WO2007128476A1 - Pharmaceutical compositions containing clopidogrel hydrochloride - Google Patents

Pharmaceutical compositions containing clopidogrel hydrochloride Download PDF

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Publication number
WO2007128476A1
WO2007128476A1 PCT/EP2007/003865 EP2007003865W WO2007128476A1 WO 2007128476 A1 WO2007128476 A1 WO 2007128476A1 EP 2007003865 W EP2007003865 W EP 2007003865W WO 2007128476 A1 WO2007128476 A1 WO 2007128476A1
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Prior art keywords
clopidogrel
pharmaceutical composition
hydrochloride
carboxylic acid
composition
Prior art date
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Ceased
Application number
PCT/EP2007/003865
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French (fr)
Inventor
Manisha Rajesh Patil
Ramaswami Bharatrajan
Kamalakar Talasila
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Sandoz AG
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Sandoz AG
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine

Definitions

  • the present invention relates to pharmaceutical compositions containing clopidogrel hydrochloride, and in particular, to a pharmaceutical composition containing clopidogrel hydrochloride suitable for oral administration.
  • the present invention provides a pharmaceutical composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient wherein said composition is at least 98%free of carboxylic acid impurity.
  • Clopidogrel chemically known as the dextro-rotatory enantiomer of methyl alpha-5-(4, 5, 6, 7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate, is disclosed in U.S. Patent No. 4,847,265 (the '265 patent). According to the '265, clopidogrel is useful as a prophylactic and for the treatment of thromboembolism disorders, such as thrombosis, or myocardial infarction, by acting as a platelet aggregation inhibitor.
  • thromboembolism disorders such as thrombosis, or myocardial infarction
  • Atherosclerosis is characterized by the buildup of plaque on the walls of arteries, leading to thickening of the arterial wall and reduction in the elasticity of the arteries.
  • High cholesterol, high blood pressure, smoking and infection also may cause injury to the inner walls of the arteries, which leads to atherosclerosis.
  • Plaque formation leads to blood clotting which is due to platelet aggregation at the site of the injury. This clotting becomes an obstacle for the flow of the blood to the organs, causing heart attacks.
  • Clopidogrel binds adenosine diphosphate to its receptor and thereby induces platelet reduction, which is desirable in fighting atherosclerosis.
  • Clopidogrel is administered as clopidogrel bisulphate and marketed as tablets, in the United States and elsewhere, under the trade name PlavixTM.
  • European Patent 281459 discloses clopidogrel bisulfate prepared to improve stability and solubility of clopidogrel.
  • the '459 patent does not disclose the polymorphism of crystalline forms of clopidogrel bisulfate. Clopidogrel is currently administered as clopidogrel bisulphate.
  • U.S. Patent No. 6,429,210 (the '210 patent) describes, however, that clopidogrel bisulfate can exist in different polymorphic crystalline forms which differ from each other in terms of stability, physical properties, spectral characteristics and the process by which the different polymorphic crystalline forms are prepared.
  • a method of preparing the novel polymorph sulfate is disclosed in the '210 patent.
  • the powder of crystalline form II is more compact and much less electrostatic than crystalline form I and may, hence, have better formulation processibility.
  • clopidogrel bisulfate in its polymorphic crystalline form II is thermodynamically more stable than crystalline form I.
  • Plavix® which is commercially available clopidogrel bisulfate, contains crystalline form II, according to the '210 patent, as the active ingredient.
  • clopidogrel tablets suffer from degradation when formulated with excipients such as lactose monohydrate and mannitol.
  • the inventors of the present invention have sought to overcome these above-mentioned problems associated with a clopidogrel tablet composition.
  • the present invention provides a pharmaceutical composition suitable for oral administration which comprises clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurities.
  • the present invention also provides a pharmaceutical tablet composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurities.
  • the present invention further provides methods for manufacturing a pharmaceutical tablet composition containing clopidogrel HCl and a pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurities.
  • the present invention also provides a pharmaceutical tablet composition suitable for oral administration comprising clopidogrel hydrochloride and a pharmaceutically acceptable excipient, wherein said excipient prevents formation of carboxylic acid impurities.
  • the present invention provides a pharmaceutical composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurity.
  • the pharmaceutical composition is at least 99% free of carboxylic acid impurity.
  • the pharmaceutical composition is at least 99.5% free of carboxylic acid impurity.
  • the present invention also provides a pharmaceutical tablet composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurity.
  • the present invention further provides a method for manufacturing a pharmaceutical tablet composition containing clopidogrel HCl and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurity.
  • Clopidogrel Related Compound A which is impurity A
  • the chemical name of Clopidogrel Related Compound A is RS[(+)-(S)-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetic acid, and is detected by HPLC.
  • the present invention discloses a process for manufacturing a clopidogrel hydrochloride composition comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient.
  • the excipient includes, but is not limited, to a cellulose base, such as, for example, microcrystalline cellulose and hydroxypropyl cellulose.
  • the excipient may also be a lubricant, such as, for example, hydrogenated vegetable oil.
  • Clopidogrel hydrochloride can be prepared, for instance, according to European Patent 99802.
  • clopidogrel hydrochloride, microcrystalline cellulose and low-substituted hydroxypropyl cellulose are mixed together, lubricated with hydrogenated vegetable oil, compacted, and the compacts milled through an oscillating granulator, leading to the formation of granules.
  • the resultant granules are mixed with extra granular material, lubricated, and compressed into tablets, which are finally film coated.
  • Clopidogrel hydrochloride, Avicel PH 112 and L-HPC LH-I l were sifted through 20 meshes and mixed.
  • Hydrogenated vegetable oil was sifted through 40 meshes and the bled was lubricated and then compacted.
  • the core tablets were film-coated.
  • Hydrogenated vegetable oil was sifted through 40 mesh and the bled was lubricated and then compacted.
  • the core tablets were film-coated.
  • Hydrogenated vegetable oil was sifted through 40 mesh and the bled was lubricated and then compacted.
  • the core tablets were film-coated.
  • Hydrogenated vegetable oil was sifted through 40 mesh and the bled was lubricated and then compacted.
  • the core tablets were film-coated.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to pharmaceutical compositions containing clopidogrel hydrochloride suitable for oral administration wherein said composition is at least 98% free of carboxylic acid impurity.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING CLOPIDOGREL
HYDROCHLORIDE
Cross-Reference to Related Application
This application claims priority to Indian Provisional Application 690/MUM/2006, filed on May 4, 2006, and entitled "Stable Compositions of Clopidogrel HCL", the contents of which are incorporated by reference herein.
Field of the Invention
The present invention relates to pharmaceutical compositions containing clopidogrel hydrochloride, and in particular, to a pharmaceutical composition containing clopidogrel hydrochloride suitable for oral administration. The present invention provides a pharmaceutical composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient wherein said composition is at least 98%free of carboxylic acid impurity.
Background of the Invention
Clopidogrel, chemically known as the dextro-rotatory enantiomer of methyl alpha-5-(4, 5, 6, 7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate, is disclosed in U.S. Patent No. 4,847,265 (the '265 patent). According to the '265, clopidogrel is useful as a prophylactic and for the treatment of thromboembolism disorders, such as thrombosis, or myocardial infarction, by acting as a platelet aggregation inhibitor. Its anti-platelet activity makes clopidogrel an effective drug for reducing ischemic strokes, heart attacks and atherosclerosis, a vascular disease causing claudication. Atherosclerosis is characterized by the buildup of plaque on the walls of arteries, leading to thickening of the arterial wall and reduction in the elasticity of the arteries. High cholesterol, high blood pressure, smoking and infection also may cause injury to the inner walls of the arteries, which leads to atherosclerosis. Plaque formation leads to blood clotting which is due to platelet aggregation at the site of the injury. This clotting becomes an obstacle for the flow of the blood to the organs, causing heart attacks. Clopidogrel binds adenosine diphosphate to its receptor and thereby induces platelet reduction, which is desirable in fighting atherosclerosis. Clopidogrel is administered as clopidogrel bisulphate and marketed as tablets, in the United States and elsewhere, under the trade name Plavix™.
European Patent 281459 (the '459 patent) discloses clopidogrel bisulfate prepared to improve stability and solubility of clopidogrel. The '459 patent, however, does not disclose the polymorphism of crystalline forms of clopidogrel bisulfate. Clopidogrel is currently administered as clopidogrel bisulphate.
U.S. Patent No. 6,429,210 (the '210 patent) describes, however, that clopidogrel bisulfate can exist in different polymorphic crystalline forms which differ from each other in terms of stability, physical properties, spectral characteristics and the process by which the different polymorphic crystalline forms are prepared. In addition, a method of preparing the novel polymorph sulfate is disclosed in the '210 patent. According to the '210 patent, the powder of crystalline form II is more compact and much less electrostatic than crystalline form I and may, hence, have better formulation processibility. In particular, clopidogrel bisulfate in its polymorphic crystalline form II is thermodynamically more stable than crystalline form I. As such thermodynamic stability results in a delay of decomposition of medicines over time, Plavix®, which is commercially available clopidogrel bisulfate, contains crystalline form II, according to the '210 patent, as the active ingredient.
Often salts of clopidogrel, other than the bisulphate salt, exhibit difficulties in stabilization as these salts have a tendency to form carboxylic acid impurities when subjected to stress conditions. Furthermore, Applicant has found that clopidogrel tablets suffer from degradation when formulated with excipients such as lactose monohydrate and mannitol. The inventors of the present invention have sought to overcome these above-mentioned problems associated with a clopidogrel tablet composition.
Summary of the Invention
The present invention provides a pharmaceutical composition suitable for oral administration which comprises clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurities. The present invention also provides a pharmaceutical tablet composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurities.
The present invention further provides methods for manufacturing a pharmaceutical tablet composition containing clopidogrel HCl and a pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurities.
The present invention also provides a pharmaceutical tablet composition suitable for oral administration comprising clopidogrel hydrochloride and a pharmaceutically acceptable excipient, wherein said excipient prevents formation of carboxylic acid impurities.
Detailed Description of the Invention
The present invention provides a pharmaceutical composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurity. In one embodiment of the present invention, the pharmaceutical composition is at least 99% free of carboxylic acid impurity. In another embodiment, the pharmaceutical composition is at least 99.5% free of carboxylic acid impurity.
The present invention also provides a pharmaceutical tablet composition suitable for oral administration comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurity.
The present invention further provides a method for manufacturing a pharmaceutical tablet composition containing clopidogrel HCl and at least one pharmaceutically acceptable excipient, wherein said composition is at least 98% free of carboxylic acid impurity.
The chemical name of Clopidogrel Related Compound A, which is impurity A, is RS[(+)-(S)-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetic acid, and is detected by HPLC. The present invention discloses a process for manufacturing a clopidogrel hydrochloride composition comprising clopidogrel hydrochloride and at least one pharmaceutically acceptable excipient. The excipient includes, but is not limited, to a cellulose base, such as, for example, microcrystalline cellulose and hydroxypropyl cellulose.
The excipient may also be a lubricant, such as, for example, hydrogenated vegetable oil.
Clopidogrel hydrochloride can be prepared, for instance, according to European Patent 99802.
According to one embodiment of the present invention, clopidogrel hydrochloride, microcrystalline cellulose and low-substituted hydroxypropyl cellulose are mixed together, lubricated with hydrogenated vegetable oil, compacted, and the compacts milled through an oscillating granulator, leading to the formation of granules. The resultant granules are mixed with extra granular material, lubricated, and compressed into tablets, which are finally film coated.
The following examples further illustrate the present invention and are not intended to limit the scope of the invention.
EXAMPLES
Figure imgf000005_0001
Manufacturing Process:
1. Clopidogrel hydrochloride, Avicel PH 112 and L-HPC LH-I l were sifted through 20 meshes and mixed.
2. Hydrogenated vegetable oil was sifted through 40 meshes and the bled was lubricated and then compacted.
3. The compacts were milled, re-lubricated, and then compressed.
4. The core tablets were film-coated.
The above batch is subjected to stress study (results shown below).
Figure imgf000006_0001
Figure imgf000006_0002
Manufacturing Process: 1. Clopidogrel hydrochloride, glycine hydrochloride, Avicel PH 112 and 1-HPC LH-I l were sifted through 20 mesh and mixed.
2. Hydrogenated vegetable oil was sifted through 40 mesh and the bled was lubricated and then compacted.
3. The compacts were milled, re-lubricated, and then compressed.
4. The core tablets were film-coated.
The above batch is subjected to stress study (results shown below).
Figure imgf000007_0001
Figure imgf000007_0002
Manufacturing Process: 1. Clopidogrel hydrochloride, Avicel PH 1 12 and 1-HPC LH-11 were sifted through 20 mesh, and BHA and BHT were sifted through 40 mesh, and mixed.
2. Hydrogenated vegetable oil was sifted through 40 mesh and the bled was lubricated and then compacted.
3. The compacts were milled, re- lubricated, and then compressed.
4. The core tablets were film-coated.
The above batch is subjected to stress study (results shown below).
Figure imgf000008_0001
Figure imgf000008_0002
Manufacturing Process: 1. Clopidogrel hydrochloride, Avicel PH 112 and 1-HPC LH-I l were sifted through 20 mesh, and macrogol was sifted through 40 mesh, and mixed.
2. Hydrogenated vegetable oil was sifted through 40 mesh and the bled was lubricated and then compacted.
3. The compacts were milled, re-lubricated, and then compressed.
4. The core tablets were film-coated.
The above batch is subjected to stress study (results shown below).
Figure imgf000009_0001
When the stress data was evaluated, it was observed that the best composition was Example 1.

Claims

CLAIMS What is claimed is:
1. A pharmaceutical composition suitable for oral administration comprising:
(a) clopidogrel hydrochloride; and
(b) at least one pharmaceutically acceptable excipient, wherein said composition is at least 98 % free of carboxylic acid impurity.
2. The pharmaceutical composition of claim 1 in the form of a tablet, a sachet or a capsule.
3. The pharmaceutical composition of claim 1 wherein said excipient is a cellulose base.
4. The pharmaceutical composition of claim 3 wherein said cellulose base is microcrystalline cellulose, hydroxypropyl cellulose or a mixture thereof.
5. The pharmaceutical composition of claim 1 wherein said excipient is a lubricant.
6. The pharmaceutical composition of claim 5 wherein said lubricant is a hydrogenated vegetable oil.
7. The pharmaceutical composition of claim 1 wherein said excipient prevents formation of said carboxylic acid impurity.
PCT/EP2007/003865 2006-05-04 2007-05-02 Pharmaceutical compositions containing clopidogrel hydrochloride Ceased WO2007128476A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN690MU2006 2006-05-04
IN690/MUM/06 2006-05-04

Publications (1)

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WO2007128476A1 true WO2007128476A1 (en) 2007-11-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2475907A (en) * 2009-12-04 2011-06-08 Tcp Innovations Ltd Composition comprising a mixture of clopidogrel and droloxifene

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005048992A1 (en) * 2003-11-03 2005-06-02 Sandoz Ag Process for preparing clopidogrel compositions
WO2005070464A2 (en) * 2004-01-21 2005-08-04 Biofarma Ilac Sanayi Ve Ticaret A.S. A tablet formulation of clopidogrel bisulphate
WO2005117866A1 (en) * 2004-06-01 2005-12-15 Ivax Pharmaceuticals S.R.O. Amorphous clopidogrel hydrochloride and its antithrombotic use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005048992A1 (en) * 2003-11-03 2005-06-02 Sandoz Ag Process for preparing clopidogrel compositions
WO2005070464A2 (en) * 2004-01-21 2005-08-04 Biofarma Ilac Sanayi Ve Ticaret A.S. A tablet formulation of clopidogrel bisulphate
WO2005117866A1 (en) * 2004-06-01 2005-12-15 Ivax Pharmaceuticals S.R.O. Amorphous clopidogrel hydrochloride and its antithrombotic use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2475907A (en) * 2009-12-04 2011-06-08 Tcp Innovations Ltd Composition comprising a mixture of clopidogrel and droloxifene

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