FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION: CLOPIDOGREL 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 that comprises of pre-coated granules of clopidogrel or salts thereof along with other 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 that comprises of pre-coated granules of clopidogrel or salts thereof along with other pharmaceutically acceptable excipients.
Clopidogrel is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/llla complex. It is a pharmaceutically active substance known for its utility as antiplatelet agent. The empirical formula of clopidogrel bisulfate (Formula I) is C16 Hi6C|N02S*H2S04 and its molecular weight is 419.9. Chemically it is (a S)-a- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H)-acetic acid methyl ester. Clopidogrel is indicated for the reduction of atherothrombotic events in patients with history of recent myocardial infarction (Ml), recent stroke, or established peripheral arterial disease and acute coronary syndrome
##STR(
\ .OCH3 c ci
H^= I
cO
•H2S04
FORMULA I
US Patent No 6,914,141 (the '141 Patent) and European equivalent EP1310245B1 discloses pharmaceutical tablets comprising clopidogrel bisulfate and a lubricant selected from zinc stearate, stearic acid, and sodium stearyl fumarate.
US Patent No 6,767,913 (the '913 Patent) and European equivalent EP 1467735A2, US Application 2003225129, US Application 2005113406 and European equivalent EP1474427A1, PCT Patent Application WO2004/052966
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provides a pharmaceutical composition comprising different polymorphic forms of clopidogrel hydrogensulfate, and pharmaceutical^ acceptable excipients.
PCT Patent Application WO2004/098593 discloses pharmaceutical composition comprising amorphous clopidogrel hydrogen sulfate; either or both of calcium stearate and magnesium stearate; a non-hygroscopic additive; and at least one excipient.
Clopidogrel being a fine powder results in sticking during compression. Sticking problem persists irrespective of the whether the method used is dry granulation or wet granulation.
The present inventors have now surprisingly found that when clopidogrel granules are coated with polymer and/or oil, and the resultant granules when blended with other excipients, it results in preventing the sticking problem during compression. Further it provides better formulation stability.
One of the aspects of the present invention provides a pharmaceutical composition that comprises of pre-coated granules of clopidogrel or salts thereof along with other pharmaceutically acceptable excipients.
The pharmaceutical composition comprising clopidogrel or salt thereof wherein clopidogrel is present as clopidogrel bisulfate.
A pharmaceutical composition comprises of pre-coated granules of clopidogrel or salts thereof along with other pharmaceutically acceptable excipients wherein granules of Clopidogrel or salt thereof are coated with polymer and/or oil mixture.
The pharmaceutical composition comprises of coating granules of clopidogrel or salts thereof with polymer and/or oil mixture, wherein polymers may be selected from a group comprising one or more of hydroxy propyl cellulose, hydroxy propyl
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methyl cellulose, ethyl cellulose, hydroxy ethyl cellulose, methyl cellulose, and the like.
The pharmaceutical composition comprises of coating granules of clopidogrel or salts thereof with polymer and/or oil mixture, wherein oils may be selected from a group comprising one or more of mineral oils and vegetable oils, wherein mineral oils and vegetable oils comprises castor oil, hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, and the like.
A pharmaceutical composition comprises of pre-coated granules of clopidogrel or salts thereof along with other pharmaceutically acceptable excipients wherein granules of Clopidogrel or salt thereof are coated with low substituted hydroxypropyl cellulose and/or castor oil mixture.
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 lactose, microcrystalline cellulose, polyethylene glycols, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, sorbitol, powdered sugar and the like.
Suitable lubricants may be selected from a group comprising one or more of mineral oils, vegetable oils and glyceryl esters of fatty acids wherein mineral oils, vegetable oils and glyceryl esters of fatty acids comprises hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, glycerol monostearate, glycerol monobehenate, glyceryl behenate, glyceryl palmitostearate and the like.
Suitable glidants may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
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Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
A pharmaceutical composition comprises of
a) mixing Clopidogrel or salts thereof with fillers and compacting the blend
b) converting the flakes in to granules and coating the granules with polymer-oil solution,
c) drying the granules, mixing the dried granules with other pharmaceutical^ acceptable excipients and compressing the final blend.
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 Clopidogrel bisulfate tablets.

S.No Ingredients Quantity/tablet (% w/w)
Ingredients used in granulation
1. Clopidogrel bisulfate 35-45
2. Microcrystalline cellulose 2-50
3. Lactose 2-50
4. Polyethylene glycol 0.1-10
5. Low substituted hydroxy propyl cellulose (L-HPC) 0.5-10
6. Castor oil 0.1-2.0
7. Isopropyl alcohol qs.
Extragranular ingredients
8. Colloidal silicon dioxide 0.5-3.0
9. Crospovidone 4-16
10. Talc 1-10
11. Glyceryl behenate 0.1-3.0
12. Hydrogenated castor oil 0.1-5.0
13. Opadry 0.5-5.0
Procedure: Clopidogrel bisulfate is mixed with microcrystalline cellulose, lactose, polyethylene glycol in double cone blender and the blend is compacted using a roll compactor. The flakes are converted into granules. The granules are granulated with alcoholic solution of low substituted hydroxy propyl cellulose (L-HPC) and castor oil in rapid mixer granulator (RMG). Granules are dried and mixed with colloidal silicon dioxide, crospovidone, talc and lubricated with glyceryl behenate, hydrogenated castor oil. Lubricated
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blend is finally compressed into tablets using suitable tooling. Tablets are coated with aqueous dispersion of Opadry.
EXAMPLE 2
Table 2: Composition of Clopidogrel bisulfate tablets.

S.No Ingredients Quantity/tablet (% w/w)
Ingredients used in granulation
1. Clopidogrel bisulfate 35-45
2. Microcrystalline cellulose 2-50
3. Lactose 2-50
4. Polyethylene glycol 0.1-10
5. Low substituted hydroxy propyl cellulose (L-HPC) 0.5-10
6. Castor oil 0.1-2.0
7. Isopropyl alcohol qs.
Extragranular ingredients
8. Colloidal silicon dioxide 0.5-3.0
9. Crospovidone 4-16
10. Talc 1-10
11. Glyceryl behenate 0.1-3.0
12. Hydrogenated castor oil 0.1-5.0
13. Opadry 0.5-5.0
Procedure: Clopidogrel bisulfate is mixed with microcrystalline cellulose, lactose, polyethylene glycol in double cone blender and the blend is compacted using a roll compactor. The flakes are converted into granules. The granules are coated with alcoholic solution of low substituted hydroxy
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propyl cellulose (L-HPC) and castor oil in fluidized bed coater. Granules are dried and mixed with colloidal silicon dioxide, crospovidone, talc and lubricated with glyceryl behenate, hydrogenated castor oil. Lubricated blend is finally compressed into tablets using suitable tooling. Tablets are coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. A pharmaceutical composition that comprises of pre-coated granules of clopidogrel or salts thereof along with other pharmaceutically acceptable excipients.
2. A pharmaceutical composition according to claim 1, wherein clopidogrel or salts thereof is present as clopidogrel bisulfate.
Dated this 1 st day of December 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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