WO2008001201A2

WO2008001201A2 - Pharmaceutical compositions of clopidogrel

Info

Publication number: WO2008001201A2
Application number: PCT/IB2007/001753
Authority: WO
Inventors: Narayanan Murali; Anandkrishna Laxmikant Kulkarni; Abdul Rehman Khan; Girish Kumar Jain; Amol Prasadrao Ujjainkar
Original assignee: Wockhardt Ltd
Priority date: 2006-06-28
Filing date: 2007-06-27
Publication date: 2008-01-03
Also published as: WO2008001201A3

Abstract

The present invention relates to pharmaceutical compositions of clopidogrel or pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of such compositions.

Description

PHARMACEUTICAL COMPOSITIONS OF CLOPIDOGREL

Field of the Invention

Background of the Invention

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 (α S)-α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H)-acetic acid methyl ester having structure of 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.

FORMULA I U.S. Patent No. 4,847,265 discloses dextro-rotatory isomer of clopidogrel substantially separated from the levo-rotatory isomer and its pharmaceutically acceptable salts.

U.S. Patent Nos. 6,429,210 and 6,504,030 disclose crystalline polymorph (Form 2) of (+)-(S) clopidogrel hydrogen sulfate, its process of preparation and pharmaceutical compositions containing it.

U.S. Patent No. 6,914,141 and European Patent No. EP 1310245B1 disclose pharmaceutical tablets comprising clopidogrel bisulfate and a lubricant selected from zinc stearate, stearic acid, and sodium stearyl fumarate.

Several references disclose pharmaceutical compositions comprising different polymorphic forms of clopidogrel hydrogensulfate, and pharmaceutically acceptable excipients. For example, U.S. Patent Nos. 6,767,913; 7,074,928; European Patent Application Nos. EP 1467735; EP 1474427; U.S. Patent Application Nos. 2003225129; 2005113406 and International Publication No. (PCT) WO2004/052966.

International Publication No. (PCT) WO2004/098593 discloses compositions comprising amorphous clopidogrel hydrogen sulfate; either or both of calcium stearate and magnesium stearate; a non-hygroscopic additive; and at least one excipient.

International Publication No. (PCT) W 02007008045 discloses compositions containing clopidogrel bisulfate and pregelatinized starch.

Clopidogrel being a fine powder and hygroscopic in nature, absorbs moisture and poses problem of sticking during tabletting. Sticking problem has also been observed with a dry granulation technique. Further, use of magnesium stearate, which is the most commonly used lubricant also causes degradation of clopidogrel bisulfate. The present invention addresses and overcomes these commonly encountered, problems.

Summary of the Invention

In one general aspect there is provided a melt-granulated pharmaceutical composition of clopidogrel or salts thereof. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.

In another general aspect there is provided a melt-granulated pharmaceutical composition that includes clopidogrel or salts; polyethylene glycol (PEG) and one or more pharmaceutically acceptable excipients.

The one or more pharmaceutically pharmaceutically acceptable excipients may include one or more of binders, fillers, lubricants, disintegrants, and glidants. The lubricants may include one or more of mineral oils, vegetable oils or glyceryl esters of fatty acids.

In another general aspect there is provided a process for preparation of a melt granulated pharmaceutical composition that includes clopidogrel or salts thereof. The process includes melt granulating clopidogrel or salts thereof with PEG and blending the granules with one or more pharmaceutically acceptable excipients.

In another general aspect there is provided a pharmaceutical composition that includes a pre-coated clopidogrel or salts thereof. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the clopidogrel or salts thereof may be coated with one or more polymers and/or oil mixture. Alternatively, the clopidogrel or salts thereof may be coated with one or more low substituted hydroxypropyl celluloses and/or castor oil mixture.

In another general aspect there is provided a pharmaceutical composition that includes pre-coated granules of clopidogrel or salts thereof. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the granules of clopidogrel or salts thereof may be coated with one or more polymers and/or oil mixture. Alternatively, the granules of clopidogrel or salts thereof may be coated with one or more low substituted hydroxypropyl celluloses and/or castor oil mixture.

In another general aspect there is provided a process for preparation of a pharmaceutical composition. The process includes mixing clopidogrel or salts thereof with one or more pharmaceutically acceptable excipients to form a pre- mix and granulating the pre-mix with a polymer-oil mixture. The process may further include mixing the granules with one or more pharmaceutically acceptable excipients.

Alternatively, the pre-mix may be compacted to form flakes and the flakes, may be granulated with a polymer-oil mixture or optionally compacting the pre-mix to form granules and coating the granules with a polymer-oil mixture. The process may further include mixing the granules with one or more pharmaceutically acceptable excipients.

The "pharmaceutical composition" of the present invention as used herein, is meant for oral administration to mammals and refers to tablets, capsules, granules, beads, caplets, disc, pills, sachet, suspension, spheroids, minitablets, granules in a capsule, beads in a capsule, minitablets in a capsule, and the like. Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutical composition may include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more of binders, fillers, lubricants, glidants, disintegrants, and the like.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

The present inventors have now developed melt granulated pharmaceutical compositions of clopidogrel or salts thereof. The clopidogrel may be melt- granulated with one or more polyethylene glycols (PEG). The melt, granulation with PEG leads to coating of clopidogrel or salts thereof with PEG, which results in preventing the sticking problem and providing better formulation stability. The inventors have avoided the use of stearates and used melt granulation process for better processing and increased formulation stability. It was further noticed that when clopidogrel or salt thereof as such or granules of clopidogrel or salts thereof are coated with polymer and/or oil mixture, it also results in preventing the sticking problem and provides better formulation stability.

The pharmaceutical composition may be prepared by a melt granulation process that includes the granules of clopidogrel bisulfate. The granules may be prepared by heating a mixture of clopidogrel and PEG from about 50 ⁰C to about 80 ⁰G.

The granulation process may be carried out in two steps. In the first step, a mixture of clopidogrel and a part of PEG may be heated from about 50 °C to about 80 °C along with fluidization to coat the clopidogrel thereby resulting in the formation of granules after drying. In the second step of granulation, these granules may be mixed with remaining part of PEG and again heated from about 50 °C to about 80 ⁰C along with fluidization to granulate clopidogrel. The resultant granules that include clopidogrel and PEG may be further mixed with extragranular pharmaceutically acceptable excipients, and may be compressed into tablets.

Suitable PEG may include 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 of the invention may also be prepared by mixing clopidogrel or salts thereof with pharmaceutically acceptable excipients to form a pre-mix. The pre-mix may be granulated with a solution of a polymer-oil mixture. The obtained granules may be mixed with other pharmaceutically acceptable excipients and can be compressed into tablets.

The pharmaceutical composition of the invention may also be prepared by mixing clopidogrel or salts thereof with pharmaceutically acceptable excipients to form a pre-mix. The pre-mix may be compacted to form flakes. The flakes may be granulated with a solution of a polymer-oil mixture. The obtained granules may be mixed with other pharmaceutically acceptable excipients and may be compressed into tablets.

The pharmaceutical composition of the invention may also be prepared by mixing clopidogrel or salts thereof with pharmaceutically acceptable excipients to form a pre-mix. The pre-mix may be compacted to form flakes. The flakes may be converted into granules. The obtained granules may be coated with a solution of a polymer-oil mixture in a fluid bed coater. The obtained granules may be mixed with other pharmaceutically acceptable excipients and may be compressed into tablets. /

Suitable polymers may include one or more of hydroxy propyl cellulose, hydroxy propyl methylcellulose, ethyl cellulose, hydroxy ethyl cellulose, methylcellulose, and the like.

Suitable oils may include one or more of mineral oils and vegetable_^oils, wherein mineral oils and vegetable oils comprises castor oil, hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, and the like.

The solution of polymer-oil mixture can be made in methanol, ethanol, isopropanol, ether, chloroform, dimethylsulfoxide (DMSO), dimethylformamide (DMF), methylene chloride and the like.

The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, d i si nteg rants, and glidants.

Suitable binders may include one or more of sugars, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.

Suitable fillers may include one or more of lactose, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, sorbitol, powdered sugar, and the like.

Suitable lubricants may include 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 may further include one or more of hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, glycerol monostearate, glycerol monobehenate, glyceryl behenate, glyceryl palmitostearate, and the like.

Suitable glidants may include one or more of colloidal silicon dioxide, talc or cornstarch, and the like. Suitable disintegrants may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycollate, and the like.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications¹ 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 provides the composition of batches of the present invention.-

Table 2 provides the dissolution data for the clopidogrel bisulfate 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.

Table 1

Procedure: Melt granulation of clopidogrel bisulfate with PEG 6000 was carried out in two steps. In the first step, clopidogrel bisulfate and a part of PEG-6000 were sifted, mixed and heated from 50 °C to 80 °C along with fluidization resulting in melting of PEG 6000 which led to coating of clopidogrel particles with PEG 6000. The mixture thus obtained was mixed with remaining quantity of PEG 6000 to get a uniform mixture. In the second step, this mixture was again heated resulting in melting of PEG 6000 and hence granulation of clopidogrel bisulfate with molten PEG 6000. The granules were dried, 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. The final blend thus obtained was compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of opadry.

Table 2: Dissolution data

Example 2:

Table 3 provides the composition of batches of the present invention.

Table 4 provides the dissolution data for the clopidogrel bisulfate tablets prepared as per the formula given in Table 3. 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.

Table 3

Procedure: Melt granulation of clopidogrel bisulfate with PEG 6000 was carried out in two steps. In the first step, clopidogrel bisulfate, mannitol and a part of PEG-6000 were sifted, mixed and heated from 50 ⁰C to 80 ⁰C along with fluidization resulting in melting of PEG 6000 which led to coating of clopidogrel particles with PEG 6000. The mixture thus obtained was mixed with remaining quantity of PEG 6000 to get a uniform mixture. In the second step, this mixture was again heated resulting in melting of PEG 6000 and hence granulation of clopidogrel bisulfate with molten PEG 6000. The granules were dried, 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. The final blend thus obtained was compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of opadry.

Table 4: Dissolution data

Example 3:

Table 5 provides composition of batches of the present invention. Table 6 provides the dissolution data for the clopidogrel bisulfate tablets prepared as per the formula given in Table 5. 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.

Table 5

Procedure: Clopidogrel bisulfate was mixed with microcrystalline cellulose, lactose in rapid mixer granulator (RMG) and granulated with alcoholic solution of a low substituted hydroxypropyl cellulose (HPC-L) and castor oil in a rapid mixer granulator (RMG). The granules were dried and mixed with colloidal silicon dioxide, crospovidone, talc and lubricated with glyceryl behenate, hydrogenated castor oil. The lubricated blend was compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of Opadry.

Table 6: Dissolution data

Example 4:

Table 7 provides composition of batches of the present invention. Table 8 provides the dissolution data for the clopidogrel bisulfate tablets prepared as per the formula given in Table 7. 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.

Table 7

Procedure: Clopidogrel bisulfate was mixed with microcrystalline cellulose, lactose, polyethylene glycol in a double cone blender and the blend was compacted using a roll compactor. The flakes were converted into granules. The granules were granulated with alcoholic solution of a low substituted hydroxypropyl cellulose (L-HPC) and castor oil in a rapid mixer granulator (RMG). The granules were dried and mixed with colloidal silicon dioxide, crospovidone, talc and lubricated with glyceryl behenate, hydrogenated castor oil. The lubricated blend was compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of Opadry.

Table 8: Dissolution data

Example 5:

Table 9 provides composition of batches of the present invention.

Table 10 provides the dissolution data for the clopidogrel bisulfate tablets prepared as per the formula given in Table 9. 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.

Table 9

Procedure: Clopidogrel bisulfate was mixed with microcrystalline cellulose, lactose, polyethylene glycol in a double cone blender and the blend was compacted using a roll compactor. The flakes were converted into granules. The granules were coated with alcoholic solution of a low substituted hydroxypropyl cellulose (HPC-L) and castor oil in fluidized bed coater. The granules were dried and mixed with colloidal silicon dioxide, crospovidone, talc and lubricated with glyceryl behenate, hydrogenated castor oil. The lubricated blend was compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of Opadry. Table 10: Dissolution data

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.

Claims

We claim:

1. A melt-granulated pharmaceutical composition comprising clopidogrel or salts thereof.

2. The pharmaceutical composition of claim 1 , wherein the composition comprises clopidogrel or salts thereof melt granulated with polyethylene glycol (PEG) and one or more pharmaceutically acceptable excipients.

3. The pharmaceutical composition of claim 2, wherein the PEG comprises one or more of PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 6000, PEG 8000, and PEG 20000.

4. The pharmaceutical composition of claim 3, wherein the PEG is PEG 6000.

5. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable excipients comprises one or more of binders, fillers, lubricants, disintegrants, and glidants.

6. The pharmaceutical composition of claim 5, wherein the lubricants comprise one or more of mineral oils, vegetable oils, glyceryl esters of fatty acids and mixtures thereof.

7. The pharmaceutical composition of claim 6, wherein the lubricant comprises one or more of hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, glycerol monostearate, glycerol monobehenate, glyceryl behenate, and glyceryl palmitostearate.

8. The pharmaceutical composition of claim 1 , wherein the composition is in the form of a tablet, a capsule, a caplet, a disc, pills, a sachet, suspension, spheroids, minitablets, granules in a capsule, pellets in a capsule, or minitablets in a capsule.

9. A process for preparing a pharmaceutical composition of clopidogrel or salts thereof, the process comprising a step of melt granulating the clopidogrel or salts thereof with PEG.

10. The process of claim 9, wherein the PEG comprises one or more of PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 6000, PEG 8000, and PEG 20000.

11. The process of claim 10, wherein the PEG is PEG 6000.

12. The process of claim 9, wherein the process further comprises blending the granules with one or more pharmaceutically acceptable excipients.

13. The process of claim 12, wherein the pharmaceutically acceptable excipients comprises one or more of binders, fillers, lubricants, disintegrants and glidants.

14. A pharmaceutical composition comprising pre-coated clopidogrel or salts thereof optionally with one or more pharmaceutically acceptable excipients.

15. The pharmaceutical composition of claim 14, wherein the clopidogrel or salts thereof is coated with one or more polymers and/or oil mixture.

16. The pharmaceutical composition of claim 15, wherein the polymers comprise one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and methyl cellulose.

17. The pharmaceutical composition of claim 15, wherein the oils comprise one or more of castor oil, hydrogenated vegetable oil, hydrogenated castor oil, and light mineral oil.

18. The pharmaceutical composition of claim 15, wherein the clopidogrel or salt thereof is coated with one or more low substituted hydroxypropyl celluloses and/or castor oil mixture.

19. The pharmaceutical composition of claim 14, wherein the composition comprises pre-coated granules of clopidogrel or salts thereof.

20. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable excipients comprise one or more of binders, fillers, lubricants, disintegrants, and glidants.

21. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a caplet, a disc, pills, sachets, suspension, spheroids, minitablets, granules in a capsule, pellets in a capsule, and minitablets in a capsule.

22. A process for preparing a pharmaceutical composition of clopidogrel or salts thereof, the process comprising a step of mixing clopidogrel or salts thereof with one or more pharmaceutically acceptable excipients to form a pre-mix, and granulating the pre-mix with a polymer-oil mixture.

23. The process of claim 22, wherein the process further comprises mixing the granules with one or more pharmaceutically acceptable excipients.

24. The process of claim 23, wherein the pharmaceutically acceptable excipients comprise one or more of binders, fillers, lubricants, disintegrants, and glidants.

25. The process of claim 22, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a capiet, a disc, pills, sachets, suspension, spheroids, minitablets, granules in a capsule, pellets in a capsule, and minitablets in a capsule.

26. A process for preparing a pharmaceutical composition of clopidogrel or salts thereof, the process comprising a step of mixing clopidogrel or salts thereof with one or more pharmaceutically acceptable excipients to form a pre-mix, compacting the pre-mix to form flakes and granulating the flakes with a polymer-oil mixture.

27. The process of claim 26, wherein the process further comprises blending , the granules with one or more pharmaceutically acceptable excipients.

28. A process for preparing a pharmaceutical composition of clopidogrel or salts thereof, the process comprising a step of mixing clopidogrel or salts thereof with one or more pharmaceutically acceptable excipients to form a pre-mix, compacting the pre-mix to form granules and coating the granules with a polymer-oil mixture.

29. The process of claim 28, wherein the process further comprises blending the granules with one or more pharmaceutically acceptable excipients.