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:
BIOEQUIVALENT PHARMACEUTICAL COMPOSITIONS OF
CLOPIDOGREL HYDROCHLORIDE

2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.

3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the pharmaceutical composition consists essentially of glyceryl behenate.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. Description
A pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the pharmaceutical composition consists essentially of glyceryl behenate.
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-I). 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.

Clopidogrel hydrochloride is known to exhibit difficulties in formulation principally due to its hygroscopicity, a property that makes it difficult to handle on industrial scale. It has been observed that hydrochloride salt of clopidogrel is very sensitive to moisture and interacts with certain formulation excipients to undergo degradation. Clopidogrel hydrochloride along with having stability constraints poses formulation and processing problems. During development of pharmaceutical formulations comprising clopidogrel hydrochloride, often drug tends to degrade even in presence of little moisture and thus makes the drug unavailable in the plasma at the time of ingestion. To overcome such problems,


usually the bisulphate salt of clopidogrel is used as it is easy to handle, not hygroscopic and easy to formulate.
US Patent No. 4,529,596 discloses thieno(3,2-c)pyridine derivatives which generically covers clopidogrel and their addition salts with pharmaceutically acceptable organic acids or mineral bases, as well as the two enantiomers or their mixture.
US Patent No. 4,847,265 discloses dextrorotatory isomer of clopidogrel substantially separated from the levorotatory 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 W02005048992 discloses compositions of clopidogrel wherein the clopidogrel is in the form of coated particles mixed with anhydrous excipients along with moisture scavengers.
PCT Application WO2007091279 discloses a pharmaceutical composition comprising clopidogrel bisulphate and the lubricant glyceryldibehenate.
Clopidogrel is available commercially in the form of bisulphate salt as it is easy to handle, not hygroscopic, easy to formulate and is stable whereas clopidogrel in the form of hydrochloride salt suffers from various stability and processing constraints. The present inventors while working on the formulations of clopidogrel hydrochloride have surprisingly found that use of glyceryl behenate


results in improved tablet formulation, which is bioequivalent to clopidogrel bisulphate tablet (Plavix®).
One of the aspects of the present invention provides a pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the pharmaceutical composition consists essentially of glyceryl behenate.
In another aspect, the present invention provides a pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the ratio % of the test to reference product for Cmax is in the range from about 90 to about 120.
In one of the embodiments the ratio % of the test to reference product for Cmax is 112.81.
In another aspect, the present invention provides a pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the ratio % of the test to reference product for AUC0-16 is in the range from about 90 to about 120.
In one of the embodiments the ratio % of the test to reference product for AUC0-16 is 99.35.
In yet another aspect, the present invention provides a pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the ratio % of the test to reference product for AUC0-16 is in the range from about 90 to about 120.
In one of the embodiments the ratio % of the test to reference product for AUC0-60 is 98.97.


With reference to the pharmacokinetic performance of pharmaceutical in accordance with the present invention, it will be appreciated that the parameters that are commonly used in the art to describe the bioequivalency are Cmax and AUC (area under the curve). These are also the parameters used by regulatory agencies to assess the bioequivalence of test product with respect to reference product. As per FDA guidelines, for a formulation to be bioequivalent, the 90% confidence interval for the ratio % of the test to reference product (using natural log-transformed data) for Cmax and AUC should be within the range of 80 to 125.
The term "Cmax" as used herein refers to the maximum plasma concentration of the clopidogrel salt.
"AUC" as used herein refers to the area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 16-hour interval (AUC0-16 and AUC0-16.
The pharmaceutical composition of the present invention may further include other pharmaceutically acceptable excipients such as diluents, lubricants, glidants, disintegrant and the like.
The suitable diluent may be one or more of lactose, microcrystalline cellulose, polyethylene glycols, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, sorbitol, powdered sugar, Prosolv and the like.
The suitable lubricants and glidants 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, colloidal silicon dioxide, talc, cornstarch and the like.


Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, hydroxypropyl cellulose or other agents known to those skilled in the art.
In one of the embodiments the pharmaceutical composition can be prepared by simple mixing, direct compression or dry granulation.
The pharmaceutical composition of the present invention can be made by directly compressing the powder blend prepared by mixing clopidogrel hydrochloride, glyceryl behenate and pharmaceutical excipients.
The pharmaceutical composition of the present invention can also be made by compacting clopidogrel hydrochloride with glyceryl behenate and other pharmaceutically acceptable excipients. The aggregates thus obtained are sized into granules or particles, which are mixed with glyceryl behenate and other pharmaceutically acceptable excipients and the mixture thus obtained is formulated into different dosage form.
The pharmaceutical composition of the present invention 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.
The bioequivalency study for the formulation of the present invention is performed by administering the formulation in a tablet form to healthy subjects and measuring the levels of clopidogrel in the plasma at different time intervals over a period of sixteen hours. Values for clopidogrel pharmacokinectic parameters including observed Cmax, AUC0-16 and AUC0-00, were calculated using standard methods. Fig. 1 illustrates that clopidogrel hydrochloride formulation of present invention is substantially equivalent to the reference clopidogrel


bisulphate formulation. Table 2 summarizes the pharmacokinetic results obtained after single dosing in the above study.
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.
EXAMPLE 1
Table 1: Composition of clopidogrel hydrochloride tablets.

S. No Ingredients %w/w
Intragranular
1 Clopidogrel Hydrochloride 15-40
2 PROSOLV SMCC HD 90 30-70
3 Low substituted HPC (LH -11) 5-10
4 Glyceryl Behenate (Compritol 888 ATO) 1-5
Extragranular
5 Low substituted HPC (LH -11) 0.5-2.0
6 PROSOLV SMCC HD 90 5-10
7 Glyceryl Behenate (Compritol 888 ATO) 1-5
8 Hydrogenated Castor oil (Cutina HR) 1-5
Core tablet weight (mg) 100
9 Opadry II pink 31K 84972
Coated tablet weight (mg)
Procedure: Clopidogrel hydrochloride is mixed with Prosolv, low substituted hydroxypropyl cellulose, and glyceryl behenate in double cone blender and the blend is compacted using a roller compactor. The aggregates are sized into granules using oscillating granulator. The granules are mixed with Prosolv, low substituted hydroxypropyl cellulose 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.


EXAMPLE 2
Pharmacokinetic study of the clopidogrel hydrochloride formulation
The bioavailability study to determine the plasma concentration-time profile for the formulation of the present invention was performed by administering the clopidogrel 75 mg Immediate release tablets corresponding to the formulation of example 1 and the 75mg IR clopidogrel bisulphate tablet (Reference Formulation), currently sold by Sanofi-Aventis under the tradename PLAVIX®, to the 14 healthy subjects. Each subject received a single dose of clopidogrel after starting breakfast. Wash out periods of one week separated doses.
Blood samples were collected prior to dosing (0 hour) and at 0.16, 0.33, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, 12, and 16 hour after each dose. Plasma samples were assayed for clopidogrel using a validated high performance liquid chromatographic procedure. Values for clopidogrel pharmacokinectic parameters including observed Cmax, AUC0-16 and AUC0-00, were calculated using standard methods. The mean plasma concentration-time profiles for the single dose study are illustrated in Fig. 1.
Table 2: Pharmacokinectic parameters - Mean Ratios % (Test/Ref) on Pharmacokinectic Parameters

PK Parameters Ratio % (Test/Ref)
Cmax 112.81
AUC0-16 99.35
AUC0-00 98.97


WE CLAIM:
1. A pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the pharmaceutical composition consists essentially of glyceryl behenate.
2. The pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the ratio % of the test to reference product for Cmax is in the range from about 90 to about 120.
3. The pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the ratio % of the test to reference product for AUC0-16 is in the range from about 90 to about 120.
4. The pharmaceutical composition of clopidogrel hydrochloride bioequivalent to clopidogrel bisulphate tablet (Plavix®), characterized in that the ratio % of the test to reference product for AUC0-00 is in the range from about 90 to about 120.
5. The pharmaceutical composition of claims 2 to 4 consists essentially of glyceryl behenate.
6. The pharmaceutical composition of claims 1 to 4, further comprises one or more pharmaceutically acceptable excipients selected from diluents, lubricants, glidants, disintegrant and the like.
7. The pharmaceutical composition of claims 1 to 4, wherein the suitable diluent may be one or more of lactose, microcrystalline cellulose,


polyethylene glycols, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, sorbitol, powdered sugar, Prosolv and the like.
8. The pharmaceutical composition of claims 1 to 4, wherein lubricants and glidants include but are not limited to one or more of hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, glycerol monostearate, glycerol monobehenate, glyceryl behenate, glyceryl palmitostearate, colloidal silicon dioxide, talc, cornstarch and the like.
9. The pharmaceutical composition of claims 1 to 4, wherein suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, hydroxypropylcellulose or other agents known to those skilled in the art.
10. The pharmaceutical composition of claims 1 to 4, wherein the pharmaceutical composition can be prepared by simple mixing, direct compression or dry granulation.

Abstract
The present invention provides a pharmaceutical composition comprising clopidogrel hydrochloride and glyceryl behenate that is bioequivalent to the commercially available Plavix® tablet.