WO2012122493A1 - Compositions de clopidogrel à base de lipides, et procédés et utilisations afférents - Google Patents

Compositions de clopidogrel à base de lipides, et procédés et utilisations afférents Download PDF

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Publication number
WO2012122493A1
WO2012122493A1 PCT/US2012/028530 US2012028530W WO2012122493A1 WO 2012122493 A1 WO2012122493 A1 WO 2012122493A1 US 2012028530 W US2012028530 W US 2012028530W WO 2012122493 A1 WO2012122493 A1 WO 2012122493A1
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Prior art keywords
lipid
clopidogrel
salt
acid
cholesterol
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PCT/US2012/028530
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English (en)
Inventor
Shoukath M. Ali
Ateeq Ahmad
Saifuddin Sheikh
Moghis U. Ahmad
Imran Ahmad
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Jina Pharmaceuticals, Inc.
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Publication of WO2012122493A1 publication Critical patent/WO2012122493A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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

Definitions

  • the invention relates to compositions comprising clopidogrel and one or more lipids, including, e.g., suspensions, complexes, micelles, emulsions, liposomes or lipidic particle, and mixture of micelles and vesicles.
  • the invention further relates to methods of preparation of such compositions, and uses in the treatment of diseases, such as mammalian diseases.
  • the invention relates to methods for using aqueous systems that are capable of encapsulating pharmaceutically active compounds having poor water solubility.
  • Methods according to the present invention are suitable for practice on an industrial manufacturing scale, and may be practiced as a batch or continuous process. These methods are simple, free from toxic organic solvents, easily scaled to large volumes, and result in the formation of lipid suspensions of high concentration and defined particle size.
  • Atherosclerosis is the leading cause of death in the United States.
  • Atherosclerosis is a common disorder that specifically affects medium and large arteries. It occurs when an artery wall thickens as the result of a build-up of fatty materials such as fats, cholesterol, and other substances commonly referred as plaques, and obstruct blood flow through the vessel.
  • the plaques can make the artery narrow and less flexible, making it harder for blood to flow through.
  • blood flow to the heart can slow down or stop. This can cause chest pain, shortness of breath, heart attack, and other symptoms.
  • the plaques can also rupture and can lead to thrombus formation that will rapidly slow or stop blood flow, leading to death of the tissues fed by the artery. This catastrophic event is called an infarction.
  • ischemic end organ damage The most common forms of ischemic end organ damage are myocardial infarction and cerebrovascular accidents. Atherosclerosis can affect different organ systems, including heart, lungs, brain, intestines, kidneys, legs, etc. [0003] Thrombosis is the formation of blood clots inside a blood vessel, obstructing the flow of blood through the circulatory system. Platelets or
  • thrombocytes are small, clear cell fragments (anucleate cells) and play a fundamental role in hemostasis.
  • the body uses platelets and fibrin to form a blood clot to prevent blood loss. If the number of platelets is too low, excessive bleeding can occur. However, if the number of platelets is too high, blood clots (thrombosis) can form, which may obstruct blood vessels and result in such events as a stroke, myocardial infarction, pulmonary embolism, or the blockage of blood flowto other parts of the body. However, blood clots may form in the body even when a blood vessel is not injured. If the clotting is too severe and the clot breaks free, the traveling clot is referred as embolus (Furie, B. and Furie, B.C 2008; Handin, R.I., 2005).
  • statins drugs that can prevent atherosclerosis or supress the platelet functions include aspirin, ibuprofen, diclofenac, clopidogrel, cilostazol, ticlopidine, abciximab, eptifibatide, torofiban, etc.
  • Clopidogrel belongs to thienopyridine class of antiplatelet agents and is used to inhibit blood clot formation in coronary artery disease, peripheral vascular disease, and cerebrovascular disease.
  • Clopidogrel is an inactive prodrug that requires oxidation by the cytochrome P450 (CYP) 3A4 isozyme to form the active metabolite.
  • the active metabolite forms an irreversible bond with the low-affinity adenosine diphosphate (ADP) receptor of platelet cell membranes.
  • the drug specifically inhibits the ADP receptor, which is important in platelets aggregation and cross-linking by the protein fibrin (Savi et al 2006).
  • Clopidogrel also inhibits platelet aggregation induced by the release of the platelet-dense granular contents.
  • the granular contents include ADP, calcium, and serotonin, all of which increase platelet aggregation.
  • Clopidogrel is indicated for the secondary prevention of atherothrombotic events in patients with atherosclerosis documented by stroke, myocardial infarction in established peripheral arterial disease. Clopidogrel, in combination with
  • acetylsalicylic acid is indicated for the early and long-term secondary prevention of atherothrombotic events in patients with acute coronary syndromes- without ST segment elevation.
  • Clopidogrel is also used as an alternative antiplatelet drug for patients who are intolerant to aspirin (Randall, M.D. and Neil, K.E 2004). Clopidogrel is also administered in hospitals prior to diagnostic coronary angiography in patients with acute coronary syndrome (ACS).
  • Clopidogrel is currently marketed as clopidogrel bisulfate for oral administration in the form of tablets containing 75 mg of clopidogrel. Platelet inhibition can occur two hours after single dose of oral clopidogrel, but the onset of action of slow, so that a loading-dose of 300-600 mg is usually administered.
  • clopidogrel Although clopidogrel is currently administered orally, it is not available for administration intravenously as an approved product.
  • the limitations of oral administration include use of high dose to reach effective drug level in blood, reaching effective blood level after several hours of dosing, bleeding complications, etc.
  • WO200933455 (Bhushan, R. et al. 2009) describes pharmaceutical compositions of clopidogrel containing Solutol HS 15 (Polyethylene glycol 660 12- hydroxy stereate) for intravenous use.
  • Solutol HS 15 Polyethylene glycol 660 12- hydroxy stereate
  • Liposomes have been used for some time as delivery vehicles for large variety of therapeutic drugs (e.g. Doxil ® Product Information; Ambisome ® , Product Information) which exhibits poor solubility or exhibits unacceptable toxicity at therapeutic dosages.
  • Doxil ® Product Information e.g. Doxil ® Product Information
  • Ambisome ® e.g., Ambisome ®
  • Intravenous administration of phospholipids and liposomes has been shown to produce regression of atherosclerotic plaques although serum lipid levels are transiently elevated (Williams et al 1984).
  • Liposome preparation systems or systems containing lipids typically involve the use of organic solvents such as dimethylsulfoxide, dimethyformamide, methylene chloride, chloroform, ethanol, or methanol (Adler-Moore, J. et al. 1993; Bissery, M-C, 2000, US6, 146,663; Proffitt, R.T. et al 1991; Proffitt, R.T. et al 1999, US5, 956,156; Straubinger, R.M. et al, 1995, US5, 415,869).
  • organic solvents can pose health risks, e.g. for production workers and removal of organic solvents is generally a cumbersome process.
  • the present invention relates to the preparing of clopidogrel complexed with lipids, and methods of using the complexes in treating disease in a subject.
  • the complex interaction may be ionic or lipophilic.
  • the complex formation takes place in a completely aqueous system.
  • the present invention comprises a composition comprising clopidogrel and one or more lipids.
  • the present invention comprises a method comprising preparing a composition comprising clopidogrel and one or more lipids, and administering the composition to a subject.
  • the subject is a mammal. In certain preferred embodiments, the subject is human.
  • An object of the present invention is to provide lipid formulations or complexes comprising clopidogrel and at least one lipid, e.g. , a phospholipid, formed without using organic solvent.
  • the amount of phospholipid included in a lipid complex according to the present invention is not limited to any particular amount or percentage ⁇ e.g. , by weight) of the final composition or complex.
  • the proportion of the at least one phospholipid is between about 5% to about 98% of a final lipid complex ⁇ e.g., a commercially usable form) by weight.
  • a final lipid complex ⁇ e.g., a commercially usable form
  • the amount of the at least one phospholipid is in between 10% to 90% of the lipid complex by weight.
  • a lipid formulation system according to the present invention has a pH of between about 4.0 and 8.5. In some preferred embodiments, the pH is between about 4.5 and 8.0.
  • clopidogrel is encapsulated or entrappeda liposome or suspension system. In certain preferred embodiment, the entrapped or
  • encapsulated clopidogrel is used to inhibit platelet aggregation.
  • pharmaceutical product is particularly suitable for injection or oral usage.
  • a composition according to the present invention comprises clopidogrel at a concentration of from about 0.5mg/mL to about 25mg/mL while in some preferred embodiments, the active compound (for example, clopidogrel) of the composition is at a concentration of from about 1 mg/mL to about 10 mg/mL. In some particularly preferred embodiments, the composition of the invention comprises clopidogrel is at a concentration of about 1 mg/mL to about 5mg/mL.
  • a composition according to the present invention comprises clopidogrel and total lipid(s) having a weight-to-weight ratio ranging from about 1 :0.1 to about 1 : 100, while in certain preferred embodiments, the ratio is in between 1 : 10 to about 1 :60.
  • a composition according to the present invention comprises a complex selected from the group consisting of a micelle, a suspension, and an emulsion.
  • the composition comprises a plurality of micelles, wherein said micelles are in the form of monomeric, dimeric, polymeric or mixed micelles.
  • a composition according to the present invention comprises complexes, liposomes, micelles, vesicles, suspensions that have a diameter of about 20 microns or less, while in some embodiments, the complexes, liposomes, micelles, vesicles that have a diameter of about 10 microns or less. In some embodiments, the complexes, liposomes, micelles, vesicles that have a diameter of about 5 microns or less, while in some embodiments, the complexes, liposomes, micelles, vesicles that have a diameter of about 1 micron or less. In some
  • the complexes, liposomes, micelles, vesicles that have a diameter of about 500 nm or less, while in some embodiments, the complexes, liposomes, micelles, vesicles that have a diameter of about 200 nm or less. In some preferred embodiments, the complexes, liposomes, micelles, vesicles that have a diameter of about 100 nm or less.
  • clopidogrel is added after the preparation of the lipid system.
  • clopidogrel is added to a lipid preparation, e.g., a lipid system, immediately before use ⁇ e.g., immediately before administration to a patient or subject).
  • a lipid preparation e.g., a lipid system
  • immediately before use e.g., immediately before administration to a patient or subject.
  • clopidogrel in dry form may be dispersed or emulsified into an aqueous unloaded lipid system, while in other embodiments, a dried lipid system may be emulsified into water in which
  • compositions prepared in this way show better transparency and may be easier to inspect, e.g., for the presence of unwanted foreign particles.
  • a complex in a composition according to the present invention is in a powder form, while in some embodiments, the complex is in a solution form. In some embodiments, the complex is in a suspension form, while in other embodiments, the complex is in an emulsion form, while in still other embodiments, the complex is in a micelle form or mixed micellar form or in a liposome form. In some embodiments, the complex is in a lyophilized or gel form, while in some embodiments, the complex is in a paste form. In some embodiments, the complex is a mixture of mixed micelles, liposomes or vesicles form.
  • a composition according to the present invention is encapsulated in a capsule.
  • the capsule is a gel capsule, while in some particularly preferred embodiments; the capsule comprises an enteric coating.
  • drugs, active agents or therapeutic agents that find use in the methods, compositions and systems of the present invention include, e.g., the cardiovascular system, the blood circulatory system,.
  • Active agents can be anticoagulants, platelet inhibitory agents, anti-thrombin agents, anti-arrhythmic agents, lipid lowering agents cardiac inotropic agents, cardiovascular agents, hypercholesterol agents, vasodilators.
  • the therapeutic agents can be aspirin, ibuprofen, nitroglycerin, isosorbide dinitrate, propranolol, carvadiol, timolol, atenolol, alprenolol, diclofenac, tirofiban, eptifibatide, abciximab, ifetroban, heparins, argatroban, lovastatin, atorvastatin, simvastatin, pravastatin, rosuvastatin, atavastib, visastatin, prasugrel, anagrelide, tirofiban, dipyridamole, cilostazol, ticlopidine.
  • the inventive method is simple, rapid and less expensive method to produce organic solvent-free aqueous lipid systems, which allow a particularly simple and rapid inspection of foreign particles. Furthermore, the lipid system produced according to the inventive method shows highly reproducible particle sizes, with average particle size below 5 micron, preferably between 50nm and 1 micron. It is also possible to filter the product through sterile filtration known in the art. The duration of the extrusion, or the high pressure split homogenization is chosen to be sufficiently long for the liposomes to show the desired average diameter. Said extrusion, high pressure split homogenization is performed until liposomes possess a mean diameter between 50nm and 1 micron.
  • the clopidogrel-lipid system produced according to the present inventive method can be filled directly in corresponding ampoules in a condition ready to use, and lyophilize the product after the adding the desired amount of carbohydrate known in the art, whereby lyophilization constitute the best method of water drying.
  • the exposing of a cell in a subject comprises oral delivery of the composition to the subject, while in other embodiments; the exposing of a cell comprises intravenous delivery of the
  • compositions to the subject include but are not limited to subcutaneous delivery, parenteral delivery, intraperitoneal delivery, rectal delivery, vaginal delivery and/or topical delivery.
  • the subject is a mammal. In some particularly preferred embodiments, the mammal is human.
  • Figures 1 A and IB provides graphs comparing the effects on bleeding time and blood loss of treatment with a lipid-based formulation of clopidogrel to treatment with reference compound clopidogrel bisulfate, water or a placebo.
  • Figures 2A-2C provides graphs showing bleeding times and blood loss (volume) at different doses of clopidogrel lipid suspension.
  • Figure 3 shows a pharmacokinetics profile of Clopidogrel Carboxylic Acid (CCA) following Intravenous (IV) administration of Clopidogrel Lipid
  • lipid composition refers to amphoteric compounds which are capable of liposome formation, vesicle formation, micelle formation, emulsion formation, suspension formation, and are substantially non-toxic when administrated at the necessary concentrations.
  • the lipid composition may include without limitation egg phosphatidylcholine (EPC),egg phosphatidylglycerol (EPG), soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosohatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), cholesterol (Choi), cholesterol sulfate and its salts (CS), cholesterol hemisuccinate and its salts (Chems), cholesterol phosphate and its salts (CP), cholesterylphospholine and other hydroxycholesterol or amino cholesterol derivatives.
  • EPC egg phosphatidylcholine
  • EPG epigallocate phosphatidylglycerol
  • aqueous refers to a water-based solvent, fluid or system that does not contain any organic solvents.
  • An aqueous system may further contain buffer(s).
  • base or buffer includes but not limited to sodium succinate dibasic, sodium acetate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, sodium citrate, sodium hydroxide, and the like.
  • encapsulating amount refers to the amount of lipid necessary to encapsulate or entrap the poorly soluble compound and form liposome or lipidic particles of appropriate mean particle size less than 5,000nm in diameter, preferably between 30-1000nm.
  • the encapsulating amount will depend on the pharmaceutically active compounds and process conditions selected, but in general range in between from 2: 1 to about 1 : 100 compound: lipid ratio; preferably about 1 : 1 to about 1 :50.
  • lipidic particle refers to particles of undefined structure which consist of a suitable lipid and an encapsulated or complexed pharmaceutically active compound. Lipidic particles may have a lamellar structure but are not required to exhibit any defined structure.
  • an effective amount refers to the amount of an active composition (e.g., a pharmaceutical compound or composition provided as a component in a lipid formulation) sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the administration may be in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term is not limited to any particular level of activity.
  • a lipid formulation of an active agent need not have the same level of activity as a different formulation of an active agent, so long as the active agent in the lipid formulation is sufficiently active that an effective amount of the active agent can be administered by
  • agent and “compound” are used herein interchangeably to refer to any atom, molecule, mixture, or more complex composition having an attributed feature.
  • an “active agent” or “active compound” refers to any atom, molecule, preparation, mixture, etc., that, upon administration or application, causes a beneficial, desired, or expected result.
  • the term "administration" refers to the act of giving a drug, prodrug, or other active agent, or therapeutic treatment ⁇ e.g., compositions of the present invention) to a physiological system ⁇ e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs).
  • a physiological system e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs.
  • exemplary routes of administration to the human body can be through the eyes (ophthalmic), mouth (oral), skin (transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, by injection ⁇ e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like.
  • Administration may be in one or more administrations, applications or dosages, and is not intended to be limited to a particular administration route.
  • co -administration refers to the administration of at least two agent(s) ⁇ e.g., two separate lipid compositions, containing different active compounds) or therapies to a subject.
  • the co-administration of two or more agents or therapies is concurrent.
  • a first agent/therapy is administered prior to a second agent/therapy.
  • the appropriate dosage for co-administration can be readily determined by one skilled in the art.
  • agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone.
  • coadministration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful ⁇ e.g., toxic) agent(s).
  • the term “toxic” refers to any detrimental or harmful effects on a subject, a cell, or a tissue as compared to the same cell or tissue prior to the administration of the toxicant.
  • the term “pharmaceutical composition” refers to the combination of an active agent (e.g., an active pharmaceutical compound) with a carrier, inert or active (e.g., a phospholipid), making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.
  • topically refers to application of the
  • compositions of the present invention to the surface of the skin and mucosal cells and tissues (e.g., alveolar, buccal, lingual, masticatory, or nasal mucosa, and other tissues and cells which line hollow organs or body cavities).
  • mucosal cells and tissues e.g., alveolar, buccal, lingual, masticatory, or nasal mucosa, and other tissues and cells which line hollow organs or body cavities).
  • the term "pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintrigrants (e.g., potato starch or sodium starch glycolate), and the like.
  • the compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants.
  • compositions of the present invention may be formulated for horticultural or agricultural use.
  • Such formulations include dips, sprays, seed dressings, stem injections, sprays, and mists.
  • the term "pharmaceutically acceptable salt” refers to any salt (e.g. , obtained by reaction with an acid or a base) of a compound of the present invention that is physiologically tolerated in the target subject (e.g., a mammalian subject, and/or in vivo or ex vivo, cells, tissues, or organs).
  • Salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, sulfonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,
  • ethanesulfonate fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartarate, thiocyanate, tosylate, undecanoate, and the like.
  • salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a Ci_ 4 alkyl group), and the like.
  • a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a Ci_ 4 alkyl group)
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • Polyethylene glycol (PEG) includes polymers of lower alkylene oxide, in particular ethylene oxide (polyethylene glycols) having an esterifiable hydroxyl group at least at one end of the polymer molecule, as well as derivatives of such polymers having esterifiable carboxy groups.
  • Polyethylene glycols of an average molecular weight ranging from 200-20,000 are preferred; those having an average molecular weight ranging from 500-2000 are particularly preferred.
  • This invention relates to the preparation of a suspension, emulsions, liposomes, lipid complex, or micelles in an aqueous system.
  • the inventive preparation involves at least one phospholipid such as Soya phosphatidylcholine in aqueous media with therapeutically active insoluble or poorly soluble compounds.
  • the present invention also relates to compositions and methods of delivering clopidogrel.
  • the present invention also relates to the process of making clopidogrel-lipid complex and delivering said clopidogrel-lipid complex to treat diseases.
  • the present invention provides compositions and methods of delivering clopidogrel to a mammalian host. Any suitable amount of clopidogrel can be used. Suitable amounts of clopidogrel are those amounts that can be stably incorporated into the complexes of the present invention. [0054] The present inventions provide compositions and method for treating cardiovascular diseases.
  • cardiovascular diseases include but are not limited to atherosclerosis, ischemic stroke, myocardial infarction, angina, peripheral vascular disease, thrombosis, coronary heart disease, high blood pressure, heart rhythm disorder, tachycardia, rheumatic heart disease, pulmonary heart disease, hypertension, cardiac arrhythmia, cardiomagaly, conginetal heart disease, valvular hear disease, infective endocarditis, coronary reperfusion, rest enosis, peril-operative (PCI) ischemic events, coagulation disorders, deep vein thrombosis, hyperlipidemia, vulnerable plaques, severe coronary ischemia, carotid and coronary artery disease, restenosis as a result of baloon angioplasty, and the like.
  • PCI peril-operative
  • clopidogrel in a clopidogrel-lipid complex is either a free base or a salt wherein a salt selected from the group consisting of hydrogen sulfate salt, bisulfate salt, hydrochloride salt, hydrobromide salt, phosphate salt, citrate salt, lactate salt, fumarate salt, tartarate salt, acetate salt, methyl sulfonate salt, benzene sulfonate salt, p-toluene sulfonate salt, succinate salt, maleate salt, oxalate salt, glutarate salt or any pharmaceutically acceptable salt.
  • a salt selected from the group consisting of hydrogen sulfate salt, bisulfate salt, hydrochloride salt, hydrobromide salt, phosphate salt, citrate salt, lactate salt, fumarate salt, tartarate salt, acetate salt, methyl sulfonate salt, benzene sulfonate salt, p-toluene
  • the present invention comprises a lipid complex with clopidogrel in which the complex contains lipid or a mixture of lipids.
  • the complexes are in the form of suspensions, micelles, emulsions or mixture of micelles and vesicles.
  • the micelles of the present invention can be in the form, e.g., of monomeric, dimeric, polymeric or mixed micelles.
  • the complexes including micelles, emulsions or mixture of micelles and vesicles are predominately in the size range of 10nm-20 micron, while in some preferred embodiments, the micelles and emulsions are in the size range of 25nm-5 micron.
  • clopidogrel can be bound to the lipid by covalent, hydrophobic, electrostatic, hydrogen, or other bonds, and is considered "bound" even where the antibiotic is simply entrapped within the interior of lipid.
  • clopidogrel-lipid complexes contain cholesterol or cholesterol derivatives.
  • cholesterol derivatives that find use in the present invention include but are not limited to cholesteryl sulfate, cholesteryl hemisuccinate, cholesteryl succinate, cholesteryl oleate, cholesteryl linoleate, cholesteryl eicosapentenoate, cholesteryl linolenate, cholesteryl arachidonate, cholesteryl palmitate, cholesteryl stearate, cholesteryl myristate, polyethylene glycol derivatives of cholesterol (cholesterol-PEG), water soluble cholesterol (for example, cholesterol methyl-P-cyclodextrin), coprostanol, cholestanol, or cholestane, cholic acid, Cortisol, corticosterone or hydrocortisone and 7-dehydrocholesterol.
  • the compositions also include ⁇ -, ⁇ -, ⁇ - tocopherols, vitamin E, calciferol, organic acid derivatives of ⁇ -, ⁇ -, ⁇ -tocopherols, such as a-tocopherol hemisuccinate (THS), a-tocopherol succinate, or mixtures thereof.
  • TSS a-tocopherol hemisuccinate
  • clopidogrel-lipid complexes contain sterols.
  • sterols that find use in the present invention include ⁇ -sitosterol, stigmasterol, stigmastanol, lanosterol, a-spinasterol, lathosterol, campesterol and/or mixtures thereof.
  • compositions of the present invention also include clopidogrel complexes with or without deoxycholate) with free and/or salts or esters of fatty acid.
  • fatty acids range from carbon chain lengths of about C 2 to C34, preferably between about C 4 and about C 24 , and include tetranoic acid (C 4:0 ), pentanoic acid (C 5:0 ), hexanoic acid (C 6 :o), heptanoic acid (C 7:0 ), octanoic acid (Cg : o), nonanoic acid (Cg-.o), decanoic acid (C 10:0 ), undecanoic acid (C 11 :0 ), dodecanoic acid (C 12:0 ), tridecanoic acid (C 13:0 ), tetradecanoic (myristic) acid (C 14:0 ), pentadecanoic acid (Ci5:o), hexa
  • fatty acid chains also can be employed in the compositions.
  • saturated fatty acids such as ethanoic (or acetic) acid, propanoic (or propionic) acid, butanoic (or butyric) acid, hexacosanoic (or cerotic) acid, octacosanoic (or montanic) acid, triacontanoic (or melissic) acid, dotriacontanoic (or lacceroic) acid, tetratriacontanoic (or gheddic) acid, pentatriacontanoic (or ceroplastic) acid, and the like; monoethenoic unsaturated fatty acids such as trans-2-butenoic (or crotonic) acid, cz ' s-2-butenoic (or isocrotonoic) acid, 2-hexenoic (or isohydrosorbic) acid, 4-decanoic (or obt) acid
  • clopidogrel formulation comprise phospholipids.
  • Any suitable phospholipids can be used.
  • phospholipids can be obtained from natural sources or chemically synthesized.
  • Examples of phospholipids that find use in the present invention include phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidic acid (PA), sphingomyelin and the like, either used separately or in combination.
  • Phosphatidylglycerols may be having short chain or long chain, saturated or unsaturated such as dimyristoylphosphatidylglycerol, dioleoylphosphatidylglycerol, distearoylphosphatidylglycerol,
  • dipalmitoylphosphatidylglycerol dipalmitoylphosphatidylglycerol, diarachidonoylphosphatidylglycerol, short chain phosphatidylglycerol (C6-C 8 ), and mixtures thereof.
  • phosphatidylcholines includes dimyristoylphophatidylcholine,
  • phosphatidylcholine can be used, as can mixtures thereof.
  • compositions of the present invention comprises a large concentration of
  • a soybean phospholipid used in the methods and compositions of the present invention contains at least 90% by weight phosphatidylcholine.
  • one or more phospholipids are pegylated (PEG) derivatives of phospholipids.
  • one or more lipids of a composition according to the present invention comprise a monoglyceride, a diglyceride, or a triglyceride lipid.
  • the method of composition, wherein said fatty acids of mono-, di-, and triglycerides are selected from a group of saturated and unsaturated fatty acids having short chain or long chain.
  • one or more lipids of a composition according to the present invention comprise a carbohydrate-based lipid.
  • the one or more lipids of the composition comprise a galactolipid, mannolipid, and galactolecithin.
  • a composition according to the present invention further comprises polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the PEG has an average molecular weight ranging from 200-20,000, while in certain preferred embodiments, the average molecular weight of the PEG is in between 500-2000.
  • the present invention provides compositions comprising clopidogrel and derivatives of mono-, di- and tri-glycerides.
  • examples of the glycerides that find use in the present invention include but are not limited to 1- oleoyl-glycerol (monoolein) and 1, 2-dioctanoyl-s/?-glycerol.
  • Another aspect of the invention is to complex clopidogrel with at least one functionalized phospholipid, including but not limited to phosphatidylethanolamme, phosphatidylthioethanol, N-biotinylphosphatidylethanolamine, and
  • clopidogrel is complexed with dioleoylphosphatidylethanolamine.
  • Yet another aspect of the invention is to complex clopidogrel with derivatives of phospholipids such as pegylated phospholipids.
  • derivatives of phospholipids such as pegylated phospholipids.
  • examples include but not limited to the polyethylene glycol (Pegylated, PEG) derivatives of distearoylphosphatidylglycerol, dimyristoylphosphatidylglycerol,
  • dioleoylphosphatidylglycerol dioleoylphosphatidylglycerol and the like.
  • the present invention provides compositions comprising clopidogrel complexed with one or more lipids.
  • Example includes compositions comprising clopidogrel, cholesterol or cholesterol derivatives and one or more phospholipids.
  • Other examples of compositions according to the invention include clopidogrel, ⁇ -sitosterol, and one or more phospholipids.
  • the composition of the present invention comprises clopidogrel, cholesteryl sulfate and hydrogenated soy phosphatidylcholine or soy
  • composition of the present invention can be made by dissolving clopidogrel in water or buffer at a concentration of about 0.5 mg/mL to about 25 mg/mL.
  • clopidogrel is dissolved at a concentration between 1 mg/mL and about 20 mg/mL.
  • clopidogrel is dissolved at a concentration of between 1 mg/mL and 10 mg/mL.
  • clopidogrel is dissolved at a concentration of between 1 mg/mL and 5 mg/mL.
  • compositions of the present invention contain about 2.5% to about 95% by weight of total lipid, preferably about 10%> to about 90%> by weight of total lipid or more, preferably about 20% to about 90% by weight of total lipid.
  • compositions of the present invention contain clopidogrel and lipid(s) in mole ratio between 1 : 1 to 1 : 100, e.g. , in between 1 : 1 and 1 :20 molar ratio or in between 1 : 1 and 1 :30 molar ratio or in between 1 : 1 and 1 :40 molar ratio or in between 1 : 1 and 1 :50 molar ratio, in between 1 : 1 and 1 :60 molar ratio, in between 1 : 1 and 1 :70 molar ratios, and in between 1 : 1 and 1 :80 molar ratios.
  • the term "in between” is inclusive of the limits of a recited range.
  • compositions of the present invention contain clopidogrel, cholesteryl sulfate and hydrogenated soy phosphatidylcholine or soy phosphatidylcholine.
  • the mole ratio of clopidogrel and cholesterol or cholesterol derivative, e.g. cholesteryl sulfate in a composition and hydrogenated soy phosphatidylcholine is in between 1 :0.1 and 1 :20, or in between
  • the mole ratio of clopidogrel and cholesterol or cholesterol derivative, e.g., cholesteryl sulfate is in between 1 :0.1 and 1 :5.
  • the term "in between” is inclusive of the limits of a recited range.
  • a mole ratio "in between" 1 :0.1 and 1 :20 mole ratio includes ratios of 1 :01 and 1 :20
  • the mole ratio of clopidogrel and cholesterol or cholesterol derivative in a composition containing clopidogrel, cholesterol or cholesterol derivative, and soy phosphatidylcholine is in between 1 :0.1 and 1 :20, such as in between 1 :0.1 and 1 : 10, or in between 1 :0.1 and 1 :5 or 1 :0.1 and 1 :2.
  • the mole ratio of clopidogrel and cholesterol or cholesterol derivative is in between 1 :0.1 and 1 :5.
  • the term "in between” is inclusive of the limits of a recited range.
  • a mole ratio "in between" 1 :0.1 and 1 :20 mole ratio includes ratios of 1 :0.1 and 1 :20.
  • the mole ratio of clopidogrel and phosphatidylcholine, e.g., soy phosphatidylcholine, in a composition containing clopidogrel, cholesteryl sulfate and phosphatidylcholine, e.g., soy phosphatidylcholine is in between about 1 : 1 and 1 :90, e.g. , in between 1 : 1 and 1 :70 or 1 : 1 and 1 :60 or 1 : 1 and 1 :50 or 1 : 1 and 1 :40 and 1 : 1 and 1 :30.
  • the mole ratio of clopidogrel and phosphatidylcholine, e.g. soy phosphatidylcholine is in between 1 :5 and 1 :60.
  • the mole ratio of clopidogrel and soy phosphatidylcholine in a composition containing clopidogrel, cholesteryl sulfate and soy phosphatidylcholine is in between 1 : 1 and 1 :90, e.g., in between 1 : 1 and 1 :70 or 1 : 1 and 1 :60 or 1 :1 and 1 :50 or 1 : 1 and 1 :40 and 1 : 1 and 1 :30.
  • the mole ratio of clopidogrel and soy phosphatidylcholine is in between 1 :5 and 1 :60.
  • compositions of the present invention contain clopidogrel and total lipids having weight-to-weight ratio between 1 : 1 to 1 : 100 ratio, such as in between 1 : 1 and 1 :20 ratio or in between 1 : 1 and 1 :30 ratio or in between 1 : 1 and 1 :40 ratio or in between 1 : 1 and 1 :50 ratio, or in between 1 : 1 and 1 :60 ratio, or in between 1 : 1 and 1 :70 ratio, and in between 1 : 1 and 1 :80 ratio, or in between 1 : 1 and 1 :90 ratio.
  • the methods of the present invention involve dissolving clopidogrel in water or buffer and mixing the dissolved clopidogrel and the lipid(s) together.
  • the clopidogrel-lipid complex solution can be filtered through suitable filters to control the size distribution of the formed complexes.
  • the present invention comprises mixing clopidogrel and one or more lipids in any suitable sequence such that the resulting composition of the present invention comprises clopidogrel and one or more lipids.
  • the method comprises mixing clopidogrel in a suitable buffer with pH between 4.00 and 9.00. Lipids such as soy phosphatidylcholine are then added to the solution, followed by one more lipids, such as cholesteryl sulfate.
  • the clopidogrel-lipid complex solution can be filtered through suitable filters to control the size distribution of the formed complexes.
  • base or buffer includes but not limited to sodium succinate dibasic, sodium acetate, sodium phosphate
  • the composition may further contain sugar.
  • sugars includes but not limited to sucrose, lactose, dextrose, trehalose maltose, and the like. The percentage of sugar may range from 5% to about 25%.
  • the resulting suspension can be homogenized or sonicated to reduce the particle size.
  • the hydrated suspension is filtered through suitable filters to control the size distribution of the formed complexes.
  • the hydrated composition can be lyophilized to obtain the composition in powder form.
  • the present invention comprises mixing clopidogrel and one or more lipids in any suitable sequence such that the resulting composition comprises clopidogrel and one or more lipids.
  • the method of preparation of present invention comprising mixing clopidogrel, cholesteryl derivative (for example, cholesteryl sulfate) and phosphatidylcholine, such as soy phosphatidylcholine or hydrogenated soy phosphatidylcholine, in water or buffer.
  • cholesteryl derivative for example, cholesteryl sulfate
  • phosphatidylcholine such as soy phosphatidylcholine or hydrogenated soy phosphatidylcholine
  • base or buffer includes but not limited to sodium succinate dibasic, sodium acetate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, sodium hydroxide, sodium citrate monobasic, sodium citrate dibasic, sodium citrate tribasic, saline, and the like.
  • the composition may further contain sugar.
  • sugars includes but not limited to sucrose, lactose, dextrose, trehalose, maltose, and the like. The percentage of sugar may range from about 5% to about 25%.
  • the resulting suspension can be homogenized or sonicated to reduce the particle size. In some embodiments, the hydrated suspension is filtered through suitable filters to control the size distribution of the formed complexes.
  • the hydrated suspension can be lyophilized to obtain the composition in powder form.
  • the pH of the composition of invention ranges from about 3 to about 11, preferably having a pH of about 3.5 to about 8, and more preferably having a pH of about 4.0 to pH 8.0.
  • aqueous solutions having suitable pH are prepared from water having appropriate amount of buffers dissolved in it.
  • buffers comprise mixtures of monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate.
  • buffers comprise sodium carbonate, sodium bicarbonate, sodium hydroxide, ammonium acetate, sodium succinate, sodium citrate, tris (hydroxyl-methyl) amino ethane, sodium benzoate, sodium acetate, and the like.
  • filters are used to obtain the desired size range of the complexes from the filtrate.
  • the complexes can be formed and thereafter filtered through a 5 micron filter to obtain complex having a diameter of about 5 micron or less.
  • 1 am, 500 nm, 200 nm, 100 nm or other filters can be used to obtain complexes having diameters of about 1 am, 500 nm, 200 nm, 100 nm or any suitable size range, respectively.
  • the composition of the present invention can be sterilized by filtering through 0.22 ⁇ or 0.45 ⁇ filter under aseptic conditions. In other embodiments, the composition of the present invention can be sterilized by autoclaving in the range of 120°C-130°C for duration of 15-20 minutes. [0086] In some embodiments, clopidogrel-lipid complex is dried, e.g., by evaporation or lyophilization. In certain embodiments of the invention, the clopidogrel-lipid complex is lyophilized with one or more cryoprotectants, such as sugars.
  • the compositions of the present invention comprise lactose and/or sucrose.
  • the lyophilization in the present invention can be done in vials having any desired volume.
  • the lyophilization can also be done as bulk, e.g., in trays.
  • the complexes can be resuspended in any desirable solvent including water, saline, dextrose and buffer.
  • compositions or forms that find use in the present invention include but are not limited to tablets, capsules, pills, dragees, suppositories, solutions, suspensions, emulsions, ointments; gels can be suitable pharmaceutical preparations.
  • clopidogrel-lipid complex is provided in the form of suspensions, solutions, and/or emulsions.
  • clopidogrel-lipid complex is used in the form of tablets, capsules, lozenges, powders, syrups, aqueous solutions, suspensions and the like.
  • clopidogrel-lipid complex is provided in the form of gels, oils, and emulsions, and may comprise e.g., suitable water-soluble or water-insoluble excipients, such as polyethylene glycols, certain fats, and esters, compounds having a higher content of polyunsaturated fatty acids and derivatives thereof.
  • suitable water-soluble or water-insoluble excipients such as polyethylene glycols, certain fats, and esters, compounds having a higher content of polyunsaturated fatty acids and derivatives thereof.
  • Derivatives include but are not limited to mono-, di-, and triglycerides and their aliphatic esters (for example, fish oils, vegetable oils etc.) or mixtures of these substances.
  • excipients that find use in conjunction with the compositions of the present invention comprise those in which the drug complexes are sufficiently stable to allow for therapeutic use.
  • preparations of clopidogrel-lipid complex are encapsulated in enteric coated capsules, e.g., to protect it from acids in the stomach.
  • Enteric refers to the small intestine
  • enteric coating generally refers to a coating that substantially prevents release of a medication before it reaches the small intestine. While not limiting the invention to any particular mechanism of action, it is understood that most enteric coatings work by presenting a surface that is stable at acidic pH but breaks down rapidly at higher pH.
  • Enteric coatings that find use in the present invention comprise capsules filled with active compound-lipid complex (for example, clopidogrel-lipid complex) as according to methods well known in the art.
  • Preparations of clopidogrel-lipid complex of the present invention can comprise complexes of varying size, or can comprise complexes of substantially uniform size.
  • the complexes have a size range of about 1 mm or less, while in preferred embodiments, the complexes are in the micron or sub-micron range.
  • the complexes have a diameter of about 5 ⁇ or less, such as 0.2 ⁇ or less, or even 0.1 ⁇ or less.
  • Clopidogrel-lipid complex of the present invention may comprise or consist essentially of suspensions, emulsions, micelles, mixed micelles, liposomes and vesicles of different shape and sizes.
  • the technology outlined in the present invention for the preparation of clopidogrel complexes is also suitable for use with any other water- insoluble drugs.
  • the clopidogrel lipid-complex of the present invention is employed to treat cardiovascular disease in a mammal.
  • the invention provides a method of treating cardiovascular disease comprising administering to a subject (e.g. a patient having a cardiovascular disease) a composition comprising a complex of clopidogrel-lipid-complex and lipid(s) in an amount sufficient to treat the cardiovascular disease within the subject.
  • cardiovascular disease examples include, but are not limited to atherosclerosis, ischemic stroke, myocardial infarction, angina, peripheral vascular disease, thrombosis, coronary heart disease, high blood pressure, heart rhythm disorder, tachycardia, rheumatic heart disease, pulmonary heart disease, hypertension, cardiac arrhythmia, cardiomegaly, congenital heart disease, valvular heart disease, infective endocarditis, coronary reperfusion, restenosis, peri-operative (PCI) ischemic events, coagulation disorders, deep vein thrombosis, hyperlipidemia, vulnerable plaques, severe coronary ischemia, carotid and coronary artery disease, restenosis as a result of balloon angioplasty, etc.
  • Other therapeutic agents can be advantageously employed with the present invention in the formation of an active combination or by separate administration.
  • Clopidogrel bisulfate (1 g), Cholesteryl sulfate (290 mg), and Soy lecithin (39.71 g) were mixed together in 0.2% sodium citrate dibasic solution (800 mL) and homogenized using high pressure homogenizer. The resulting suspension was then mixed with sucrose solution (75 g dissolved in 200 mL 0.2% sodium citrate dibasic solution). The lipid suspension and sucrose solution was mixed together thoroughly before it was filtered through 0.2 ⁇ filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm.
  • Clopidogrel bisulfate (200 mg), Cholesteryl sulfate (58.2 mg), and Soy lecithin (3.94 g) were mixed together in 0.2% sodium citrate tribasic solution (80 mL) and homogenized using high pressure homogenizer. The resulting suspension was then mixed with sucrose solution (7.5 g dissolved in 20 mL0.2%> sodium citrate tribasic solution). The lipid suspension and sucrose solution was mixed together thoroughly before it was filtered through 0.2 ⁇ filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200.
  • Clopidogrel bisulfate (2 g), Cholesteryl sulfate (580 mg), and Soy lecithin (79.42 g) were mixed together in 0.2%> sodium citrate monobasic solution ( pH 7.2- 7.4 800 mL) and homogenized using high pressure homogenizer. The resulting suspension was then mixed with sucrose solution (75 g dissolved in 200 mL 0.2%> sodium citrate monobasic solution pH 7.2-7.4). The lipid suspension and sucrose solution was mixed together thoroughly before it was filtered through 0.2 ⁇ filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200
  • Clopidogrel bisulfate (260 mg), Cholesteryl sulfate (75.4 mg), and Soy lecithin (10.32 g) were mixed together in 0.2% sodium citrate monobasic solution (pH 7.4, 80 mL) and homogenized using high pressure homogenizer. The resulting suspension was then mixed with sucrose solution (7.5 g dissolved in 20 mL 0.2%> sodium citrate monobasic solution pH 7.4). The lipid suspension and sucrose solution was mixed together thoroughly before it was filtered through 0.2 ⁇ filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm.
  • Clopidogrel bisulfate (260 mg), Cholesteryl sulfate (75.4 mg), and Soy lecithin (10.32 g) were mixed together in 0.2% sodium citrate monobasic solution (pH 8.0, 80 mL) and homogenized using high pressure homogenizer. The resulting suspension was then mixed with sucrose solution (7.5 g dissolved in 20 mL 0.2% sodium citrate monobasic solution pH 8.0). The lipid suspension and sucrose solution was mixed together thoroughly before it was filtered through 0.2 ⁇ filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm.
  • Clopidogrel Lipid Suspension at dose levels of 60, 40 and 20 mg clopidogrel/kg body weight was administered intravenously to ICR (CD-I) mice once daily for five consecutive days.
  • the mice in the control Group were similarly treated with n-saline intravenously at the equivalent volume as per kg body weight.
  • the animals were observed during the five days of the treatment period right after daily intravenous dosing and at 15 and 30 min, and approximately at 2, 3, 4 and 6 hours post dose to detect clinical signs of toxicity. The animals were also observed periodically up to 2 weeks post dosing period.
  • Clopidogrel Lipid Suspension was found to be safe when tested at 20 mg/kg body weight following daily intravenous administration for 5 consecutive days in mice. Some toxic effects were observed in mice at 40 mg/kg but all of the mice survived the dosing and post dosing period. The mortality was 50% when the drug was administered at 60 mg/kg body weight.

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Abstract

La présente invention concerne des procédés de préparation de clopidogrel complexé avec des lipides au moyen de systèmes aqueux exempts de solvants organiques, et des procédés d'utilisation de ces complexes, par exemple dans le traitement d'une maladie chez un sujet. Dans certains modes de réalisation, la présente invention porte sur un procédé comprenant la préparation d'une composition qui comporte un complexe lipidique incluant du clopidogrel et au moins un lipide, puis l'administration de ladite composition à un sujet. Dans certains modes de réalisation, ledit sujet est un mammifère. Dans des modes de réalisation préférés, ledit sujet est un humain.
PCT/US2012/028530 2011-03-10 2012-03-09 Compositions de clopidogrel à base de lipides, et procédés et utilisations afférents WO2012122493A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014124132A1 (fr) * 2013-02-06 2014-08-14 Jingjun Huang Composition pharmaceutique stable de base libre de clopidogrel pour administration orale et parentérale
CN105218559A (zh) * 2015-10-21 2016-01-06 云南省药物研究所 一种稳定的非晶态硫酸氢氯吡格雷复合物

Citations (2)

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Publication number Priority date Publication date Assignee Title
US20070003628A1 (en) * 2005-05-10 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel formulations
US20100292268A1 (en) * 2007-04-27 2010-11-18 Cydex Pharmaceuticals, Inc. Formulations Containing Clopidogrel and Sulfoalkyl Ether Cyclodextrin and Methods of Use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070003628A1 (en) * 2005-05-10 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel formulations
US20100292268A1 (en) * 2007-04-27 2010-11-18 Cydex Pharmaceuticals, Inc. Formulations Containing Clopidogrel and Sulfoalkyl Ether Cyclodextrin and Methods of Use

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014124132A1 (fr) * 2013-02-06 2014-08-14 Jingjun Huang Composition pharmaceutique stable de base libre de clopidogrel pour administration orale et parentérale
JP2016507531A (ja) * 2013-02-06 2016-03-10 ホアン，ジンジュン 経口および非経口送達用のクロピドグレル遊離塩基の安定な医薬組成物
US9480680B2 (en) 2013-02-06 2016-11-01 Jingjun Huang Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery
US9884016B2 (en) 2013-02-06 2018-02-06 Jingjun Huang Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery
CN105218559A (zh) * 2015-10-21 2016-01-06 云南省药物研究所 一种稳定的非晶态硫酸氢氯吡格雷复合物

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