Nothing Special   »   [go: up one dir, main page]

WO2011101865A2 - Compositions pharmaceutiques stables de clopidogrel pour administration parentérale - Google Patents

Compositions pharmaceutiques stables de clopidogrel pour administration parentérale Download PDF

Info

Publication number
WO2011101865A2
WO2011101865A2 PCT/IN2011/000098 IN2011000098W WO2011101865A2 WO 2011101865 A2 WO2011101865 A2 WO 2011101865A2 IN 2011000098 W IN2011000098 W IN 2011000098W WO 2011101865 A2 WO2011101865 A2 WO 2011101865A2
Authority
WO
WIPO (PCT)
Prior art keywords
clopidogrel
pharmaceutical composition
injectable pharmaceutical
concentrate
stable injectable
Prior art date
Application number
PCT/IN2011/000098
Other languages
English (en)
Other versions
WO2011101865A3 (fr
Inventor
Sunilendu Bhushan Roy
Sushrut Krishnaji Kulkarni
Maulik Kiritkumar Panchal
Shailendra Shubhashchandra Mandge
Original Assignee
Cadila Healthcare Limited
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 Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2011101865A2 publication Critical patent/WO2011101865A2/fr
Publication of WO2011101865A3 publication Critical patent/WO2011101865A3/fr

Links

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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

Definitions

  • the present invention relates to stable pharmaceutical compositions of clopidogrel or salts thereof for parenteral administration.
  • the invention relates to pharmaceutical compositions containing concentrate of clopidogrel or pharmaceutically acceptable salts thereof, which can be mixed with suitable aqueous vehicle for preparation of infusion solution suitable for administration to patients. Such compositions exhibit excellent stability.
  • the invention also includes process of preparation of such compositions.
  • Clopidogrel is a platelet aggregation inhibitor that has selective irreversible inhibition of adenosine diphosphate (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 GPHb/IIIa complex.; with no significant effect on thromboxane A2 or prostacyclin synthesis, or phospholipase A activity.
  • Clopidogrel is indicated for reduction of atherothrombotic events like recent myocardial infarction, recent stroke or established peripheral arterial disease, acute coronary syndrome.
  • Clopidogrel is available as its bisulphate salt in the form of immediate release tablets equivalent to 75 and 300 mg base. It is marketed in US under the brand name Plavix ® by Sanofi Aventis. Typically the oral formulation takes more than 2 hours to show its pharmacological effect. Intravenous injections are known to provide the activity immediately.
  • the parenteral route of administration has advantage over oral administration for immediate release, as there is no lag time corresponding to the drug reaching sufficient concentration in the systemic circulation to start surgery in cases of coronary intervention.
  • Coronary intervention is a medical emergency, during which the rapid achievement of therapeutic drug concentrations in the blood and rapid onset of action is a priority and to achieve the same, intravenous administration is the best preferred route.
  • the medication is used particularly for the reduction of accidents related to atherosclerosis (myocardial infarction, stroke, arthritis, vascular death) in patients who have had a recent myocardial infarction, stroke or with recent arterial obstructions proved in the lower limbs.
  • atherosclerosis myocardial infarction, stroke, arthritis, vascular death
  • U. S. Patent No. 6,284,277 discloses freeze-dried or lyophilized compositions containing mannitol and alanine. However, at the time of reconstitution of such lyophilisate in solvent, one often encounters a problem of self-aggregation of the clopidogrel.
  • compositions comprising clopidogrel and sulfoalkyl ether cyclodextrin (SAE- CD).
  • European Patent No. EP 099802 discloses composition of clopidogrel or a pharmaceutically acceptable salt thereof for parenteral administration as an injectable solution.
  • This type of formulation containing a salt of clopidogrel in isotonic solution in a solvent is difficult to use. Since salts of the clopidogrel are strong acids, in aqueous solution, it gives solutions presenting a pH below 2, making the resulting injection very painful and thus can hinder patient compliance.
  • European Patent No. EP 1105102 discloses injectable aqueous solutions containing a salt of clopidogrel, pluronic F68, a basic pH modifier and solutol HS 15.
  • the patent application further discloses lyophilized formulations containing these ingredients and kits containing such lyophilized compositions in two parts.
  • PCT International Publication No. WO 2009/133455 discloses ready-to-use aqueous injection of clopidogrel or its salts.
  • the various variables which affect the stability of the formulation are mainly the pH, the quantity of salts present, the type and quantity of excipients in the formulation, the type of cryoprotective chosen, as well as the temperature, pressure and time chosen for freezing, sublimation and drying operations. Also these variables influence the physical state of the freeze-dried product obtained, namely: vitreous amorphous, soft amorphous, crystalline or a combination of these states.
  • aqueous based Intravenous injection of clopidogrel it is preferred to provide aqueous based Intravenous injection of clopidogrel so that biocompatibility is achieved.
  • the aqueous solution has only a limited shelf-life at room temperature and it is also known that aqueous solution of salts of the clopidogrel gives solutions presenting a pH below 2, making the resulting injection very painful and thus can affect patient compliance to parenteral dosage.
  • compositions of the invention overcome all the encountered problems exemplified above.
  • a stable injectable pharmaceutical composition comprising concentrate of clopidogrel or salts thereof.
  • a stable injectable pharmaceutical composition comprising concentrate of clopidogrel or salts thereof, wherein said concentrate further comprises of one or more of suitable aqueous solvents, surfactants optionally with a co-solvent.
  • a stable injectable pharmaceutical composition comprising concentrate of clopidogrel or salts thereof, wherein said concentrate is adjusted to the form suitable for parenteral administration.
  • a stable injectable pharmaceutical composition comprising concentrate of clopidogrel or salts thereof, wherein said concentrate is adjusted to the form suitable for parenteral administration by addition of suitable aqueous vehicle.
  • a stable injectable pharmaceutical composition comprising concentrate of clopidogrel or salts thereof, wherein said concentrate is adjusted to the form suitable for administration by addition of suitable aqueous vehicle, characterized in that the vehicle comprises one or more of buffers, surfactants and aqueous solvents.
  • kits for the reduction of atherothrombotic events comprising concentrate of clopidogrel or salts thereof, and a suitable aqueous vehicle.
  • kits for the reduction of atherothrombotic events comprising concentrate of clopidogrel or salts thereof, and a suitable diluent, wherein the concentrate and aqueous vehicle are admixed together for preparation of infusion prior to administration to patients.
  • a process for preparation of stable Injectable pharmaceutical composition comprising concentrate of clopidogrel or salts thereof, which process comprises of mixing concentrate of clopidogrel or pharmaceutically acceptable salts thereof with suitable aqueous solvent, which is subsequently adjusted to form suitable for administration.
  • a method of reducing of atherothrombotic events like recent myocardial infarction and treating recent stroke or established peripheral arterial disease, acute coronary syndrome comprising administering to human patient in need thereof an injectable pharmaceutical composition comprising a concentrate of clopidogrel or salts thereof.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include surfactants, solvents, buffering agents, co-solvents and stabilizers.
  • the inventors of the present invention have surprisingly found that it is possible to develop stable and aqueous based injectable compositions of clopidogrel or pharmaceutically acceptable salts thereof.
  • the inventors have prepared clopidogrel or its salt in the form of a concentrate which can be further admixed or reconstituted with a suitable aqueous vehicle prior to administration to patient.
  • aqueous based injectable compositions of clopidogrel or salts thereof using aforesaid technique, the stability issues associated with ready to use aqueous solutions of clopidogrel can be circumvented.
  • such formulation also provides an alternative treatment for cardiac interventions which many a time requires emergency consideration, which is not possible with oral route.
  • the invention provides a method of stabilizing an injectable pharmaceutical composition comprising clopidogrel or salt thereof comprising admixing or reconstituting a clopidogrel concentrate and aqueous vehicle together for preparation of infusion prior to administration.
  • compositions with long shelf life • homogeneous and thermodynamically stable compositions with long shelf life. ⁇ compositions with small and narrow particle size distribution suitable for parenteral administration and rapid onset.
  • compositions having a hydrophilic surfactant and organic solvent in amount such that upon dilution with intravenous infusion a clear aqueous dispersion is formed.
  • clopidogrel used throughout the specification refers to not only clopidogrel per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. It is also possible to use any salts and free base form of memantine, including polymorphs, hydrates, solvates or amorphous forms.
  • the preferred salt of clopidogrel is besylate and bisulphate salt. Particularly preferred salt is besylate.
  • concentrate of clopidogrel or “clopidogrel concentrate” or “concentrate” used throughout the specification refers to a clopidogrel and pharmaceutically acceptable salt thereof per se suitable for parenteral administration, for example, sterilized clopidogrel or salts thereof and lyophilized clopidogrel or salts thereof.
  • the term also includes solution, suspension or admixture of clopidogrel or salt thereof in which clopidogrel is present in concentrated form in a parenterally acceptable excipient.
  • concentrate means a concentration of clopidogrel or salt thereof which is usually too high to enable the corresponding concentrate, solution or suspension to be used therapeutically without being diluted.
  • the clopidogrel concentration in the concentrate ranges between 0.5% and 50% w/v, preferably the concentration ranges between 1.5% w/v and 15% w/v of the composition.
  • the concentration range is related to % weight of free base clopidogrel relative to % volume of the composition.
  • the stable injectable pharmaceutical composition in accordance with the present invention comprises concentrate of clopidogrel or salt thereof.
  • the injectable composition in accordance with the present invention is prepared in two parts. First part comprises clopidogrel concentrate and second part comprises aqueous vehicle.
  • the concentrate of clopidogrel is in the form of sterilized clopidogrel or salt thereof and optionally with one or more parenterally acceptable excipients.
  • the concentrate of clopidogrel is in the form of lyophilized mixture of clopidogrel or salt thereof per se or with one or more parenterally acceptable excipient suitable for lyophilization.
  • the concentrate of clopidogrel comprises one or more parenterally acceptable excipients selected from surfactants, aqueous solvents, co- solvents, diluents or mixtures thereof.
  • the second is an aqueous vehicle which comprises one or more of aqueous solvents and/or co-solvents.
  • aqueous based diluent when prepared using mixture of surfactant and buffer in addition to aqueous solvent, it leads to improvement in the stability of solutions containing clopidogrel or salt thereof and moreover, resulting solution is also suitable for parenteral administration.
  • the injectable pharmaceutical composition comprises a concentrate of clopidogrel diluted with aqueous vehicle comprising one or more surfactant/s, one or more buffer/s and one or more aqueous solvents and optionally one or more co-solvents.
  • the injectable pharmaceutical composition comprises a concentrate of clopidogrel comprising polyethylene glycol hydroxyl stearate (e.g. Solutol® HS 15) diluted with aqueous vehicle comprising a copolymer of ethylene oxide and propylene oxide (e.g. Pluronic F68®), citrate buffer and one or more aqueous solvents and optionally one or more co-solvents.
  • the injectable pharmaceutical composition comprises a concentrate of clopidogrel comprising polyethylene glycol hydroxyl stearate (e.g. Solutol® HS 15) diluted with aqueous vehicle comprising a polyoxyethylene castor oil derivative (e.g. Cremophor®), citrate buffer and one or more aqueous solvents and optionally one or more co-solvents.
  • a concentrate of clopidogrel comprising polyethylene glycol hydroxyl stearate (e.g. Solutol® HS 15) diluted with aqueous vehicle comprising a polyoxyethylene castor oil derivative (e.g. Cremophor®), citrate buffer and one or more aqueous solvents and optionally one or more co-solvents.
  • the injectable pharmaceutical composition comprises a concentrate of clopidogrel diluted with aqueous vehicle system comprising polyethylene glycol hydroxyl stearate (e.g. Solutol® HS 15), a polyoxyethylene castor oil derivative (e.g. Cremophor®), citrate buffer and one or more aqueous solvents and optionally one or more co-solvents.
  • aqueous vehicle system comprising polyethylene glycol hydroxyl stearate (e.g. Solutol® HS 15), a polyoxyethylene castor oil derivative (e.g. Cremophor®), citrate buffer and one or more aqueous solvents and optionally one or more co-solvents.
  • a pharmaceutical kit which present in the form of two containers (preferably, sterile), one containing a clopidogrel concentrate and the other contains aqueous vehicle comprising a surfactant, a buffer, a solvent and optionally a cosolvent.
  • one of the compartments contains clopidogrel concentrate and the other compartment containing aqueous vehicle comprising a surfactant, a buffer, a solvent and optionally a cosolvent.
  • the injectable composition of the invention is prepared in two parts.
  • First part involves preparation of concentrate by dissolving clopidogrel or salts thereof in suitable solvent/co-solvent systems along with one or more surfactants.
  • the concentrate may be sterilized and aseptically filled in sealed vials.
  • Second part involves preparation of aqueous vehicle by mixing one or more surfactants, buffers, aqueous solvents and optionally co-solvents.
  • the diluent may be sterilized and aseptically filled in suitable device or container. Both the parts may be suitably mixed to form a infusion solution prior to administration to patients.
  • Suitable devices or containers which can be used to accommodate clopidogrel concentrate and aqueous vehicle in accordance of the present invention may be any container or device suitable for parenteral formulation those are know to person skilled in the art. Examples of such devices are vials, ampoules, bottles, prefilled syringes (e.g. two compartment syringes).
  • the process for the preparation of a stable injectable pharmaceutical composition of clopidogrel or salt thereof comprises-
  • the clopidogrel concentrate and aqueous based diluent may be sterilized by methods known to person skilled in the art, such as filtration, and aseptically filled in sealed vials.
  • compositions of the present invention can be administered parenterally by direct injection or with infusion.
  • the resulting solution can provide advantages of aqueous based parenteral formulations and thus can improve patient compliance.
  • the stable injectable pharmaceutical composition of clopidogrel or salt thereof comprising concentrate of clopidogrel or salts thereof admixed or reconstituted with an aqueous vehicle for preparation of infusion prior to administration, wherein said concentrate retains at least 80% of the potency of clopidogrel or salts thereof in the said concentrate after storage for three months at 40° C and 75% relative humidity.
  • Suitable "surfactants" which can be used for preparing injectable pharmaceutical composition of clopidogrel or salt thereof may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants or mixtures thereof. These surfactants may comprise from about 0.01% to about 65% w/v of the composition.
  • the surfactant used in preparing injectable pharmaceutical composition of clopidogrel or salt thereof is one or more polyoxyethylene fatty alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters (Myrj), sorbitan esters (Span), glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxomers), polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol, and polyvinylpyrrolidone.
  • polyoxyethylene fatty acid esters is included those having short alkyl chains.
  • Preferred non-ionic surfactant is Solutol®. HS 15,
  • surfactant suitable for employing in the injectable pharmaceutical composition possesses HLB (hydrophilic-lipophilic Balance) value ranging from 6 to 20.
  • Suitable "aqueous solvents and co-solvents” may include one or more of water and its various grades suitable for parenteral administration such as water for injection, bacteriostatic water for injection, sterile, aqueous solutions of electrolytes and/or dextrose; alcohols such as ethanol, isopropanol; polyols such as propylene glycol, polyethylene glycol, glycerol; dimethyl sulfoxide (DMSO); dimethyl acetamide (DMAC); 3-dimethyl-2-imidazolidinone (DMI) and N-Methyl-2-Pyrrolidone (M- PYROL).
  • the amount of aqueous solvent and co-solvent may range from about 0.01% w/v to about 95% w/v of the composition.
  • Suitable “buffers” may include one or more of borate buffers, tartarate buffers, lactate buffers, citrate buffers, phosphate buffers, citric acid/phosphate buffers, carbonate/carbonic acid buffers, succinate/succinic acid buffers, and tris(hydroxymethyl)aminomethane /hydrochloric acid buffers and the like.
  • the amount of aqueous solvent and co-solvent may range from about 0.01% w/v to about 15% w/v of the composition.
  • the buffer system is useful over the desired dose range of the composition to provide ease of manufacture of the composition, to maintain pH stability during and after manufacture including terminal sterilization by filtration and thus to render the composition compatible with a range of infusion fluids.
  • the pH of the injectable pharmaceutical composition of clopidogrel or salts thereof in accordance with the present invention ranges from about 3.5 to about 7.5, preferably from about 4.0 to about 6.5.
  • the control of pH of the injectable composition is essential to maintain the aqueous solubility of the clopidogrel salts to a sufficient extent that the therapeutically desirable dose strengths can be manufactured and are physically stable, i.e. do not give evidence of precipitation. Maintenance of the necessary pH range can be controlled by the use of a suitable buffer system.
  • the pharmaceutically acceptable buffer may be selected from any of the buffers that are effective to maintain the pH in the range of about 3.0-7.0. More preferably, the buffer may be selected from citrate, acetate, phosphate and lactate buffers. Most preferably, the buffer is a citrate or acetate buffer, for example, citric acid plus sodium citrate in appropriate proportions which will maintain the pH at about 3.5-7.0.
  • the buffer is essentially a mixture of a sodium citrate prepared by the neutralization of citric acid by sodium hydroxide plus residual citric acid.
  • the ratio of citric acid to sodium citrate determines the pH of the buffer.
  • Such a buffer system is well known to those skilled in the art and is described in neary all standard textbooks e.g., Physical Pharmacy by A. N. Martin, J. Swarbrick and A. Cammarata, Lee and Fabiger, 2nd edition, page 237 onwards.
  • Suitable “stabilizers” may include one or more of EDTA (ethylene diamine tetraacetic acid), para-hydroxybenzoic acid ester derivatives, alcohol, benzalkonium chloride, phenol derivatives, thiomersal, acetic anhydride, ascorbic acid, sorbic acid, boric acid, adipic acid, sodium carboxylate, lauryl sulfate, retinol, tocopherol or sodium ascorbate, sulfite compounds, amino acid such as L-cysteine, thiodipropionic acid, thiolactic acid, and monothioglycerol, sulfurous acid, sulfite, ascorbate, L-cysteine, and tocopherol. N-acetyl amino acid, tocopherol, sodium formaldehyde, or tertiary-butyl hydroquinone, sodium sulfite, sodium phosphate and the like.
  • EDTA ethylene diamine tetra
  • parenterally acceptable pharmaceutical excipients that can also be used in the injectable pharmaceutical composition in accordance with the present invention include tonicity modifier, diluents, antioxidants, preservatives and the like.
  • Suitable "diluents” may include, but not limited to mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll or gelatin and the like.
  • the amount of diluents may range from about 0.01% w/v to about 90% w/v of the composition.
  • Suitable “preservatives” may include, but not limited to benzyl alcohol, EDTA, combinations thereof, and any other similar preservative known to those of skill in the art.
  • Suitable "tonicity modifier” may include one or more physiologically tolerated salt, such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering physiologically acceptable isotonicity.
  • physiologically tolerated salt such as, for example, sodium chloride or potassium chloride
  • physiologically tolerated polyol such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering physiologically acceptable isotonicity.
  • the present invention provides a method of reducing of atherothrombotic events like recent myocardial infarction and treating recent stroke or established peripheral arterial disease, acute coronary syndrome comprising administering to human patient in need thereof a stable injectable pharmaceutical composition comprising a concentrate of clopidogrel or pharmaceutically acceptable salts thereof.
  • Cremophor was mixed with small quantity of Water for Injection. Citric Acid and Tri Sodium Citrate were mixed with small quantity of Water for Injection. Both solutions were mixed and the volume is adjusted with remaining quantity of Water for Injection. The solution was sterilized by aseptic filtration and aseptically filled.
  • Clopidogrel or its salt (Clopidogrel besylate) was dissolved in ethanol in presence of solubilizer. Mannitol / Lactose monohydrate was dissolved in water. These solutions were mixed under stirring, filtered and lyophilized as per suitable temperature and cycle.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques stables de clopidogrel ou de sels de celui-ci pour administration parentérale. Elle concerne des compositions pharmaceutiques contenant un concentré de clopidogrel ou des sels de celui-ci pharmaceutiquement acceptables, qui peuvent être mélangés à un véhicule aqueux approprié pour la préparation d'une solution d'infusion convenant à une administration à des patients. Ces compositions présentent une excellente stabilité. L'invention concerne également un procédé de préparation de ces compositions.
PCT/IN2011/000098 2010-02-19 2011-02-17 Compositions pharmaceutiques stables de clopidogrel pour administration parentérale WO2011101865A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN465MU2010 2010-02-19
IN465/MUM/2010 2010-02-19

Publications (2)

Publication Number Publication Date
WO2011101865A2 true WO2011101865A2 (fr) 2011-08-25
WO2011101865A3 WO2011101865A3 (fr) 2011-10-27

Family

ID=44454050

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000098 WO2011101865A2 (fr) 2010-02-19 2011-02-17 Compositions pharmaceutiques stables de clopidogrel pour administration parentérale

Country Status (1)

Country Link
WO (1) WO2011101865A2 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802A1 (fr) 1982-07-13 1984-02-01 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
US4847265A (en) 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
EP1105102A1 (fr) 1998-08-20 2001-06-13 Sanofi-Synthelabo Composition pharmaceutique injectable a base d'un sel pharmaceutiquement acceptable du clopidogrel ou de ticlopidine
US6284277B1 (en) 1995-11-03 2001-09-04 Sanofi-Synthelabo Stable freeze-dried pharmaceutical formulation
WO2008034600A1 (fr) 2006-09-21 2008-03-27 Novartis Ag Derives de pyrrole utilises dans le traitement des maladies induites par les cytokines
WO2009033455A1 (fr) 2007-09-13 2009-03-19 Grenzebach Maschinenbau Gmbh Dispositif et procédé de séparation d'une bande de verre continue

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100562309C (zh) * 2006-07-14 2009-11-25 北京赛科药业有限责任公司 氯吡格雷及其盐的可注射组合物与其制备方法
WO2008060934A2 (fr) * 2006-11-14 2008-05-22 Acusphere, Inc. Formulations d'agents de tetrahydropyridine antiplaquettes pour administration parentale ou orale
BRPI0809838B1 (pt) * 2007-04-27 2021-10-05 Cydex Pharmaceuticals, Inc Composição, método para a estabilização do (s)-clopidogrel e uso de uma composição
WO2009133455A2 (fr) * 2008-05-01 2009-11-05 Cadila Healthcare Limited Composition pharmaceutique de clopidogrel

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802A1 (fr) 1982-07-13 1984-02-01 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
US4847265A (en) 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
US6284277B1 (en) 1995-11-03 2001-09-04 Sanofi-Synthelabo Stable freeze-dried pharmaceutical formulation
EP1105102A1 (fr) 1998-08-20 2001-06-13 Sanofi-Synthelabo Composition pharmaceutique injectable a base d'un sel pharmaceutiquement acceptable du clopidogrel ou de ticlopidine
WO2008034600A1 (fr) 2006-09-21 2008-03-27 Novartis Ag Derives de pyrrole utilises dans le traitement des maladies induites par les cytokines
WO2009033455A1 (fr) 2007-09-13 2009-03-19 Grenzebach Maschinenbau Gmbh Dispositif et procédé de séparation d'une bande de verre continue

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A. N. MARTIN, J. SWARBRICK, A. CAMMARATA: "Physical Pharmacy", LEE AND FABIGER, pages: 237

Also Published As

Publication number Publication date
WO2011101865A3 (fr) 2011-10-27

Similar Documents

Publication Publication Date Title
JP4972750B2 (ja) 非経口抗真菌生成物
KR102656841B1 (ko) 레파뮬린의 주사가능한 약제학적 제형
JP2018528242A (ja) 非プロトン性極性溶媒中の安定な治療用グルカゴン製剤を製造するための方法
AU2015256331B2 (en) Formulations of Cyclophosphamide liquid concentrate
US20170224789A1 (en) Stable injectable composition of bivalirudin and process for its preparation
MXPA05002561A (es) Nuevas formulaciones de liberacion prolongada inyectables.
JP2018531268A (ja) ダントロレンを含む水性組成物
JP2018531268A6 (ja) ダントロレンを含む水性組成物
JP2012167132A (ja) Ｎ−［ｏ−（ｐ−ピバロイルオキシベンゼンスルホニルアミノ）ベンゾイル］グリシン・モノナトリウム塩・４水和物の凍結乾燥製剤
CA2410446C (fr) Formulation d'esmolol
CN102342931B (zh) 替莫唑胺的可注射的胃肠外用药物制剂及其制备方法
JP2015526463A (ja) 改善されたダプトマイシン注射用製剤
WO2009133455A2 (fr) Composition pharmaceutique de clopidogrel
JP2002508330A (ja) ダルホプリスチンおよびキヌプリスチンに基づく医薬組成物ならびに調製
WO2011101865A2 (fr) Compositions pharmaceutiques stables de clopidogrel pour administration parentérale
US20230068866A1 (en) Daptomycin formulation
EP3679925B1 (fr) Composition pharmaceutique de conjugué de docétaxel et procédé de préparation
JP2015520142A (ja) 非経口エスモロール製剤
WO2023214433A1 (fr) Compositions parentérales stables de parécoxib
WO2023209731A1 (fr) Formes posologiques injectables liquides ou lyophilisées de sélexipag et leur procédé de préparation
WO2014139677A1 (fr) Préparation parentérale d'agent antibactérien à base de fluoroquinolone et procédé de préparation associé
WO2016079749A2 (fr) Procédé de préparation de formulation parentérale d'anidulafungine
EA023081B1 (ru) Инъекционная лекарственная форма флупиртина

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11725819

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11725819

Country of ref document: EP

Kind code of ref document: A2