FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. Title of the invention: "Stable solid pharmaceutical composition of Clopidogrel"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

STABLE SOLID PHARMACEUTICAL COMPOSITION OF CLOPIDOGREL
Field of the Invention
The invention relates to solid oral pharmaceutical composition comprising clopidogrel or pharmaceutically acceptable salt thereof, a mixture of pharmaceutically acceptable liquid and solid lubricant along with at least one more pharmaceutically acceptable excipient. The invention further relates to solid oral composition of clopidogrel or pharmaceutically acceptable salts thereof, which exhibits improved processability along with desired dissolution profile and comparable stability with innovator composition.
Background
Clopidogrel is a dextro-rotatory enantiomer of methyl alpha-5-(4, 5, 6, 7-tetrahydro (3, 2-c) thieno pyridyl) (2-chlorophenyl)-acetate. Clopidogrel and its preparation are described in U.S. Patent No. 4,529,596 and 4,847,265.
U. S. Patent No. 4,847,265 discloses that the dextro-rotatory isomer possesses platelet aggregation inhibiting activity in comparison to the levo-rotatory isomer which is less active and less well tolerated. This patent specifically discloses the hydrogen sulphate, hydrochloride, hydrobromide and taurocholate salts of clopidogrel. Different polymorphic forms of clopidogrel salts are described in the prior art, for example WO 1999065915 discusses polymorphic Form II of the clopidogrel bisulphate salt and PCT applications WO2006034451, WO2005026174, WO2005026174, WO2005068471 and WO 2005117866 report other polymorphic forms of clopidogrel hydrobromide and clopidogrel hydrochloride.
Clopidogrel is shown to decrease morbidity in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial

infarction or unstable angina. Thus it is useful as a medicine for prophylaxis and treatment of thrombotic events. It is commercially available as clopidogrel bisulphate salt in the product sold as PLAVIX™ tablets by Bristol-Meyers Squibb. PLAVIX® is administered as an oral tablet at a recommended dose of 75 mg once daily. It is provided as pink, round, biconvex, debossed film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base.
Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but is freely soluble at pH 1.0. It also dissolves freely in methanol; it dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It is well known that formulating clopidogrel salts into suitable tablet dosage forms is problematic from the manufacturing perspective. The principle reason for such difficulty is attributed to the hygroscopic nature of these salts. This results into adhesion of clopidogrel tablet formulations to the surfaces of the punches and/or the dies of the conventional tablet compression machines. This causes picking, sticking or other kind of surface irregularities leading to formation of poor quality finished product. In the manufacture of tablets, it is generally necessary to include a lubricant in the blend of ingredients to prevent sticking of the compressed tablets to the punches, and also to prevent binding between the punches and the dies. Use of proper lubricant with anti-adherent property could thus solve the problem of adhesion.
However, choice of excipients for manufacturing of clopidogrel tablets is also very critical, because clopidogrel exhibits rapid degradation when co-processed with certain excipients, especially, alkaline metal salts such as magnesium stearate and sodium stearyl fumarate, which are commonly used as lubricants in the tablet dosage forms. Furthermore, certain excipients enhance the inherent stickiness of the clopidogrel salts. Hence, selection of the pharmaceutically acceptable excipients should be aimed at their compatibility with clopidogrel salts and also reduction of their hygroscopic nature.

The core of PLAVIX is comprised of exicipients like lactose, hydrogenated castor oil, microcrystalline cellulose, polyethylene glycol 6000 and pregelatinized starch. It is thus unusual that Plavix™ tablets do not contain magnesium stearate as the lubricant, but instead contain hydrogenated castor oil and polyethylene glycol as lubricants. Both of these ingredients have occasionally been used as lubricants, but they are not as effective as magnesium stearate. The use of alternative lubricants is attempted to avoid interaction between clopidogrel bisulfate and magnesium stearate resulting into instability of the product.
Many efforts are directed towards getting stable formulation of clopidogrel by proper choice of excipients that would be compatible with the active agent, and allow easy processing during formulation, especially to take care of sticking and picking of the solid compressed dosage forms.
U.S. Patent No. 6,914,141 discloses pharmaceutical tablets comprising clopidogrel bisulfate and a lubricant selected from zinc stearate, stearic acid, and sodium stearyl fumarate. PCT application WO 2006044548 discloses solid premixes comprising clopidogrel base, adsorbed onto at least one pharmaceutically acceptable excipient. Another PCT application WO 2004098593 discloses formulations comprising amorphous clopidogrel hydrogen sulfate, either or both of calcium stearate and magnesium stearate, a non-hygroscopic additive, and at least one excipient.
U. S. Patent application US20100086590 discloses oral pharmaceutical compositions comprising clopidogrel bisulfate Form 1 coated with hydrophilic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxyethyl cellulose. The composition additionally comprises of one or more chelating agents and antioxidants. One more PCT application WO2005048992 suggests coating of clopidogrel particles with polyvinyl acetate or polyvinyl alcohol to overcome hygroscopic nature of clopidogrel. It also suggests a process of preparing stable clopidogrel compositions by dry granulation process using anhydrous excipients.

However, coating of drug particles for purpose of stabilization is very tedious and time consuming process.
PCT application WO2010009745 relates to stable Clopidogrel formulation employing an acidifying agent, such as citric acid to protect the active ingredient from degradation and a method for the preparation thereof.
Such formulation only tackles with stability aspect of the drug; but does not take care of processing difficulty, such as sticking of blend to dies and punches.
PCT application WO2007091279 discloses a pharmaceutical composition of clopidogrel bisulphate and a lubricant glyceryl dibehenate. However, use of these excipients or processes does not result in the formulation with either improved stability or processability.
Still there is a need for developing stable solid formulations comprising clopidogrel or pharmaceutically acceptable salts thereof, wherein the formulations can be processed using conventional tabletting equipments like compression machines and are devoid of any substantial impurities upon storage.
By rigorous experimentation, researchers of the present invention have found that mixture of liquid and solid lubricant such as hydrogenated castor oil and dimethicone result into stable clopidogrel formulations with improved processability. None of the prior art references teach or suggest the use of such mixture of lubricants in clopidogrel formulation.
This combination reduces tendency of the active to stick to the punches and/ die surfaces of conventional tablet compression machine. Thus it ensures proper lubrication of the tablet blend and facilitates the large scale production using high speed machines without facing any content uniformity or dissolution issue.

Summary
The present invention describes solid oral clopidogrel bisulfate tablets comprising a mixture of liquid and solid lubricant such as dimethicone and hydrogenated castor oil along with one more pharmaceutically acceptable excipient. The invention further details process for preparation of pharmaceutical composition comprising clopidogrel bisulfate and a mixture of liquid and solid lubricant, which exhibits improved processability, stability and desired dissolution profile.
Detailed Description
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease and cerebrovascular disease. They are widely used in primary and secondary prevention of thrombotic cerebrovascular or cardiovascular disease. Clopidogrel is a prodrug, the action of which may be related to an adenosine diphosphate (ADP) receptor on platelet cell membranes. The drug specifically and irreversibly inhibits the P2Yn subtype of ADP receptor, which is important in aggregation of platelets and cross-linking by the protein fibrin.
The present invention relates to the stable solid oral pharmaceutical formulation of therapeutically effective amount of clopidogrel, or pharmaceutically acceptable salt thereof, which exhibits improved processability along with desirable dissolution profile. The stability of the formulation is comparable to Innovator formulation Plavix.
The terms "formulation", "dosage form" and "composition" are used interchangeably herein and denote the clopidogrel solid oral composition of the present invention comprising a therapeutically effective amount of clopidogrel, or a pharmaceutically acceptable salt thereof, and a mixture of lubricants along with at least one pharmaceutically acceptable excipient. The term "therapeutically effective amount" as used herein refers to a nontoxic but sufficient amount of the active agent required to

provide the desired therapeutic, preventive and/or beneficial effect. The amount of active agent that is "effective" will vary from subject to subject, depending on the age, type of disorder and general condition of the individual, and the like. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
The term "mixture" as used in the present invention denotes the physical blend of two lubricants, one of which is liquid and it is added to the solid powder of another lubricant to form semisolid mass.
The term "adsorbate" as used in the present invention denotes the free flowing product formed by adding the semisolid mixture of liquid and solid lubricants to another powder excipient, like mannitol to get final product. This adsorbate can be used to lubricate the blend of drug with other excipients, before subjecting it to the compression process. Adsorption is a surface phenomenon and there is no chemical interaction between the lubricants and mannitol.
Clopidogrel is very hygroscopic and thus difficult for pharmaceutical processing, due to its sticking tendency to die and punches. Further it is also incompatible with certain excipients, thus develop impurities in the form of related substances over the shelf life period. Hence it is important to tackle with these two problems while formulating clopidogrel formulation.
One of these problems could be taken care of with a lubricant which facilitates tablet manufacture by reducing friction in the tablet die during compression and ejection. It also prevents the tablet from sticking to the surface of tablet punch and die wall. As per one embodiment of the present invention, the composition is comprised of mixture of at least one pharmaceutically acceptable liquid and one solid excipient, functioning as lubricant. The liquid excipient is polydimethylsiloxane which is obtained by hydrolysis

and polycondensation of dichlorodimethylsilane and chlorotrimethylsilane. It is known as 'dimethicone' as per USPNF 23 and PhEur 2005. It is clear, colorless liquid and hydrophobic in nature. Dimethicone is used as an emollient and antifoaming agent in pharmaceutical preparations. It is employed as a novel lubricant in clopidogrel formulation of the present invention along with hydrogenated castor oil.
As per one more embodiment of the present invention, hydrogenated castor oil is used as a solid lubricant. It is described in USPNF 23 as the refined, bleached, hydrogenated, and deodorized castor oil, consisting mainly of the triglyceride of hydroxystearic acid. It is obtained by hydrogenation of virgin castor oil. It is employed as an extended release agent, stiffening agent and lubricant in tablet and capsule dosage forms. Hydrogenated castor oil occurs as a fine, almost white or pale yellow powder or flakes.
Use of hydrogenated castor oil alone did not remove sticking tendency of the tablets. However, combination of hydrogenated castor oil with dimethicone showed favorable results. The preferred lubricant is thus a mixture of dimethicone and hydrogenated castor oil. Dimethicone may comprise from about 0.5 % to about 5% by weight of the tablet; while hydrogenated castor oil may comprise from 0.5 to 4% by weight of the tablet.
The liquid excipient dimethicone is mixed well with hydrogenated castor oil, which is further adsorbed on diluent. This adsorbate is used as lubricant before compression of the drug blend into tablets. Use of such mixture of solid and liquid lubricant resulted into stable clopidogrel formulations which exhibit desirable dissolution profile.
The choice of diluents is very important, as the inherent adhering tendency of clopidogrel salt is enhanced by the use of certain diluents. This excipient should be compatible with the drug to avoid development of toxic products.

As per one more embodiment of the present invention, the composition may include one or more diluents including, but not limited to, lactose, lactose monohydrate, sugar, dextrate, dextrate hydrated, dextrins, fructose, lactitol, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose, or mixtures thereof in an amount within the range of from about 10 to about 80% by weight. In one embodiment the diluent is mannitol.
Binders employed in the dosage form include, but are not limited to, starch, microcrystalline cellulose, highly dispersed silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, copovidone, polymethacrylic acid derivative, ethyl cellulose, cross-linked carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose (L-HPC), natural or synthetic gums and the like or mixtures thereof. In one embodiment, the binder is L- hydroxypropyl cellulose. Binders may be incorporated into the system in an amount of about 0.5% to about 20% by weight of the dosage form. In another embodiment, the binder may be incorporated in an amount of about 1 % to about 10% by weight of dosage form. In a further embodiment, the binder may be present in an amount of about 2% to about 7.5% by weight of the dosage form.
Glidants may be selected from talc, colloidal silicon dioxide and the like. Suitable glidants may be present in an amount of about 0.1% to about 3% by weight of the tablet. Preferred glidant is colloidal silicon dioxide.
The dosage form of present invention is a solid dosage form such as, but not limited to, tablet, granule, spheroid, bead, pellet or capsule. In one embodiment, the solid dosage form is a tablet which may vary in shape such as round, oval, triangle, almond, peanut, parallelogram, pentagonal, hexagonal, and trapezoidal. In one embodiment, the dosage form shapes are round.

The tablets will also optionally be coated with a film coat. Conventional coatings which are well known to the skilled person may be employed. In useful embodiments of the invention, the tablets are coated, e.g. by sugar coating or more preferably by film coating. A number of substances may be used for film coating the tablets of the Invention, including methyl cellulose, ethyl cellulose and hydroxymethyl cellulose based coatings as well as methyl hydroxyl ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose (e.g. Methocel (Dow)) based coatings, and polyvinyl alcohol (PVA) based coatings such as Opadry system. Such coatings allow distinctive coloring and may enhance the stability of the tablets.
The clopidogrel bisulfate tablets of this invention can be prepared by conventional tablet forming techniques such as, for example, wet granulation and dry granulation. In the wet granulation process, the active ingredient is mixed with some or all of the diluent. This blend is then wet granulated with water or an organic solvent, optionally containing a binder in solution. The resultant wet granulation is then dried and milled. The granules are then mixed with the remaining ingredients, which will include the mixture of lubricants adsorbed on diluent, to produce the final mix, which is then compressed into tablets.
In the dry granulation process, the active ingredient is mixed with the other ingredients without addition of any solvent, and thus without the need for drying. Again the final mix is lubricated and compressed into tablets. The dry granulation approach is preferred as it is simpler and thus less costly.
The tablets of clopidogrel salts free of sticking tendency as described herein may be prepared by direct compression.
The present invention relates to tablets of a salt of clopidogrel, which tablets are free of sticking problems and comprise of a therapeutically effective amount of clopidogrel bisulphate; mixture of lubricants, one or more of suitable diluents; and optionally other pharmaceutically acceptable excipients, wherein the said diluents and lubricants help in

counteracting the inherent hygroscopicity of clopidogrel salts. It also relates to a process of preparation of such tablets.
In one embodiment, the tablets are prepared by direct compression process comprising the steps of
(a) blending clopidogrel salt with one or more of the diluents and optionally other pharmaceutically acceptable excipients in a suitable blender;
(b) mixing liquid lubricant with solid lubricant and adsorbing the mixture on remaining part of diluent,
(c) lubricating blend of (a) with adsorbate of (b)
(d) compressing the final blend of step (c) into tablets.
In another embodiment, the tablets are prepared by the process comprising the steps of
(a) blending clopidogrel salt with mannitol and optionally other pharmaceutically acceptable excipients in a suitable blender;
(b) mixing dimethicone with hydrogenated castor oil and adsorbing the mixture on remaining part of mannitol,
(c) lubricating blend of (a) with mannitol adsorbate of (b)
(d) compressing the final blend of step (c) into tablets.

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. The invention is further illustrated by the following examples, which are for illustrative purposes and should not be construed as limiting the scope of the invention in any way.
Examples

Ingredients Quantity in mg/tablet
A B C D E
Clopidogrel bisulphate equivalent to clopidogrel 97.875 97.875 97.875 97.875 97.875
Microcrystalline cellulose 77.125 85.00 85.0 85.0 85.0
Mannitol 50.00 141.125 136.125 132.125 126.125
Hydroxypropyl cellulose, low substituted 17.50 17.50 17.50 17.50 17.50
Colloidal silicon dioxide 5.00 5.00 5.0 5.0 5.0
Hydrogenated castor oil 2.50 3.50 3.5 2.5 3.5
Dimethicone ~ ~ 5.0 10.0 15.0
Total 250.00 350.00 350 350 350
Process of Preparation
Formulations A and B
Excipients like microcrystalline cellulose, mannitol, hydroxypropyl cellulose and colloidal silicon dioxide were sifted and mixed well with clopidogrel bisulphate to get a blend. Hydrogenated castor oil was used for lubrication of drug blend and compressed to get the
tablets.

Formulations C, D and E
Excipients like microcrystalline cellulose, mannitol, hydroxypropyl cellulose and colloidal silicon dioxide were sifted and mixed well with clopidogrel bisulphate to get a blend. Dimethicone was added to hydrogenated castor oil and mixed well further with a part of mannitol. This adsorbate of dimethicone was then used for lubrication of drug blend and compressed to get the tablets.
Processing Parameter

Formulations using Formulations with
Observation only hydrogenated Dimethicone +
castor oil as lubricant hydrogenated castor oil
A B C D E
Sticking to punches Yes Yes No No No
and Die
Formulations A and B, wherein only hydrogenated castor oil was used as lubricant, experienced the problem of sticking to die and punches and resulted into surface irregularities.
Formulations C, D and E were produced using mixture of dimethicone and hydrogenated castor oil. The tablets from were produced without any problem of sticking or picking. The final formulation had optimum content uniformity and exhibited desired dissolution profde.

Dissolution Profile
The dissolution was carried out in Hydrochloric acid buffer of pH 2, volume 1000 ml in USP Type 2 apparatus at 50 rpm and 37°C+ 0.5. The drug release profile was checked at 30 minutes.

Formulation Drug Release (%)
C 99
D 98
E 99
The formulations C, D and E with mixture of dimethicone and hydrogenated castor oil employed as lubricant exhibited desired dissolution profile.

We claim,
1. Solid oral pharmaceutical composition comprising:
a. a therapeutically effective amount of clopidogrel or pharmaceutically acceptable salt
thereof;
b. a mixture of pharmaceutically acceptable liquid and solid lubricant, and
c. at least one more pharmaceutically acceptable excipient.
2. The pharmaceutical composition of claim 1, which comprises mixture of
polydimethylsiloxane and polyoxyethylene castor oil derivative as pharmaceutically
acceptable liquid and solid lubricant.
3. The pharmaceutical composition of claim 2, wherein polydimethylsiloxane liquid lubricant is dimethicone.
4. The pharmaceutical composition of claim 2, wherein polyoxyethylene castor oil derivative solid lubricant is hydrogenated castor oil.

5. The pharmaceutical composition of claim 1, wherein said composition is present as a tablet, granule, spheroid, bead, pellet or a capsule.
6. The pharmaceutical composition of claim 5, wherein said composition is present as a tablet.
7. The pharmaceutical composition of claim], wherein said excipient is diluent, filler, binder or glidant.
8. The pharmaceutical composition of claim 7, wherein said diluent is mannitol.

9. A process for preparing solid oral pharmaceutical composition of clopidogrel,
comprising:
(a) Physically mixing clopidogrel or pharmaceutically acceptable salt thereof, with part of mannitol and other pharmaceutically acceptable excipients;
(b) mixing liquid dimethicone with solid hydrogenated castor oil, which is further added to remaining part of mannitol to get the adsorbate

(c) lubricating the powder mix of step (a) using adsorbate of step (b); and
(d) compressing the powder mix of step (c) into tablet composition.
10. Solid oral Clopidogrel tablet formulation comprising mixture of pharmaceutically
acceptable solid and liquid lubricant as described in the example.