 72 89
Table 2 provides the comparative dissolution data for entacapone tablets (mean particle diameter more than 40 microns vis-a-vis mean particle diameter of 40 microns or less) prepared as per the formula given in Table 1. For determination
of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 900 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C was used as a medium.
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WE CLAIM:
1) Entacapone having mean particle diameter of 40 microns or less.
2) A pharmaceutical composition comprising entacapone having mean particle diameter of 40 microns or less along with pharmaceutical^ acceptable excipients.
3) A pharmaceutical composition, which comprises of granules of entacapone having size of 900 microns or less along with pharmaceutically acceptable excipients.
4) A pharmaceutical composition, which comprises of entacapone having mean particle diameter of 40 microns or less along with pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 80% of entacapone or salt thereof is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C.
5) The pharmaceutical composition according to claims 1, 2, 3 and 4 comprises one or more of a tablet, capsule, powder, disc, caplet, granule and pellet.
6) The pharmaceutical composition according to claims 1, 2, 3 and 4 wherein pharmaceutically acceptable excipients are fillers, lubricants, disintegrants, and glidants.
7) The pharmaceutical composition of claim 6, wherein fillers are selected from a group comprising one or more of, microcrystalline cellulose, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
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8) The pharmaceutical composition of claim 6, wherein lubricants are selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate and the like.
9) The pharmaceutical composition of claim 6, wherein disintegrants are selected from a group comprising one or more of starch, croscarmellose
sodium, crospovidone, sodium starch glycolate and the like.
10) The pharmaceutical composition of claim 6, wherein glidants are selected
from a group comprising one or more of colloidal silicon dioxide, talc or
cornstarch and the like.


Dated this 27th day of December, 2006