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 CLOPIDOGREL OR MONOBASIC ACID SALTS THEREOF
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 clopidogrel or monobasic acid salts thereof and one or more hydrated excipients optionally along with suitable lubricant.
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 clopidogrel or monobasic acid salts thereof and one or more hydrated excipients optionally along with suitable lubricant.
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. Chemically it is (a S)-a- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H)-acetic acid methyl ester (Formula-!). 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.

FORMULA I
Clopidogrel salts of monobasic acids are known to exhibit difficulties in formulation. Clopidogrel in' base or monobasic acid salt form e.g. mesylate, hydrochloride, hydrobromide, besylate, benzoate, salicylate, lactate, gluconate is problematic to formulate for example as a tablet principally due to hygroscopicity. Clopidogrel tablets suffer from degradation on storage. To overcome such problems, prior art describes formulations, wherein clopidogrel is either in the
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form of coated particles or mixed with anhydrous excipients along with moisture scavengers.
US Patent No. 4,847,265 discloses dextro-rotatory isomer of clopidogrel substantially separated from the levo-rotatory isomer and its pharmaceutically acceptable salts.
US Application 2005113406 discloses crystalline form I of clopidogrel hydrochloride.
US Application 20070048370 discloses clopidogrel compositions wherein tablet contains no ionic and/or basic tabletting excipients and no PEG 6000.
PCT Application WO2005117866 and WO2006074066 disclose amorphous form of clopidogrel hydrochloride and its compositions.
PCT Application WO2005048992 discloses compositions of clopidogrel wherein the clopidogrel is in the form of coated particles mixed with anhydrous excipients along with moisture scavengers.
The present inventors have now surprisingly found that even if clopidogrel or monobasic acid salts thereof are mixed with hydrated excipients; it results in stable clopidogrel formulation that does not suffer degradation on storage.
The term "hydrated excipients" as used herein refers to the sufficient amount of water present in them so as to get them in hydrated state.
One of the aspects of the present invention provides a pharmaceutical composition comprising clopidogrel or monobasic acid salts thereof and one or more hydrated excipients optionally along with suitable lubricant.
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Monobasic acid salts of clopidogrel are selected from a group comprising of clopidogrel hydrochloride, clopidogrel hydrobromide, clopidogrel mesylate, clopidogrel besylate, clopidogrel salicylate, clopidogrel lactate and clopidogrel gluconate.
The pharmaceutical composition of the present invention comprises of clopidogrel or monobasic acid salts thereof, wherein clopidogrel or monobasic acid salts thereof is present in the form of clopidogrel hydrochloride.
In another aspect of the present invention there is provided a process of preparing pharmaceutical composition comprising clopidogrel or monobasic acid salts thereof which process comprises
a) processing clopidogrel or monobasic acid salts thereof with hydrated excipients optionally with suitable lubricant so as to form aggregates,
b) breaking down the aggregates of step a) so as to form granules or particles,
c) optionally mixing the granules or particles of step b) with other pharmaceutically acceptable excipients, and
d) converting the granules or particles thus formed of step c) in to suitable dosage form.
Hydrated excipients may be one or more of microcrystalline cellulose such as Avicel PH 101, low substituted hydroxy propyl cellulose, high substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide 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.
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The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include fillers, disintegrants, and glidants.
Suitable filler may be one or more of lactose, microcrystalline cellulose, polyethylene glycols, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, sorbitol, powdered sugar 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, crospovidone, sodium starch glycolate and the like.
The pharmaceutical composition of the present invention can be made by compacting clopidogrel or monobasic acid salts there of with hydrated excipients along with lubricant. The aggregates thus obtained are sized into granules or particles, which are mixed with other pharmaceutically acceptable excipients, lubricated and the mixture thus obtained can be present in the form of tablet, capsule, caplet, disc, pills, spheroids, minitablets, granules in capsule, pellets in capsule, minitablets in capsule or any other dosage form for oral administration.
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 hydrochloride tablets.

S.No Ingredients Quantity/tablet (% w/w)
Intragranular ingredients
1. Clopidogrel hydrochloride 15-35
2. Microcrystalline cellulose 30-70
3. Low substituted hydroxy propyl cellulose (L-HPC) 0.1-20
4. Colloidal silicon dioxide 0.5-5
5. Glyceryl behenate 0.1-5
6. Hydrogenated castor oil 0.5-5
7. Opadry 0.5-5.0
Procedure: Clopidogrel hydrochloride is mixed with microcrystalline cellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide and glyceryl behenate in double cone blender and the blend is compacted using a roll compactor. The aggregates are sized into granules using oscillating granulator. The granules are mixed with low substituted hydroxypropyl cellulose, colloidal silicon dioxide, crospovidone, talc and lubricated with glyceryl behenate, hydrogenated castor oil in double cone blender. 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 comprising clopidogrel or monobasic acid salts thereof and one or more hydrated excipients optionally along with suitable lubricant.
2. The pharmaceutical composition of claim 1, wherein the monobasic acid salts of clopidogrel salt are selected from a group comprising of clopidogrel hydrochloride, clopidogrel hydrobromide, clopidogrel mesylate, clopidogrel besylate, clopidogrel salicylate, clopidogrel lactate and clopidogrel gluconate.
3. The pharmaceutical composition of claim 2, wherein clopidogrel or monobasic acid salt thereof is present in the form of clopidogrel hydrochloride.
4. A process of preparing pharmaceutical composition comprising clopidogrel or monobasic acid salts thereof which process comprises

a) processing clopidogrel or monobasic acid salts thereof with hydrated excipients optionally with lubricant so as to form aggregates,
b) breaking down the aggregates of step a) so as to form granules or particles,
c) mixing the granules or particles of step b) optionally with other pharmaceutically acceptable excipients, and
d) converting the granules or particles thus formed of step c) in to suitable dosage form.
5. The pharmaceutical composition of claim 1, wherein hydrated excipients
comprises one or more of microcrystalline cellulose, low substituted
hydroxy propyl cellulose, high substituted hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, colloidal silicon dioxide and the like.
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6. The pharmaceutical composition of claim 1, wherein lubricants comprises one or more of hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, glycerol monostearate, glycerol monobehenate, glyceryl behenate, glyceryl palmitostearate and the like.
7. The pharmaceutical composition of claim 1, wherein pharmaceutically acceptable excipients are fillers, disintegrants, glidants.
8. The pharmaceutical composition of claim 1 comprises one or more of tablet, capsule, caplet, disc, pills, spheroids, minitablets, granules in capsule, pellets in capsule, minitablets in capsule.
Dated this 20TH day of Apr, 2007 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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