WO2004026879A1 - Clopidogrel - Google Patents
Clopidogrel Download PDFInfo
- Publication number
- WO2004026879A1 WO2004026879A1 PCT/GB2003/003988 GB0303988W WO2004026879A1 WO 2004026879 A1 WO2004026879 A1 WO 2004026879A1 GB 0303988 W GB0303988 W GB 0303988W WO 2004026879 A1 WO2004026879 A1 WO 2004026879A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- clopidogrel
- amoφhous
- pvp
- salt
- pharmaceutically acceptable
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to amorphous clopidogrel, pharmaceutical compositions, medicaments and products containing the same, processes for preparing amo ⁇ hous clopidogrel and to therapeutic uses and therapeutic methods of treatment employing amo ⁇ hous clopidogrel or such pharmaceutical compositions, medicaments or products.
- Clopidogrel is the international non-proprietary name of methyl (S)-a-(2- chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester. Clopidogrel is a well known antithrombotic agent and the preparation thereof is described in European patent 0099802B.
- European patent 028 1459B describes enantiomers of clopidogrel, in particular the preparation of the bisulfate salt of the (+), or dextro rotatory, form of clopidogrel, also known as clopidogrel bisulfate Form 1.
- European patent application 1087976A describes a further polymo ⁇ h of the bisulfate salt of the (+) form of clopidogrel, known as clopidogrel bisulfate Form 2.
- the invention provides amo ⁇ hous clopidogrel and pharmaceutically acceptable salts thereof.
- salts refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature.
- Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like.
- Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite
- the invention provides the bisulfate salt of the (+) form of clopidogrel, in an amo ⁇ hous form.
- the present invention also provides amo ⁇ hous clopidogrel bisulfate having an X-ray diffraction pattern as shown in Figure 1.
- US 6284277 describes a freeze-dried formulation said to consist of an amorphous phase and a crystalline phase.
- the amo ⁇ hous phase consists predominantly of mannitol and an active ingredient, and the crystalline phase consists predominantly of alanine.
- Clopidogrel is named as a possible active in the list spanning columns 6 to 9 of US 6284277.
- the amo ⁇ hous phase cryoprotects the active, we have found that when crystalline and amo ⁇ hous phases are brought together in this way, the active converts to the crystalline phase.
- the crystalline alanine has a seeding effect, thus triggering the transformation.
- amo ⁇ hous denotes a physical state which is not crystalline and may be verified by X-ray diffraction and other means including but not limited to observation with a polarized light microscope and differential scanning calorimetry. More particularly, amo ⁇ hous clopidogrel in accordance with the present invention is preferably essentially free from any crystalline form of clopidogrel.
- Amo ⁇ hous clopidogrel according to the present invention exhibits a number of advantages compared to crystalline forms of clopidogrel.
- amo ⁇ hous clopidogrel according to the present invention is stable. It may be preferred, however, that conversion of amo ⁇ hous clopidogrel according to the present invention to a crystalline form may be further obviated by the addition of any number of stabiliser materials known in the art, such as, for example, a PVP polymer, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyethylene glycol (PEG), cyclodextrin, and the like. Furthermore, in terms of stability, we have also demonstrated that amo ⁇ hous clopidogrel according to the present invention is substantially non-hygroscopic.
- the present invention further provides amo ⁇ hous clopidogrel substantially as hereinbefore described together with a PVP polymer and more particularly there is further provided by the present invention a pharmaceutically acceptable preparation comprising an effective amount of amo ⁇ hous clopidogrel substantially as hereinbefore described, together with an excipient matrix comprising at least a homopolymer or copolymer of N- vinyl pyrrolidone, wherein said homopolymer or copolymer of N- inyl pyrrolidone is complexed with said amo ⁇ hous clopidogrel.
- a homopolymer of N- vinyl pyrrolidone suitable for use according to the present invention can comprise water soluble polyvinylpyrrolidones, such as PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP Kl-60, PVP Kl-90 and PVP Kl-120.
- PVP K-30, PVP K-60 or PVP K-90 is employed according to the present invention, in particular PVP K-30.
- a homopolymer of N-vinyl pyrrolidone suitable for use according to the present invention might comprise a water insoluble cross linked polyvinylpyrrolidone.
- a water insoluble cross linked polyvinylpyrrolidone that might be employed according to the present invention can include crospovidone.
- compositions according to the present invention are easily isolated in the form of stable powders which exhibit excellent handling properties.
- Pharmaceutical preparations according to the present invention can, for example, be easily and conveniently processed into final dosage forms (such as tablets, capsules and the like) substantially as hereinafter described in greater detail without the need for substantial stabilising precautions during processing.
- Amo ⁇ hous clopidogrel according to the present invention can be further characterised as having a solubility in the range of about 0.2 to 0.3 g/ml in methanol, typically about 0.25 g/ml, which is approximately 1.5 times greater than the solubility of a crystalline form of clopidogrel.
- Advantages of increased solubility include, but are not limited to, improved bioavailability, ease in processing the amo ⁇ hous material, ease in formulation and delivery of the material, and the like.
- Amo ⁇ hous clopidogrel according to the present invention also exhibits a low bulk density in the range of about 0.2 to 0.5 g/ml compared to crystalline forms exhibiting a density in the range of about 0.6 to 0.9g/ml.
- This low density can offer further advantages in terms of formulation of dosage forms, for example milling operations might be avoided which in turn might lead to avoidance of racemisation due to heat sensitivity and / or abrasion.
- Amo ⁇ hous clopidogrel according to the present invention can also be further characterised as having a melting point in the range of 85 to 95°C, more typically in the range of 88 to 92°C and even more typically a melting point of about 90°C. Crystalline clopidogrel exhibits a melting point in the range of about 174 to l86°C.
- clopidogrel is an antithrombotic agent. More particularly, clopidogrel inhibits platelet aggregation.
- Amo ⁇ hous clopidogrel according to the present invention is therapeutically useful in the treatment of symptoms of, and / or occurrence of, thrombotic disorders in animal patients.
- treatment denotes the management and care of an animal patient for the pu ⁇ ose of combating thrombotic disorders and includes the administration of amo ⁇ hous clopidogrel of the present invention to prevent the onset of the symptoms or complications associated with thrombotic disorders, alleviating or ameliorating the symptoms or complications associated with thrombotic disorders, or substantially eliminating thrombotic disorders.
- thrombotic disorders denotes a disorder relating to, or affected with, the formation or presence of a blood clot within a blood vessel.
- Thrombotic disorders include, but are not limited 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
- the present invention further provides for pharmaceutically acceptable compositions for administering to an animal patient, including humans, in need of treatment for thrombotic disorders, which comprises an effective amount of amo ⁇ hous clopidogrel as described herein (optionally provided by a pharmaceutically acceptable preparation substantially as hereinbefore described), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
- the term "effective amount” means an amount of amo ⁇ hous clopidogrel which is capable of treating (for example inhibiting, alleviating, ameliorating or preventing) thrombotic disorders.
- pharmaceutically acceptable preparation it is meant that the excipient matrix component or components must be compatible with amo ⁇ hous clopidogrel of the preparation, and not be deleterious to the recipient thereof.
- compositions can be prepared by procedures known in the art.
- amo ⁇ hous clopidogrel of this invention can be formulated with common carriers, diluents or excipients, and formed into tablets, capsules, and the like.
- carriers, diluents or excipients that are suitable for such compositions include the following: fillers and extenders; binding agents; moisturising agents; surface active agents; and lubricants.
- Final pharmaceutical forms may be: pills, tablets, powders, lozenges, sachets, cachets, or sterile packaged powders, and the like, depending on the type of excipient used.
- amo ⁇ hous clopidogrel required to treat, inhibit, or prevent thrombotic disorders as described herein in an animal patient, including humans, will depend upon the particular thrombotic disease or condition, and the symptoms, and severity thereof. Dosage, routes of administration, and frequency, of dosing is best decided by an attending physician. When the compositions of the invention are administered to an animal patient by the oral or parenteral route, it is typically preferable that the daily dose of amorphous clopidogrel is in the range of 50 and 100 mg.
- compositions according to the present invention are, however, preferably made so as to be administrable by the oral or parenteral route.
- compositions of the present invention may be administered in unit forms, for example the forms for oral administration include tablets, gelatin capsules, powders, granules and oral solutions or suspensions.
- amo ⁇ hous clopidogrel can be mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
- a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
- the tablets can be coated with sucrose or other appropriate materials or alternatively they can be treated such that they have a prolonged or delayed activity and that they continuously liberate a predetermined quantity of amo ⁇ hous clopidogrel.
- a preparation in the form of gelatin capsules can be obtained by mixing amo ⁇ hous clopidogrel with a diluent and by pouring the mixture obtained into soft or hard gelatin capsules.
- the water-dispersible granules or powders may contain amo ⁇ hous clopidogrel mixed with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.
- aqueous suspensions for parenteral administration, aqueous suspensions, isotonic saline solutions, or sterile and injectable solutions, can be used which contain dispersing agents and/or wetting agents which are pharmacologically compatible, for example propylene glycol or butylene glycol.
- Amo ⁇ hous clopidogrel can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
- amo ⁇ hous clopidogrel may be administered along with an effective amount of an additional therapeutic agent, including one or more further antithrombotic agents that might exhibit synergistic activity with amo ⁇ hous clopidogrel according to the present invention.
- additional therapeutic agents including one or more further antithrombotic agents that might exhibit synergistic activity with amo ⁇ hous clopidogrel according to the present invention.
- the different forms of these additional antithrombotic therapeutic agents available and the applicable dosing regimens are well known to those of skill in the art.
- the present invention therefore, further provides a product containing amo ⁇ hous clopidogrel and one or more further antithrombotic agents, for simultaneous, separate or sequential use in the treatment of thrombotic disorders, wherein suitably amo ⁇ hous clopidogrel may be provided by a pharmaceutically acceptable preparation substantially as hereinbefore described for inclusion in the product.
- the present invention further provides amorphous clopidogrel for use in the manufacture of a medicament for the treatment of thrombotic disorders as described herein.
- the amo ⁇ hous clopidogrel may suitably be present in a pharmaceutically acceptable preparation substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of thrombotic disorders as described herein.
- the present invention also provides a method of treating thrombotic disorders in an animal patient in need of such treatment, which method comprises administering to the animal patient an effective amount of amo ⁇ hous clopidogrel for treating thrombotic disorders in the animal patient.
- the amo ⁇ hous clopidogrel employed in such a method may suitably be present in a pharmaceutically acceptable preparation or composition substantially as hereinbefore described.
- Amo ⁇ hous clopidogrel according to the present invention is conveniently prepared by a process which constitutes a further feature of the present invention, and which comprises recovering clopidogrel from a solution thereof under conditions whereby an amo ⁇ hous product is obtained.
- the amo ⁇ hous clopidogrel of the instant invention can be prepared by dissolving a crystalline form of clopidogrel in a suitable solvent or solvent mixture, such as, for example, methanol and / or water, followed by recovery of the material by any suitable means.
- a suitable solvent or solvent mixture such as, for example, methanol and / or water
- Techniques which may be employed to recover amo ⁇ hous clopidogrel from the solution include those wherein the solvent is removed from the solution, preferably rapidly, and the product deposited. Methods involving the use of these procedures which have been found to be satisfactory include spray drying, roller drying, solvent precipitation, rotary evaporation, and freeze drying. Particularly preferred for the practice of the present invention are the methods of spray drying or rotary evaporation.
- a preferred process according to the present invention comprises dissolving a first salt of clopidogrel (for example, clopidogrel (-) camphor- 10-sulfonate) in crystalline form in a solvent or solvent mixture, converting the first clopidogrel salt (for example, clopidogrel (-) camphor- 10-sulfonate) to the free base and subsequently to a second salt of clopidogrel (for example clopidogrel bisulfate) and recovering the second clopidogrel salt from the solution thereof under conditions whereby an amo ⁇ hous product is obtained.
- a first salt of clopidogrel for example, clopidogrel (-) camphor- 10-sulfonate
- a second salt of clopidogrel for example clopidogrel bisulfate
- clopidogrel (-) camphor- 10- sulfonate in crystalline form suitably for use as an intermediate in the preparation of amo ⁇ hous clopidogrel, or a pharmaceutically acceptable salt thereof.
- Solvents which may be employed in the practice of the present invention will be chosen according to the technique and conditions to be employed, and include water, methanol, ethanol, and the like, including mixtures thereof if desired.
- the concentration of crystalline clopidogrel in the solvent is typically in the range of about 1 to 300 mg/ml, preferably about 10 to 200 mg/ml.
- the solvents may, if desired, be heated as an aid to solubility and solvent removal.
- Clopidogrel exhibits sufficient heat stability to withstand spray drying and the like, and accordingly, spray drying is the preferred method of recovery.
- Spray drying systems may be operated in a known manner to obtain an amo ⁇ hous product essentially free from crystalline material as well as free from particulate contaminants.
- the drying gas employed in a spray drying process according to the present invention can suitably be air, but other drying gases such as, for example, nitrogen, argon and carbon dioxide may be employed.
- the gas inlet temperature to the spray dryer is chosen according to the solvent employed, but would be, for example, in the range of from about 75°C to about 150°C, preferably in the range of from about 85°C to about 115°C.
- Amo ⁇ hous clopidogrel may also be combined with a number of other materials prior to or after spray drying, or otherwise processed to provide amorphous clopidogrel, which may in turn be further formulated for processing.
- the present invention also provides a process of preparing a preparation substantially as hereinbefore described, which process comprises complexing an effective amount of amo ⁇ hous clopidogrel substantially as hereinbefore described, with at least a homopolymer or copolymer of N- vinyl pyrrolidone.
- amo ⁇ hous clopidogrel and the homopolymer or copolymer of N- vinyl pyrrolidone is or are present in solution.
- a suitable organic solvent such as methanol, ethanol, isopropanol, acetone, ethyl acetate or any suitable solvent.
- suitable solvents include methanol, ethanol, isopropanol or any other suitable solvent.
- a complex present in a preparation according to the present invention is formed in solution, it is advantageously recovered from the solution for storage or use in solid form.
- solvent can be removed from the solution such as by evaporation, to cause the complex to precipitate.
- Other recovery methods can also be used such as, for example, spray drying.
- Figure 1 shows the powder X-ray diffraction pattern of amo ⁇ hous clopidogrel prepared according to the present invention.
- Crystalline Clopidogrel bisulfate Form-2 25g was stirred in 100ml of methanol to obtain a clear solution.
- This solution was spray dried in a Lab Plant Spray Drier SD 05 with an inlet temperature of 90°C, outlet temperature of 70°C, compressed air rate of 0.3m 3 /hr and a feed rate of 8ml/min to obtain 18g of the title product.
- Crystalline Clopidogrel bisulfate Form-1 25g was stirred in 500ml of water to obtain a clear solution.
- This solution was spray dried in a Lab Plant Spray Drier SD 05 with inlet temperature of 110°C, outlet temperature of 80°C, compressed air rate of 0.3m /hr and a feed rate of 8ml/min to obtain 19g of the title product.
- amo ⁇ hous title product was characterised by powder X-ray diffraction.
- amo ⁇ hous title product was characterised by powder X-ray diffraction.
- Clopidogrel (-) camphor- 10-sulfonate was taken in 100ml of water and 100ml of dichloromethane. To this was added 10% aq. sodium bicarbonate solution and the organic layer was separated. Concentration of the solvent yielded the base, which was dissolved in 100ml of methanol and sulphuric acid 3g was added and the solution spray-dried as in Example 1 to obtain 11.5g of the title product.
- amo ⁇ hous product was characterised by powder x-ray diffraction.
- a solid oral pharmaceutical fonnulation according to the present invention can be manufactured by any granulation process known in the art. The following is illustrative of one such process.
- the amo ⁇ hous Clopidogrel bisulfate was blended with the excipients and then lubricated with stearic acid. The resulting mixture was then compressed to form tablets and the resulting tablets were film coated.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0504151A GB2407814A (en) | 2002-09-19 | 2003-09-16 | Clopidogrel |
DE10393290T DE10393290T5 (en) | 2002-09-19 | 2003-09-16 | clopidogrel |
AU2003269140A AU2003269140A1 (en) | 2002-09-19 | 2003-09-16 | Clopidogrel |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0221788A GB2393181A (en) | 2002-09-19 | 2002-09-19 | Amorphous clopidogrel |
GB0221788.3 | 2002-09-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004026879A1 true WO2004026879A1 (en) | 2004-04-01 |
Family
ID=9944408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2003/003988 WO2004026879A1 (en) | 2002-09-19 | 2003-09-16 | Clopidogrel |
Country Status (6)
Country | Link |
---|---|
KR (1) | KR20050071495A (en) |
AU (1) | AU2003269140A1 (en) |
DE (1) | DE10393290T5 (en) |
GB (2) | GB2393181A (en) |
RU (1) | RU2005110917A (en) |
WO (1) | WO2004026879A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
WO2005097804A1 (en) * | 2004-04-09 | 2005-10-20 | Hanmi Pharm. Co., Ltd. | Crystalline clopidogrel naphthalenesulfonate or hydrate thereof, method for preparing same and pharmaceutical composition containing same |
WO2005117866A1 (en) * | 2004-06-01 | 2005-12-15 | Ivax Pharmaceuticals S.R.O. | Amorphous clopidogrel hydrochloride and its antithrombotic use |
WO2006023676A1 (en) * | 2004-08-21 | 2006-03-02 | Ivax Pharmaceuticals S.R.O. | Clopidogrel napsylate salt |
WO2007008045A1 (en) * | 2005-07-14 | 2007-01-18 | Cj Cheiljedang Corp. | Pharmaceutical compositions containing clopidogrel bisulfate |
DE102005060690A1 (en) * | 2005-12-15 | 2007-06-21 | Capsulution Nanoscience Ag | Salts of clopidogrel with polyanions and their use in the preparation of pharmaceutical formulations |
WO2007113857A2 (en) * | 2006-04-05 | 2007-10-11 | Cadila Healthcare Limited | Modified release clopidogrel formulation |
WO2008034912A2 (en) * | 2006-09-22 | 2008-03-27 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the synthesis of clopidogrel and new forms of pharmaceutically acceptable salts thereof |
EP2095815A1 (en) | 2008-02-26 | 2009-09-02 | Laboratorios Lesvi, S.L. | Pharmaceutical formulations containing clopidogrel |
EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
CN102358743A (en) * | 2011-11-05 | 2012-02-22 | 江南大学 | Simple method for preparing amorphous clopidogrel hydrosulphate |
CN102443010A (en) * | 2011-11-05 | 2012-05-09 | 江南大学 | Method for preparing amorphous clopidogrel hydrogen sulfate |
WO2015189650A1 (en) | 2014-06-13 | 2015-12-17 | Skillpharm Kft. | Clopidogrel for use in the treatment of benign prostatic hyperplasia |
CN105218559A (en) * | 2015-10-21 | 2016-01-06 | 云南省药物研究所 | A kind of stable non-crystalline state bisulfate clopidogrel mixture |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006074066A1 (en) * | 2004-12-30 | 2006-07-13 | Nektar Therapeutics | Non-crystalline formulation comprising clopidogrel |
EP1970054A3 (en) * | 2007-03-14 | 2009-06-03 | Ranbaxy Laboratories Limited | Clopidogrel tablets |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6284277B1 (en) * | 1995-11-03 | 2001-09-04 | Sanofi-Synthelabo | Stable freeze-dried pharmaceutical formulation |
WO2003051362A2 (en) * | 2001-12-18 | 2003-06-26 | Teva Pharmaceutical Industries Ltd. | Polymorphs of clopidogrel hydrogensulfate |
-
2002
- 2002-09-19 GB GB0221788A patent/GB2393181A/en not_active Withdrawn
-
2003
- 2003-09-16 KR KR1020057004672A patent/KR20050071495A/en not_active Application Discontinuation
- 2003-09-16 RU RU2005110917/04A patent/RU2005110917A/en not_active Application Discontinuation
- 2003-09-16 GB GB0504151A patent/GB2407814A/en not_active Withdrawn
- 2003-09-16 DE DE10393290T patent/DE10393290T5/en not_active Withdrawn
- 2003-09-16 WO PCT/GB2003/003988 patent/WO2004026879A1/en not_active Application Discontinuation
- 2003-09-16 AU AU2003269140A patent/AU2003269140A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6284277B1 (en) * | 1995-11-03 | 2001-09-04 | Sanofi-Synthelabo | Stable freeze-dried pharmaceutical formulation |
WO2003051362A2 (en) * | 2001-12-18 | 2003-06-26 | Teva Pharmaceutical Industries Ltd. | Polymorphs of clopidogrel hydrogensulfate |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005070464A3 (en) * | 2004-01-21 | 2005-11-03 | Biofarma Ilac Sanayi Ve Ticare | A tablet formulation of clopidogrel bisulphate |
WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
WO2005097804A1 (en) * | 2004-04-09 | 2005-10-20 | Hanmi Pharm. Co., Ltd. | Crystalline clopidogrel naphthalenesulfonate or hydrate thereof, method for preparing same and pharmaceutical composition containing same |
WO2005117866A1 (en) * | 2004-06-01 | 2005-12-15 | Ivax Pharmaceuticals S.R.O. | Amorphous clopidogrel hydrochloride and its antithrombotic use |
WO2006023676A1 (en) * | 2004-08-21 | 2006-03-02 | Ivax Pharmaceuticals S.R.O. | Clopidogrel napsylate salt |
WO2007008045A1 (en) * | 2005-07-14 | 2007-01-18 | Cj Cheiljedang Corp. | Pharmaceutical compositions containing clopidogrel bisulfate |
GB2442664A (en) * | 2005-07-14 | 2008-04-09 | Cj Cheiljedang Corp | Pharmaceutical compositions containing clopidogrel bisulfate |
DE102005060690B4 (en) * | 2005-12-15 | 2008-09-25 | Capsulution Nanoscience Ag | Salts of clopidogrel with polyanions and their use in the preparation of pharmaceutical formulations |
DE102005060690A1 (en) * | 2005-12-15 | 2007-06-21 | Capsulution Nanoscience Ag | Salts of clopidogrel with polyanions and their use in the preparation of pharmaceutical formulations |
WO2007068495A1 (en) * | 2005-12-15 | 2007-06-21 | Capsulution Nanoscience Ag | Salts of clopidogrel with polynions and their use for manufacturing pharmaceutical formulations |
WO2007113857A2 (en) * | 2006-04-05 | 2007-10-11 | Cadila Healthcare Limited | Modified release clopidogrel formulation |
WO2007113857A3 (en) * | 2006-04-05 | 2008-02-28 | Cadila Healthcare Ltd | Modified release clopidogrel formulation |
WO2008034912A2 (en) * | 2006-09-22 | 2008-03-27 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the synthesis of clopidogrel and new forms of pharmaceutically acceptable salts thereof |
WO2008034912A3 (en) * | 2006-09-22 | 2008-08-07 | Krka Tovarna Zdravil D D Novo | Process for the synthesis of clopidogrel and new forms of pharmaceutically acceptable salts thereof |
EP2095815A1 (en) | 2008-02-26 | 2009-09-02 | Laboratorios Lesvi, S.L. | Pharmaceutical formulations containing clopidogrel |
EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
CN102358743A (en) * | 2011-11-05 | 2012-02-22 | 江南大学 | Simple method for preparing amorphous clopidogrel hydrosulphate |
CN102443010A (en) * | 2011-11-05 | 2012-05-09 | 江南大学 | Method for preparing amorphous clopidogrel hydrogen sulfate |
WO2015189650A1 (en) | 2014-06-13 | 2015-12-17 | Skillpharm Kft. | Clopidogrel for use in the treatment of benign prostatic hyperplasia |
CN105218559A (en) * | 2015-10-21 | 2016-01-06 | 云南省药物研究所 | A kind of stable non-crystalline state bisulfate clopidogrel mixture |
Also Published As
Publication number | Publication date |
---|---|
KR20050071495A (en) | 2005-07-07 |
GB0221788D0 (en) | 2002-10-30 |
GB2393181A (en) | 2004-03-24 |
GB2407814A (en) | 2005-05-11 |
AU2003269140A1 (en) | 2004-04-08 |
RU2005110917A (en) | 2006-01-20 |
DE10393290T5 (en) | 2005-09-29 |
GB0504151D0 (en) | 2005-04-06 |
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