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:
PREPARATION OF CLOPIDOGREL FORMULATIONS BY MELT GRANULATION PROCESS
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 process of preparing a pharmaceutical composition, which comprises of granules of clopidogrel or salt thereof and PEG prepared by melt granulation process. Granules are blended with other pharmaceutically acceptable excipients, which may be formulated as tablets, capsules and pellets. Granules of clopidogrel coated with PEG overcome the sticking problem and provides better formulation stability.
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 process of preparing a pharmaceutical composition, which comprises of granules of clopidogrel or salt thereof and PEG prepared by melt granulation process. Granules are blended with other pharmaceutically acceptable excipients, which may be formulated as tablets, capsules and pellets. Granules of clopidogrel coated with PEG overcome the sticking problem and provides better formulation stability.
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


.H2S04

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.
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US Patent No 6,767,913 (the '913 Patent) and European equivalent EP 1467735A2 discloses a pharmaceutical composition comprising clopidogrel hydrogensulfate selected from the group consisting of clopidogrel hydrogensulfate Form III, Form IV, Form V, Form VI and amorphous form, and a pharmaceutical^ acceptable excipient.
US Application 2003225129 (the '129 Application) discloses a pharmaceutical composition comprising clopidogrel hydrogensulfate Form VI, and pharmaceutical^ acceptable excipients.
US Application 2005113406 (the '406 Application) and European equivalent EP1474427A1 discloses pharmaceutical composition comprising as active ingredient crystalline forms I and II of Clopidogrel hydrochloride or hydrate thereof in admixture with inert solid or liquid pharmaceutical carriers and/or auxiliary agents.
PCT Patent Application WO2004/052966 discloses pharmaceutical composition comprising clopidogrel hydrogen sulfate polymorph (Form III) associated with one or more pharmaceutically acceptable carriers, excipients, or diluents.
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.
It is known in the prior art (US '141) that use of magnesium stearate (most commonly used lubricant) causes degradation of clopidogrel bisulfate and results in stability problem. The present inventors have also noticed the problem of increase in impurities on using magnesium stearate in clopidogrel formulation. The present inventors have observed that clopidogrel being a fine powder and hygroscopic in nature, absorbs moisture and poses problem of sticking during
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tabletting. Sticking problem has also been observed with dry granulation technique. Wet granulation of clopidogrel with water and isopropyl alcohol results in increase in impurities and change in polymorphic form of clopidogrel bisulfate respectively.
In light of this prior art and problems exemplified above, the present inventors have now surprisingly found that when clopidogrel is melt- granulated with polyethylene glycol (hereinafter PEG), it coats clopidogrel bisulfate and results in preventing the sticking problem and provides better formulation stability. The present inventors have avoided the use of stearates and used melt granulation process for better processing and increased formulation stability.
One of the aspects of the present invention provides a melt granulation process of preparing a pharmaceutical composition of clopidogrel or salt thereof wherein the process comprises of granulating clopidogrel or salt thereof with PEG under heating followed by blending the granules with other pharmaceutically acceptable excipients.
The pharmaceutical composition comprises of the granule of clopidogrel bisulfate wherein the granules are prepared by heating mixture of clopidogrel and PEG from 50 °C to 80 °C. The granulation process is carried out in two steps. In the first step, mixture of clopidogrel, mannitol and a part of PEG is heated from 50 °C to 80 °C along with fluidization to coat the clopidogrel thereby resulting in formation of granules after drying. In the second step of granulation, these granules are then mixed with remaining part of PEG and again heated from 50 °C to 80 °C along with fluidization to granulate clopidogrel. Resultant granules comprising clopidogrel and PEG are mixed with extragranular pharmaceutically acceptable excipients which includes microcrystalline cellulose, lactose, crospovidone, mannitol, talc and colloidal silicon dioxide and then lubricated with hydrogenated castor oil and glyceryl behenate and may be formulated as tablet, capsule and pellets.
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The pharmaceutical composition comprising clopidogrel or salt thereof wherein clopidogrel is present as clopidogrel bisulfate.
The pharmaceutical composition comprises of PEG wherein a PEG may be selected from a group comprising one or more of PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and the like.
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, 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.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those
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skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
Table 1: Composition of Clopidogrel bisulfate tablets.

S.No Ingredients Quantity/tablet (mg)
Ingredients used in granulation
1. Clopidogrel bisulfate 97.875
2. Mannitol 5.0
2. Polyethylene glycol-6000 20.0
Core tablet weight 122.875
Extragranular ingredients
3. Microcrystalline cellulose 48.425
4. Lactose 20.0
5. Mannitol 5.0
6. Crosspovidone 20.0
7. Colloidal silicon dioxide 2.35
8. Talc 10.0
9. Hydrogenated castor oil 4.0
10. Glyceryl behenate 2.35
Weight of core tablet 235.0
Ingredients used in coating
11. Opadry 7.05
12. Purified water qs
Total 242.05

Procedure: Melt granulation of clopidogrel bisulfate with PEG 6000 is carried out in two steps. In first step, clopidogrel bisulfate, mannitol and a part of PEG-6000 are sifted, mixed and heated from 50 °C to 80 °C along with fluidization where PEG 6000 melts and covers clopidogrel particles. This mix is then sifted, and mixed with remaining quantity of PEG 6000 to get uniform mixture. In the second step, this mixture is again heated where PEG 6000 melts and granulates the clopidogrel bisulfate. Granules are sifted and mixed with extragranular material, which includes microcrystalline cellulose, lactose, crospovidone, mannitol, talc and colloidal silicon dioxide and then lubricated with hydrogenated castor oil and glyceryl behenate. Final blend is compressed into tablets using suitable tooling. Tablets are coated with aqueous dispersion of opadry.
Table 2 -Dissolution data of the tablets prepared as per the present invention

Duration Plavix® Example 1
0 min 0 0
10 min 54.0 49.0
20 min 90.0 91.0
30 min 100.0 100.5
45 min 102.0 102.0
Table 2 provides the dissolution data for the Clopidogrel tablets prepared as per the formula given in Table 1. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein pH 2.0 hydrochloric acid buffer in 1000 ml was used as a medium.
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WE CLAIM:
1. A melt granulation process for preparing a pharmaceutical composition of clopidogrel or salt thereof optionally containing suitable excipients wherein the process comprises of granulating the clopidogrel or salt thereof with PEG under heating followed by blending the granules with other pharmaceutically acceptable excipients.
2. A process according to claim 1, wherein clopidogrel and salts thereof is present as clopidogrel bisulfate.
3. A process according to claim 1, wherein clopidogrel bisulfate and PEG are heated from 50 °C to 80 °C.
4. A process according to claim 1, wherein Polyethylene glycol (PEG) is selected from a group comprising one or more of PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 6000, PEG 8000 and PEG 20000.
5. A process according to claim 3, wherein polyethylene glycol is PEG 6000.
6. A process according to claim 1, wherein pharmaceutically acceptable excipients are fillers, lubricants, disintegrants and glidants.
Dated this 28th day of June, 2006 For Wockhardt Limited
(Yatendra Kumar) Authorized Signatory
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