EP1802280A2 - Compositions contenant du clopidogrel - Google Patents

Compositions contenant du clopidogrel

Info

Publication number
EP1802280A2
EP1802280A2 EP05807697A EP05807697A EP1802280A2 EP 1802280 A2 EP1802280 A2 EP 1802280A2 EP 05807697 A EP05807697 A EP 05807697A EP 05807697 A EP05807697 A EP 05807697A EP 1802280 A2 EP1802280 A2 EP 1802280A2
Authority
EP
European Patent Office
Prior art keywords
clopidogrel
premix
pharmaceutically acceptable
clopidogrel base
acceptable excipient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05807697A
Other languages
German (de)
English (en)
Other versions
EP1802280A4 (fr
Inventor
Mamta C/O Hrudaya Womens Hostel MISHRA
Arunava Ghosh
Gurvinder Singh
Billa Praveen Flat No. 504 Block A Usha REDDY
Mailatur Sivaraman Flat No. 508 MOHAN
Indu Flat No. 1401 Sai Raghava Towers BHUSHAN
Prasada Raju Flat No. 404 Shiva Durga VETUKURI
Sreenadhacharyulu Flat No.: G13 Saiteja KANDALA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP1802280A2 publication Critical patent/EP1802280A2/fr
Publication of EP1802280A4 publication Critical patent/EP1802280A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to premix compositions comprising clopidogrel and a pharmaceutically acceptable excipient, and processes for the preparation of the premix compositions.
  • the invention further relates to pharmaceutical dosage forms, medicaments and products containing the premix and processes for preparing the same.
  • the invention also discloses therapeutic uses and methods of treatment employing the premix composition comprising clopidogrel or such pharmaceutical dosage forms, medicaments or products.
  • Atherosclerosis is the buildup of plaque in the wall of the arteries leading to thickening and reduction in the elasticity of the arteries. Atherosclerosis results from injury to the inside layer of the artery. The injury is caused by common activities and diseases such as high cholesterol, high blood pressure, smoking, and infections.
  • Plaques form on the inner walls of the arteries at the sites of injury to the blood vessels.
  • the plaques are mainly composed of fatty tissue and smooth muscle cells.
  • the formation of plaque often leads to blood clotting due to platelet aggregation at the site of injury. This clotting may result in a reduction or elimination of blood flow to vital organs causing heart attacks or other serious conditions.
  • the plaque may also rupture and send a blood clot through the artery, referred to as an embolus, which if deposited in a smaller blood vessel may completely block blood flow to the organ which it supplies blood.
  • Antiplatelet activity is desirable in inhibiting the often-fatal results of atherosclerosis.
  • Clopidogrel is an inhibitor of induced platelet aggregation and acts by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into the active form. It shows antiplatelet activity for a duration of about ten days after medication has been stopped. Clopidogrel has the chemical name S-(+)-methyl- (2-chlorophenyl)-(6,7- dihydro-4H-thieno [3,2-C] pyrid-5-yl) acetate, or (+)-(S)- ⁇ -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate, and has structural Formula I.
  • Clopidogrel is a well known antithrombotic agent commercially available as PLAVIXTM tablets which contain about 98 mg of clopidogrel hydrogen sulfate (the molar equivalent of 75 mg of clopidogrel base).
  • Clopidogrel is disclosed in U.S. Patent Nos. 4,529,596 (EP 0099802, JP 59027895) and 6,258,961.
  • U.S. Patent No. 4,529,596 discloses a racemic mixture of clopidogrel and processes for preparing such mixture.
  • U.S. Patent No. 5,036,156 EP 0420706, JP 3120286
  • U.S. Patent No. 5,036,156 discloses a method for preparing an intermediate in the synthesis of clopidogrel, 2-chloro-a-bromophenylacetic acid, and a process for condensing its methyl ester with tetrahydrothienopyridine.
  • French Patent No. 2769313 discloses an intermediate in the synthesis of clopidogrel, (R)-2-benzenesulfonyloxy-2-(2-chlorophenyl)acetic acid methyl ester, and processes for its preparation. This document further discloses converting the ester to clopidogrel by nucleophilic substitution with tetrahydrothienopyridine.
  • U.S. Patent No. 5,036,156 discloses preparation of pyridine derivatives by reacting a benzaldehyde with tribromomethane and potassium hydroxide in water and in the presence of an inert solvent.
  • European Patent 0 281 459 B describes crystalline Form 1 of (+)- clopidogrel bisulfate and European Patent Application 1 087 976 A describes its crystalline Form 2.
  • Amorphous clopidogrel and its salts pharmaceutically acceptable preparations containing amorphous clopidogrel with a homo- or co-polymer of N-vinyl pyrrolidone and methods to prepare and use them.
  • Amorphous clopidogrel specially in the form of a complex with a homo- or co-polymer of N-vinyl pyrrolidone, is said to have several advantages over the crystalline clopidogrel salts, such as improved stability, higher solubility, non- hygroscopicity and improved processability.
  • the application describes the preparation of the complexes through the co-dissolution of the clopidogrel base (either directly as a base or generated in situ through the addition of an acid to a solution of clopidogrel bisulfate) and the N-vinyl pyrrolidone polymer followed by evaporation of solvent to form a dry residue.
  • Example 6 of PCT application WO 2004/026879 describes the conversion of clopidogrel base into a complex with polyvinylpyrrolidone.
  • the present invention relates to a premix composition comprising clopidogrel base and a pharmaceutically acceptable excipient and processes for the preparation of the premix composition.
  • the invention further relates to pharmaceutical dosage forms, medicaments and products containing the clopidogrel base premix and processes for preparing the same.
  • the invention also relates to clopidogrel base premixes and pharmaceutical compositions thereof comprising clopidogrel base having polymorphic stability.
  • Clopidogrel base in accordance with an aspect of the present invention is substantially free from crystalline clopidogrel.
  • a premix composition containing clopidogrel is prepared by adsorbing a solution comprising clopidogrel base onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent.
  • the premix can be used directly, or used in combination with additional excipients to prepare desired pharmaceutical dosage forms.
  • the invention further includes use of the clopidogrel base premix and the pharmaceutical compositions containing the premix in the treatment of disease conditions.
  • Fig. 1 is an X-ray diffraction pattern of a clopidogrel base premix.
  • Fig. 2 is an X-ray diffraction pattern of tablets containing a clopidogrel base premix.
  • Fig. 3 is an X-ray diffraction pattern of placebo tablets.
  • premix refers to a solid composition, generally powders or granules, of clopidogrel base adsorbed onto at least one pharmaceutically acceptable excipient that is compatible with clopidogrel base.
  • the flowability, processability and other characteristics of the clopidogrel base premix of the invention can be readily controlled through the choice of appropriate pharmaceutically acceptable excipients onto which the clopidogrel base is adsorbed.
  • the particle size and distribution of the clopidogrel base premix of the invention can be readily controlled by the proper choice of the pharmaceutically acceptable excipient(s) with a defined particle size and distribution. Subsequent processing, during which the clopidogrel base is adsorbed onto these excipients is generally does not result in a significant change in the particle size and distribution of the final premix.
  • an excipient having the required large particles should be appropriately chosen and vice versa if a smaller particle size premix is desired.
  • Mixing of more than one particle size excipient species is within the scope of the invention. Also, included are mixtures of premixes of clopidogrel base wherein the excipients onto which the clopidogrel base has been adsorbed, are different.
  • the clopidogrel base premix typically has a weight ratio of clopidogrel base to the pharmaceutically acceptable excipient from about 1 :1 to about 1 :10.
  • the pharmaceutically acceptable excipient can be a mixture of more than one excipients.
  • the solid-state physical properties of clopidogrel base such as for example, the flowability and handling of the semisolid mass, are significantly modified.
  • Clopidogrel base occurs as a semisolid mass which is difficult to handle and to process into a pharmaceutical formulation.
  • the flowability of the clopidogrel base is significantly enhanced by its conversion into the premix according to this invention.
  • the Carr Index is the percent ratio of the difference between tapped density and bulk density to tapped density described as:
  • Carr Index [(Tapped density - Bulk density) ⁇ Tapped density] x 100%
  • the densities can be determined using the standard test method 616 (Bulk Density and Tapped Density) of United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland, U.S.A., 1999.
  • Carr Index values below about 15% represent materials with very good flow properties and values above about 40% represent materials with very poor flow properties.
  • the clopidogrel base premix of the present invention has a Carr Index which is substantially lower than the 40% described for products with poor flow properties.
  • Values for Carr Index for the clopidogrel premix of the invention are generally less than about 35%, or less than about 30%, or less than about 25%, or less than about 20%, or less than about 15%. This indicates significantly improved flowability for the clopidogrel base through its conversion into a premix when compared with the clopidogrel base alone, which is a sticky semisolid material that does not flow when poured from a vial. Such a significant improvement in the flow properties of a material indicates superior handling capabilities during processing into pharmaceutical dosage forms.
  • Another important solid-state property of a pharmaceutical compound is its rate of dissolution in an aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach or in intestinal fluids can have therapeutic consequences because it affects the rate at which an orally-administered active ingredient reaches the bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid-state form of a compound may also affect its behavior on compaction and its storage stability.
  • the clopidogrel base in the form of the premix of the invention can be used to prepare pharmaceutical products having rapid release of the clopidogrel base into the digestive system of a patient.
  • a process for the manufacture of a clopidogrel base premix which comprises:
  • the organic solvents suitable for the preparation of the clopidogrel base solution include but are not limited to alcohols, such as, for example, ethanol and isopropanol, water, acetic acid, acetone, anisole, ethyl acetate, isopropyl acetate, and the like, including mixtures thereof.
  • alcohols such as, for example, ethanol and isopropanol
  • water acetic acid, acetone, anisole, ethyl acetate, isopropyl acetate, and the like, including mixtures thereof.
  • Any organic solvent is acceptable as long as the solvent is volatile (allowing substantially complete removal from the clopidogrel base premix), is a good solvent for the clopidogrel base and is compatible with the clopidogrel at the temperatures of processing.
  • the temperature of the solvent can be raised to achieve complete solubilization of the clopidogrel base in the solvent(s), and/or to achieve a higher solute concentration.
  • the concentration of clopidogrel base in the solution can be any concentration desired by the process operator, but is generally in the range of about 100 to 300 mg/ml, or about 145 to 300 mg/ml, or about 290 to 300 mg/ml.
  • concentration of the clopidogrel base in the solution will result from lower amounts of solvent(s) that are utilized, and this is usually desired to maximize clopidogrel concentration in the final premix.
  • concentration of the clopidogrel base in the solvent(s) will be determined by the solubility in the solvent(s), temperature of dissolution, compatibility, ease of solvent removal and other parameters that are readily apparent to a person skilled in the art.
  • the clopidogrel base solution can optionally also contain other pharmaceutically acceptable additives such as, without limitation thereto, an antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and the like; an oil; a povidone; and mixtures of two or more additives.
  • an antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and the like
  • an oil such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and the like
  • oil such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and the like
  • oil such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and the like
  • a povidone such as butylated hydroxyanisole, butylated hydroxytoluene,
  • Useful excipients for adsorbing the clopidogrel solution to prepare the premix include, but are not limited to: diluents like starch, pregelatinized starch, lactose, mannitol, sorbitol, xylitol, sucrose, dextrates, dextrin, dextrose, microcrystalline cellulose, powdered cellulose, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, and mixtures thereof; disintegrants like starch, pregelatinized starch, alginic acid, sodium alginate, crospovidone, sodium starch glycolate, croscarmellose and mixtures thereof; binders such as starches, microcrystalline cellulose, methylcellulose, cellulose ethers, sodium carboxymethylcellulose, ethylcellulose, dextrose, lactose, sucrose, sorbitol, mannitol, polyethylene glycol, polyvinylpyr
  • the solution of clopidogrel base in the organic solvent is adsorbed onto an excipient or a mixture of excipients, typically using equipment such as a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor, and the like to achieve uniformity.
  • the clopidogrel base solution can be added to the mixture of excipients rapidly or gradually, as desired.
  • the mode of addition could be, for example, simple pouring or more refined techniques such as pumping using a positive displacement pump or sprinkling or spraying onto the surface of the mixture of excipients.
  • Other techniques known to those skilled in the art for mixing solutions with solid substances are all included herein without limitation.
  • the solution containing clopidogrel base in the solvent can be added to the excipient or mixture of excipients either at the temperature of solubilization or at another temperature, as desired.
  • the wet mass thus produced is dried to provide the clopidogrel base premix of the invention.
  • the drying conditions are adjusted such as to obtain a desired solvent content, such as about 0.5-3 percent by weight, using any drying method such as, for example, tray drying, fluid bed drying, rotary cone vacuum drying, agitated thin film drying, lyophilization, and the like. Other methods of drying are all included herein without limitation.
  • the drying temperature can frequently be made lower by applying a reduced pressure.
  • Clopidogrel base used in the present invention can be obtained by techniques and processes known to a person skilled in the art. Such processes include, for example, dissolution of any clopidogrel salt in a suitable organic solvent or mixture of solvents followed by neutralization of acidic components to provide the free base required for the invention. Other processes to convert a salt form of clopidogrel into its free base could also be used.
  • the salts of clopidogrel which find use in the conversion to the base required for the invention include, without limitation, any pharmaceutically acceptable salt of clopidogrel and include, for example, salts with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, or phosphoric acids and the like; salts with organic acids such as, for example, aliphatic mono- and di- carboxylic acids, phenyl-substituted acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids; and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, or phosphoric acids and the like
  • salts with organic acids such as, for example, aliphatic mono- and di- carboxylic acids, phenyl-substituted acids, phenyl-substituted
  • Such salts with organic acids include for example acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methyl benzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, oxalate, phthalate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propionate, phenyl propionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenes
  • the clopidogrel base premix of the invention can be further processed into various pharmaceutical dosage forms as is, or by combining with pharmaceutically acceptable excipients.
  • the different pharmaceutical dosage forms where the clopidogrel premix of the invention finds utility include, for example, tablets, capsules (hard and soft gelatin), granules, lozenges, sachets, pills, oral solutions, suspensions, and the like.
  • Other pharmaceutically acceptable additives may be utilized as required for conversion of the premix into the final pharmaceutical dosage form and include, for example, diluents, lubricants, glidants, disintegrating agents, wetting agents, and the like.
  • Useful pharmaceutically acceptable excipients include all of those excipients which are compatible with clopidogrel base, a number of which have been previously mentioned, for example as clopidogrel adsorbents.
  • the various excipients include diluents or fillers such as sugar alcohols having 1-6 carbon atoms, saccharides, including monosaccharides and disaccharides, or cellulose and cellulose derivatives, disintegrants such as cellulose derivatives, both cross- linked or non cross-linked, disintegrants, and lubricants such as oils, waxes, stearates, metal oxides, and the like.
  • Useful sugar alcohols include mannitol, erythritol, sorbitol, xylitol, lactitol, maltitol etc.
  • Useful disaccharides include lactose, sucrose, maltose, etc.
  • Useful monosaccharides include dextrose.
  • Useful disintegrants include micro-crystalline cellulose, powdered cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose.
  • Useful lubricants include stearic acid, magnesium stearate, zinc stearate, colloidal silicon dioxide, talc and the like.
  • Clopidogrel premix is useful to prepare pharmaceutical compositions that can be administered for the treatment, alleviation or amelioration of the symptoms or complications associated with thrombotic disorders.
  • Thrombotic disorders are due to the formation or presence of a blood clot within a blood vessel due to prior and acute myocardial infarction, unstable and stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis, thrombotic stroke, prior transient ischemic attack (TIA) and reversible ischemic neurological deficit (RIND).
  • PTCA percutaneous transluminal coronary angioplasty
  • TIA prior transient ischemic attack
  • RIND reversible ischemic neurological deficit
  • compositions containing clopidogrel premix can optionally be administered with one, or more than one, other therapeutic agents in the treatment of thrombotic disorders including, but not limited to, salicylates such as aspirin, angiotensin Il receptor antagonists such as candesartan, valsartan, eprosartan, losartan, irbesartan, saprisartan, zolasartan, saralasin, telmisartan, tasosartan, isoteoline, HMG CoA reductase inhibitors such as atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitvastatin, fluindostatin, mevastatin, velostatin and dalvastatin and their pharmaceutically acceptable salts, solvates, hydrates, enantiomers thereof.
  • salicylates such as
  • the clopidogrel base premix renders clopidogrel base amenable for processing into a pharmaceutical composition.
  • the clopidogrel premix offers numerous advantages to the formulator.
  • the base premix occurs as free flowing particles and thereby offers the advantage to the formulator to directly compress the particles thereby minimizing various unit operations as granulation, drying, milling, sieving and the like.
  • the clopidogrel base premix has bulk density not less than about 0.3 g/ml, a tapped density (determined after about 300-1250 taps) not less than about 0.4 g/ml and a Carr index not more than about 40%.
  • the enhanced flow property and density enables compression of clopidogrel base premix into tablets, with or without granulation, and filling into capsules or sachets.
  • the components are required to be in a finely divided form.
  • the clopidogrel premix of the present invention can be subject to operations such as size reduction, particle size classification such as by sieving, blending with other components, and the like, without substantial alteration of the flow properties and other important features of the premix.
  • Clopidogrel base present in the premix compositions, will generally be substantially free of crystalline forms of clopidogrel. Typically, crystalline clopidogrel will be present at less that about 5 percent by weight, or less than about 2 percent by weight, or less than about 1 percent by weight, in the premix.
  • the clopidogrel base premix prepared according to the present invention and further processed into a pharmaceutical composition exhibits polymorphic stability.
  • a clopidogrel base premix was prepared, using the following:
  • Tablets containing 75 mg of clopidogrel were prepared from the following:
  • Placebo tablets were prepared from the following:
  • Tablets containing 75 mg of clopidogrel were prepared from the following:
  • Capsules containing 75 mg of clopidogrel were prepared from the following:
  • Clopidogrel base and BHA were charged to a reactor at 27.5°C ⁇ 7.5 0 C along with isopropanol and mixed for 15 to 20 minutes until a clear solution was obtained.
  • step 3 Mannitol, lactose, microcrystalline cellulose, and fumed silica were charged to a rapid mixer granulator and mixed for 10 to 15 minutes at slow impeller and chopper speed. 4. The solution from step 2 was slowly poured onto the dry blend of step 3 under a slow speed of the impeller and chopper, over 10 to 15 minutes.
  • the wet mass was dried in a rotary vacuum drier at 40-45 0 C under 600 mm Hg vacuum for 2 to 3 hours, until loss on drying at 105 0 C was 0.71 %.
  • Material obtained from the above process had the following characteristics: off-white powder with an assay of 21.9% clopidogrel w/w; bulk density untapped 0.53 g/ml, and tapped 0.59 g/ml; Carr Index 10.5%; and a particle size distribution as follows:
  • Tablets containing 75 mg of clopidogrel were prepared using the following:
  • Example 2 and commercial PLAVIX tablets was compared, using the standard test method 711 (Dissolution) from United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland U.S.A. (1999). Apparatus Il of the test was used, and the dissolution medium was 1000 ml of a pH 2 buffer, with stirring at 75 rpm and a temperature of 37 0 C. The results were as follows:
  • Tablets containing the clopidogrel base premix thus provide a rapid release of clopidogrel, comparable to that of the commercially available product.
  • a clopidogrel base premix was prepared, using the following:
  • a clopidogrel base premix was prepared, using the following:
  • a clopidogrel base premix was prepared, using the following:
  • a clopidogrel base premix was prepared, using the following:
  • a clopidogrel base premix is prepared, using the following:
  • Step 1 solution Adsorb the Step 1 solution by pouring onto the Step 2 material. 4. Dry the wet material at 40-45 0 C until a loss on drying at 105 0 C of 1 - 2% w/w is achieved.
  • a clopidogrel base premix is prepared, using the following:

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Abstract

L'invention concerne des prémélanges à base de clopidogrel avec des excipients pharmaceutiques, des formulations pharmaceutiques contenant les prémélanges ainsi que leur utilisation dans le traitement de troubles thrombotiques.
EP05807697A 2004-10-14 2005-10-14 Compositions contenant du clopidogrel Withdrawn EP1802280A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN1067CH2004 2004-10-14
US65046605P 2005-02-07 2005-02-07
PCT/US2005/036835 WO2006044548A2 (fr) 2004-10-14 2005-10-14 Compositions contenant du clopidogrel

Publications (2)

Publication Number Publication Date
EP1802280A2 true EP1802280A2 (fr) 2007-07-04
EP1802280A4 EP1802280A4 (fr) 2008-02-20

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EP2107061A1 (fr) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement
EP2440191A2 (fr) 2009-06-08 2012-04-18 Schering Corporation Antagoniste du récepteur de la thrombine et comprimé de clopidogrel à dose fixe
CN101766573B (zh) 2010-02-05 2013-02-13 上海安必生制药技术有限公司 硫酸氢氯吡格雷固体制剂的制备工艺
KR102487879B1 (ko) * 2017-11-13 2023-01-12 주식회사유한양행 클로피도그렐 및 로수바스타틴을 포함하는 이중층 정제의 제조방법

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WO2004072084A1 (fr) * 2003-02-13 2004-08-26 Helm Ag Sel de l'acide benzenesulfonique comprenant du clopidogrel et son utilisation pour produire des formulations pharmaceutiques

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WO2004072084A1 (fr) * 2003-02-13 2004-08-26 Helm Ag Sel de l'acide benzenesulfonique comprenant du clopidogrel et son utilisation pour produire des formulations pharmaceutiques
WO2004072085A2 (fr) * 2003-02-13 2004-08-26 Helm Ag Sel d'un acide sulfonique comprenant du clopidogrel et son utilisation pour produire des formulations pharmaceutiques

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