FIELD OF INVENTION

The present invention relates to oral pharmaceutical compositions comprising clopidogrel or its pharmaceutically acceptable monobasic acid salts, in admixture with at least one pharmaceutically acceptable excipient, wherein said compositions are bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

More particularly, the present invention is related to oral pharmaceutical compositions comprising clopidogrel, in the form of hydrogen bromide salt; in admixture with at least one pharmaceutically acceptable excipient, wherein said compositions exhibit at least 35 mg drug release within 45 minutes, when measured in pH 4.5 acetate buffer and further said compositions are also bio- equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

BACKGROUND OF THE INVENTION

Clopidogrel, chemically designated as (α S)-α-(2-chlorophenyl)-6,7- dihydrothieno [3,2-c] pyridine-5 (4H)-acetic acid methyl ester and having chemical structure as shown (Fig. I) is a platelet aggregation inhibitor which acts by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GP IIb/IIIa complex; and used for reducing the incidence of ischemic strokes, heart attacks or diseases like atherosclerosis.

Clopidogrel is commercialized in its bisulfate salt form (equivalent to 75mg clopidogrel) under the proprietary name PLAVDC™ tablets by Sanofi- Aventis Limited, France. It is indicated for use in reduction of recent myocardial infarction, recent stroke or established peripheral arterial disease and acute coronary syndrome.

Clopidogrel in its dextrorotatory form is described specifically in U.S. Patent No. 4,847,265. This patent specifically discloses the hydrogensulphate, hydrochloride, hydrobromide and taurocholate salts of clopidogrel.

Clopidogrel in a base or a monobasic acid salt form, is well known in the prior art to exhibit difficulties in formulating solid stable dosage forms, owing to their extreme hygroscopicity. The monobasic acid salts of clopidogrel are known to interact with certain formulation excipients and undergo degradation. The pharmaceutical compositions containing clopidogrel or monobasic acid salts thereof are not commercially available, except the bisulfate salt.

Hence there arises a need to formulate an oral pharmaceutical composition of clopidogrel salts other than bisulfate, for example hydrobromide salt which are bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

WO 2005/026174 discloses various polymorphic forms such as form 1, 2 and 3 of clopidogrel hydrobromide and pharmaceutical compositions comprising them.

WO 2005/048992 discloses pharmaceutical compositions comprising clopidogrel and its acid salts wherein clopidogrel particles are coated with polyvinyl acetate or a polyvinyl alcohol to overcome hygroscopic nature of clopidogrel.

EP 1970054A2 discloses clopidogrel tablets, especially that of hydrobromide salt and process of preparation thereof, wherein the tablets have a
reduced tendency of sticking to the punch and/or die surfaces of a conventional tablet compression machine.

WO 2008/129468 discloses pharmaceutical compositions comprising clopidogrel or monobasic acid salts thereof; especially hydrochloride salt in admixture with one or more hydrated excipients, wherein said compositions are bio-equivalent to PLAVIX™.

None of the prior arts disclose specifically oral pharmaceutical compositions of clopidogrel hydrobromide being bioequivalent to the commercially available tablets of PLAVIXTM.

It would have been a matter of routine skill for any person skilled in the art to formulate oral pharmaceutical compositions of clopidogrel hydrobromide from the teachings of the prior art.

However, the present inventors have surprisingly found that not all such pharmaceutical compositions of clopidogrel hydrobromide would be bio-equivalent to PLAVIX™, instead only those compositions which exhibit a drug release profile of at least 35 mg within 45 minutes, when measured in pH 4.5 acetate buffer; would purport to be bio-equivalent to the commercially available tablets of PLAVIX™.

The present inventors have thus disclosed oral pharmaceutical compositions of clopidogrel hydrobromide that reflect the above release parameter and hence are bio-equivalent to PLAVIX™.

SUMMARY AND OBJECTIVE OF THE INVENTION

The present invention relates to oral pharmaceutical compositions comprising clopidogrel or its pharmaceutically acceptable monobasic acid salts, in admixture with at least one pharmaceutically acceptable excipient, wherein said compositions are bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

More particularly, the present invention is related to oral pharmaceutical compositions comprising clopidogrel, in the form of hydrogen bromide salt; in admixture with at least one pharmaceutically acceptable excipient, wherein said compositions exhibit at least 35 mg drug release within 45 minutes, when measured in pH 4.5 acetate buffer and further said compositions are also bio- equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].
An aspect of the present invention provides a tablet comprising clopidogrel, in the form of hydrogen bromide salt, polymorphic forms and mixtures thereof and at least one pharmaceutically acceptable excipient.

An aspect of the present invention provides for clopidogrel hydrobromide compositions wherein the active ingredient is primarily present in the polymorphic form designated as "Form 1".

An aspect of the present invention provides for clopidogrel compositions in the form of oral tablet wherein the composition releases at least 35 mg of clopidogrel, more preferably at least 40mg of clopidogrel within 45 minutes, when measured in pH 4.5 acetate buffer.

An aspect of the present invention provides for clopidogrel compositions in the form of oral tablet wherein said tablet is bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

An aspect of the present invention provides for oral pharmaceutical compositions comprising clopidogrel hydrobromide in polymorphic form designated as 'Form 1' in admixture with at least one pharmaceutically acceptable excipient, wherein said compositions exhibit at least 35 mg drug release, more preferably at least 40 mg drug release within 45 minutes; when measured in pH 4.5 acetate buffer and further said compositions are also bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

An aspect of the present invention also provides for the process of preparing clopidogrel compositions in the form of oral tablet, wherein said tablet exhibits at least 35 mg drug release, more preferably at least 40 mg drug release within 45 minutes; when measured in pH 4.5 acetate buffer and further said tablet is also bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to oral pharmaceutical compositions comprising clopidogrel, in the form of hydrogen bromide salt; in admixture with at least one pharmaceutically acceptable excipient, wherein said compositions exhibit at least 35 mg drug release within 45 minutes, when measured in pH 4.5 acetate buffer and further said compositions are also bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

In context of the present invention, the terms "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for clopidogrel hydrobromide, its polymorphic forms and mixtures thereof.
The term "pharmaceutical compositions" as used herein refers to dosage form for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferred dosage forms are tablets or mini-tablets.

"Clopidogrel" as used herein refers to the hydrobromide salt and their pharmaceutically acceptable solvates, enantiomers, diastereomers and polymorphs thereof Preferably, clopidogrel is used herein as hydrobromide salt in various polymorphic form disclosed in the prior arts. More preferably, clopidogrel hydrobromide in the polymorphic form designated as "Form 1" and process to make the same as disclosed in W02005/026174 is used, which is specifically incorporated herein by reference.

Clopidogrel hydrobromide as described herein is used in a therapeutically effective amount in the composition. The term "therapeutically effective amount" intends to describe a dose of a clopidogrel salt, with respect to the free base, that is effective for the treatment or prophylaxis of a disease related to inhibition of platelet aggregation activity. The dose may range from about Img to about 300mg of clopidogrel, preferably in an amount from about l0mg to about 125mg, more preferably in an amount from about 50mg to about l00mg. The recommended dose of PLAVIX™ may be considered as a standard dose.

"Acetate Buffer" as used herein refers to acetate buffer as described in the official USP. Unless otherwise specified, it is usually prepared by dissolving 8.2 g of anhydrous CH3COONa (or 13.6 g of CH3C00Na.3H20) in 800 ml of distilled water; adding 5.75 ml of glacial CH3COOH and checking and adjusting the pH and finally bringing to volume with distilled water, in a 1 liter volumetric flask. It is well known to a person skilled in the art that pH 4.5 acetate buffer is a bio- relevant media which is an important tool to map the in-vivo behavior of any dosage form.

"Bio-equivalent" or "bio-equivalency" is well known to a person skilled in the art. It is generally established by a 90% Confidence Interval [CI] of between 0.80 and 1.25 for both Maximum Concentration of drug in plasma [Cmax] and Area Under the Curve [AUC] under USFDA regulatory guidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI for Cmax of between 0.70 to 1.43 under the European EMEA regulatory guidelines.

An embodiment of the present invention provides a tablet comprising clopidogrel, in the form of hydrogen bromide salt, in the polymorphic form designated as 'Form 1' and at least one pharmaceutically acceptable excipient that is bio-equivalent to commercially available PLAVIX™

One or more pharmaceutically acceptable excipients used according to the present invention includes without any limitations, those that are conventionally used, for e.g. fillers, disintegrants, binders, surfactants, glidants, lubricants, and optionally outer coating ingredients.

Suitable fillers according to the invention may include, but are not limited to lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, sugar alcohols such as mannitol and the likes, dextrates, dextrin, calcium carbonate, calcixmi sulfate, dibasic calcium phosphate dihydrate, tribasic calciimi phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch, and the like.

Suitable disintegrants according to the invention may include, but are not limited to cross-linked polypyrollidone commercially available as Crospovidone™ & Polyplasdone™, sodiimi starch glycolate, maize starch, pregelatinized starch, salts of carboxy methyl cellulose, microcrystalline cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl cellulose and the like.

Suitable binders according to the invention may include, but are not limited to starches, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, polyvinylpyrrolidone, gelatin, and the like.

Suitable surfactants according to the invention may include, but are not limited to sodium lauryl sulfate, quaternary ammonium salts, polysorbates, sorbitan esters, poloxamer, betaines, higher fatty alcohols such as cetyl alcohol and oleyl alcohol and the like.

Suitable glidants and lubricants according to the invention may include, but are not limited to silica, colloidal silica, magnesium trisilicate, talc, stearates, behenates, fumarates, hydrogenated castor oil, and the like.

Other pharmaceutically acceptable excipients that are of use include but not limited to film former, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

According to the present invention, the weight of the orally administrable tablet comprising from about 50-100mg of clopidogrel ranges between 125 to 375mg; and more preferably ranges about 150 to 350mg.

The active ingredient may be present in various polymorphic forms and mixtures thereof as disclosed in the prior art. More preferably, the active ingredient is present in polymorphic form designated as 'Form 1' disclosed in W02005/026174, which is specifically incorporated herein by reference.

The tablets according to this invention are prepared by granulation techniques such as dry granulation or wet granulation.

In dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable equipments. The ground particles or granules are then compressed into tablet form in conventional manner using lubricants, glidants, etc., which can take any of the conventional shapes, e.g., round, elongated, oval, etc. A tablet press fitted with suitably sized punches and dies is used to form the tablet.
Alternatively, wet granulation technique can also be used. According to this technique, the active ingredient, and other excipients are blended, for example, in a planetary mixer or a rapid mixer granulator. The powders are wetted with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and other hydro-alcoholic solvents such as isopropyl alcohol- water mixture. Binders, surfactants and other excipients may optionally be included in the granulating liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, and, if desired, the particles further reduced in size. Granulates obtained above are then compressed in conventional manner, using lubricants, glidants, etc., as required.

In an another embodiment, the process may involve combination of wet granulation and direct compression wherein the granules prepared by wet granulation are further blended with extra-granular inactive ingredients, lubricated and compressed to form the tablet.

The tablet can optionally be coated with an aesthetic or protective outer coat comprising polymers such as cellulose derivatives such as one which is commercially available as Opadry™.

Conventional coating machines, for example, pan coaters, rotary drum- type coaters, Wurster-type fluidizing coaters and fluidizing coaters may be employed in the method of the invention.

Another embodiment of the present invention provides for clopidogrel compositions in the form of oral tablet wherein the composition releases at least 35 mg of clopidogrel, more preferably at least 40 mg clopidogrel within 45 minutes; when measured in pH 4.5 acetate buffer. The in-vitro drug release profile of said compositions was measured in U. S. Dissolution apparatus II [Paddle] at 50 rpm in 1000ml of pH 4.5 acetate buffer.

A further embodiment of the present invention provides for clopidogrel compositions in the form of oral tablet wherein said tablet is bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

Bioequivalence studies were carried out between PLAVIX™ and compositions of the invention in the fasted state. The study was monitored in terms of Cmax & AUC achieved with the test product and reference product [PLAVIX™].

Plasma samples were assayed for clopidogrel using a validated high performance liquid chromatographic procedure. Values for clopidogrel pharmacokinetic parameters including observed Cmax, AUC^ and AUCo-t were calculated using standard methods.

As discussed above, the present inventors have surprisingly found that not all pharmaceutical compositions of clopidogrel hydrobromide would be bio- equivalent to PLAVIX™, instead only those compositions which exhibit a drug release profile of at least 35 mg, or more preferably at least 40 mg drug release within 45 minutes; when measured within pH 4.5 acetate buffer; reflects to be bio- equivalent to the commercially available tablets of PLAVIX™.
Hence a comparative composition is disclosed which does not exhibit the said dissolution limitation, thereby fails to be bioequivalent to PLAVIX™.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example-1

B. Brief Manufacturing Process:

1. Sift together Clopidogrel HBr, hydrogenated castor oil, pregelatinized starch, microcrystalline cellulose and mannitol through suitable mesh and load this in blender. Mix this for sufficient time.

2. Compact the above material in roll compacter to get sufficient hardness flakes.

3. Mill the compacted flakes and load it to a blender.

4. Sift Hydrogenated caster oil (extra-granular) through 50 mesh and add to blend of step 3. Blend this for sufficient time to get final blend.

5. Compress the final blend.

6. Disperse Opadry in suitable quantity of Purified water using stirrer.

7. Coat the compressed tablets from step 5 using coating suspension from step 6

Example-2

B. Brief Manufacturing Process:

1. Sift together Clopidogrel HBr, hydrogenated castor oil, pregelatinized starch, microcrystalline cellulose and mannitol through suitable mesh and load this in granulator. Mix this for sufficient time.

2. Dissolve polysorbate 80, povidone K-30 in isopropyl alcohol to get clear solution.

3. Add the solution from step 2 to the powder mix of step 1 to get sufficient wet mass.

4. Dry the wet mass from step 3 in drier.

5. Mill the dried granules and load it to a blender.

6. Sift crospovidone through 40 mesh and add to blend of step 5. Blend this for sufficient time

7. Sift hydrogenated caster oil through 60 mesh and add to the blend of step 6. Blend this for sufficient time to get final blend.

8. Compress the final blend.

9. Disperse Opadry White in suitable quantity of purified water using stirrer.

10. Coat the compressed tablets from step 8 using coating suspension fix)m step 9.
Example-3

B. Brief Manufacturing Process:

1. Sift together Clopidogrel HBr, Hydrogenated castor oil, Pregelatinized starch, microcrystalline cellulose and Maimitol through Quadro-co-mill/ mechanical sifter fitted with suitable screen and load this in rapid mixer granulator. Mix this for 15 minutes.

2. Dissolve polysorbate 80, povidone K 30 in isopropyl alcohol to get clear solution.

3. Add the solution from step 2 to the powder mix of step 1 keeping agitator at slow speed. Add extra isopropyl alcohol to get sufficient wet mass.

4. Dry the wet mass from step 3 in fluidized bed drier at 45 degree inlet temperature.

5. Mill the dried granules and load it to a blender.

6. Sift crospovidone through 40 mesh and add to blend of step 5. Blend this for 10 minutes

7. Sift Hydrogenated caster oil through 60 mesh and add to the blend of step 6. Blend this for 5 minutes to get final blend.

8. Compress the final blend.

9. Disperse Opadry in suitable quantity of Purified water using mechanical stirrer.

10. Coat the compressed tablets from step 8 using coating suspension from step 9.

Dissolution Study:

The tablets obtained from the above examples were studied for in-vitro drug release in U. S. Dissolution apparatus II [Paddle] at 50 rpm in 1000ml of pH 4.5 acetate buffer. The results are disclosed in the table below:

It should be noted that the composition disclosed in Example 1 does not meet the required dissolution limitation of at least 35 mg of drug release; more preferably at least 40 mg drug release within 45 minutes in the said dissolution media, thus emphasizing the importance of selective compositions comprising clopidogrel hydrobromide.

On the other hand, the composition disclosed in Example 2 and 3 do meet the required dissolution limitation and purports to be bioequivalent to the commercially available tablets of clopidogrel bisulphate [Plavix™], as seen in the bio-equivalency studies disclosed here.

Bio-equivalence Study:

Reference Product (R): Plavix™ (Clopidogrel bisulphate) Tablets 75 mg (Clopidogrel Bisulphate equivalent to 75 mg of Clopidogrel).

Test Product (T): Clopidogrel Hydrobromide tablets 75mg (Clopidogrel Hydrobromide equivalent to 75 mg of Clopidogrel).

The test and reference products were evaluated for the in-vivo studies under fasting condition (n=18) in healthy human volunteers. The plasma samples were analyzed for clopidogrel. The results of the study are shown below:

Table 2

The above result shows that tablet of Example 2 is bio-equivalent to the commercially available tablets of PLAVIX™.

Hence the bio-equivalence study demonstrate the importance of drug release of clopidogrel in pH 4.5 acetate buffer, which should be at least 35 mg, or preferably at least 40 mg within 45 minutes; failing which, said compositions of clopidogrel are not bio-equivalent to the commercially available tablets of PLAVIX™.

WE CLAIM

1. An oral pharmaceutical composition comprising clopidogrel or its salts thereof, in admixture with at least one pharmaceutically acceptable excipient, wherein said composition exhibits at least 35 mg drug release within 45 minutes when measured in pH 4.5 acetate buffer and is bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

2. The oral pharmaceutical composition according to claim 1, wherein said composition exhibits at least 40 mg drug release within 45 minutes when measured in pH 4.5 acetate buffer.

3. The oral pharmaceutical composition according to claim 1, wherein said clopidogrel salt is hydrogen bromide.

4. An oral pharmaceutical composition consisting essentially of:

wherein said composition exhibits at least 35 mg drug release within 45 minutes when measured in pH 4.5 acetate buffer and is bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVIX™].

5. An oral pharmaceutical composition consisting essentially of:

wherein said composition exhibits at least 35 mg drug release within 45 minutes when measured in pH 4.5 acetate buffer and is bio-equivalent to the commercially available tablets of clopidogrel bisulfate [PLAVDC™].

6. The oral pharmaceutical composition according to claim 1, wherein said pharmaceutically acceptable excipient is selected from a group consisting of fillers, disintegrants, binders, surfactants, glidants, lubricants, and optionally outer film formers.

7. The oral pharmaceutical composition according to claim 1, wherein said composition is in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads or mini-tablets.

8. The oral pharmaceutical composition according to claim 4 or 5, wherein said composition is optionally coated with a film coat.

9. A process for preparing an oral pharmaceutical composition comprising clopidogrel or its salts thereof, in admixture with at least one pharmaceutically acceptable excipient, wherein said process comprises
a. admixing clopidogrel HBr together with hydrogenated caster oil, pregelatinized starch, microcrystalline cellulose and mannitol to form a mixture;

b. dissolving polysorbate 80, povidone in isopropyl alcohol to get the binder solution;

c. granulating said mixture in step a) with said binder solution of step b to get the wet mass;

d. drying said wet mass and milling of the dried mass to get the granules;

e. mixing crospovidone and hydrogenated castor oil with said granules of step d;

f . compressing said granules of step e) to get the tablets;

g. optionally coating said tablet with Opadry™.