WO1999038827A1 - INHIBITION DE L'AGREGATION PLAQUETTAIRE AU MOYEN D'UNE COMBINAISON D'HEPARINE A FAIBLE POIDS MOLECULAIRE ET D'ANTAGONISTE DE RECEPTEUR DE GP IIb/IIIa - Google Patents

INHIBITION DE L'AGREGATION PLAQUETTAIRE AU MOYEN D'UNE COMBINAISON D'HEPARINE A FAIBLE POIDS MOLECULAIRE ET D'ANTAGONISTE DE RECEPTEUR DE GP IIb/IIIa Download PDF

Info

Publication number
WO1999038827A1
WO1999038827A1 PCT/US1999/002035 US9902035W WO9938827A1 WO 1999038827 A1 WO1999038827 A1 WO 1999038827A1 US 9902035 W US9902035 W US 9902035W WO 9938827 A1 WO9938827 A1 WO 9938827A1
Authority
WO
WIPO (PCT)
Prior art keywords
molecular weight
low molecular
weight heparin
therapeutically effective
safe
Prior art date
Application number
PCT/US1999/002035
Other languages
English (en)
Inventor
Jacquelynn J. Cook
Robert J. Gould
Frederic L. Sax
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9809793.4A external-priority patent/GB9809793D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP2000530066A priority Critical patent/JP2002501936A/ja
Priority to CA002318215A priority patent/CA2318215A1/fr
Priority to EP99903499A priority patent/EP1068172A4/fr
Priority to AU23506/99A priority patent/AU740941B2/en
Publication of WO1999038827A1 publication Critical patent/WO1999038827A1/fr

Links

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Platelet activation and aggregation are involved in unstable angina and acute myocardial infarction, in reocclusion following thrombolytic therapy and angioplasty, in transient ischemic attacks and in a variety of other vaso-occlusive disorders.
  • thrombolytic therapy and angioplasty in transient ischemic attacks and in a variety of other vaso-occlusive disorders.
  • platelets When a blood vessel is damaged either by acute intervention such as angioplasty, or, more chronically, by the pathophysiological processes of atherosclerosis, platelets are activated to adhere to the disrupted surface and to each other. This activation, adherence and aggregation may lead to occlusive thrombus formation in the lumen of the blood vessel.
  • the final obligatory step in platelet aggregation is the binding of fibrinogen to an activated membrane-bound glycoprotein complex, GP Ilb/IIIa ( ⁇ ll ⁇ 3).
  • Platelet activators such as thrombin, collagen, epinephrine or ADP, are generated as an outgrowth of tissue damage.
  • GP Ilb/IIIa undergoes changes in conformation that result in exposure of occult binding sites for fibrinogen.
  • fibrinogen can potentially act as a hexavalent ligand to crossing GP Ilb/IIIa molecules on adjacent platelets.
  • a deficiency in either fibrinogen or GP Ilb/IIIa prevents normal platelet aggregation regardless of the agonist used to activate the platelets. Since the binding of fibrinogen to its platelet receptor is an obligatory component of normal aggregation, GP Ilb/IIIa is an attractive target for an antithrombotic agent. Results from clinical trials of GP Ilb/IIIa inhibitors support this hypothesis.
  • the monoclonal antibody 7E3, which blocks the GP Ilb/IIIa receptor, has been shown to be an effective therapy for the high risk angioplasty population. It is used as an adjunct to percutaneous transluminal coronary angioplasty or atherectomy for the
  • Integrilin is a cyclic peptide that is based on the KGD sequence in the snake venom protein barbourin (Cook et al. ibid.: and Cox et al. ibid.). It inhibits ligand binding to GPIIb/IIIa but has very little effect on ligand binding to ⁇ v ⁇ 3- Among the non-peptide compounds are RO 44-9883 and MK-383, which are administered intravenously, and are also selective for GPIIb/IIIa (Cook et al. ibid.: and Cox et al. ibid.).
  • Orally active agents include SC54684, a prodrug with high oral bioavailability, and R043- 8857, GR144053, and DMP728, which are themselves the active inhibitors (Cook et al. ibid.: and Cox et al. ibid.).
  • results showed that antithrombotic therapy with enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction in the early phase.
  • the benefit with enoxaparin was achieved with an increase in minor but not major bleeding.
  • the invention is a method for inhibiting platelet aggregation in a mammal comprising administering to the patient a safe and therapeutically effective amount of a GPIIb/IIIa receptor antagonist or a pharmaceutically acceptable salt thereof and a safe and therapeutically effective amount of low molecular weight heparin.
  • the invention also is the use of a GPIIb/IIIa receptor antagonist or a
  • the invention is also a method for inhibiting platelet aggregation in a mammal comprising administering to the patient a safe and therapeutically effective amount of a GPIIb/IIIa receptor antagonist or a pharmaceutically acceptable salt thereof, a safe and therapeutically effective amount of low molecular weight heparin, and a safe and therapeutically effective amount of aspirin.
  • One example of the invention is a method for inhibiting platelet aggregation in a mammal comprising administering to the patient a safe and therapeutically effective amount of 2-S-(n- butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid or a pharmaceutically acceptable salt thereof (e.g. 2-S-(n- butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid hydrochloride, also called "tirofiban”) and a safe and therapeutically effective amount of low molecular weight heparin.
  • a pharmaceutically acceptable salt thereof e.g. 2-S-(n- butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid hydrochloride, also called "tirofiban”
  • a further example of the invention is the use of 2-S-(n-butylsulfonylamino)-3[4-(piperidin-4- yl)butyloxyphenyl]propionic acid or a pharmaceutically acceptable salt thereof, and a safe and therapeutically effective amount of low molecular weight heparin, in the manufacture of a medicament for inhibiting platelet aggregation in a mammal.
  • Another example of the invention is a method for inhibiting platelet aggregation in a mammal comprising administering to the patient a safe and therapeutically effective amount of 2-S-(n- butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid or a pharmaceutically acceptable salt thereof (e.g. 2-S-(n- butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid hydrochloride), a safe and therapeutically effective amount of low molecular weight heparin, and a safe and therapeutically effective amount of aspirin.
  • a safe and therapeutically effective amount of 2-S-(n- butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid or a pharmaceutically acceptable salt thereof e.g. 2-S-(n- butyls
  • the invention takes advantage of the reduced prolongation of bleeding time experienced with, a GP Ilb/IIIa receptor antagonist,
  • Tirofiban means 2-S-(n-butylsulfonylamino)-3[4-piperidin- 4-yl)butyloxyphenyl]propionic acid hydrochloride.
  • “Pharmaceutically acceptable salts” means non-toxic salts of the compounds (which are generally prepared by reacting the free acid with a suitable organic or inorganic base) which include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate
  • “Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • “Mammal” includes, within its meaning, primates (e.g. humans, monkeys, etc.), dogs, rabbits, and other species commonly known to be mammals.
  • the methods of the present invention are useful in combination with procedures for treating patients with other anticoagulants (e.g. thrombin inhibitors such as heparin, Factor Xa inhibitors such as warfarin, tissue factor pathway inhibitors, or thrombin receptor antagonists), thrombolytic agents (e.g. streptokinase and tissue plasminogen activator), and platelet antiaggregation agents (e.g. aspirin and dipyridamole).
  • anticoagulants e.g. thrombin inhibitors such as heparin, Factor Xa inhibitors such as warfarin, tissue factor pathway inhibitors, or thrombin receptor antagonists
  • thrombolytic agents e.g. streptokinase and tissue plasminogen activator
  • platelet antiaggregation agents e.g. aspirin and dip
  • the methods are suitable for patients where prevention of thrombosis by inhibition of binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired.
  • Such administration is useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) for treatment of peripheral vascular disease, and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. Since aggregated platelets may form thrombi and thromboemboli, the methods may be used on these surgical patients to prevent the formation of thrombi and thromboemboli.
  • the GP Ilb/IIIa receptor antagonists may also be administered to treat stroke, carotid percutaneous transluminal coronary revascularization, or carotid endarterectomy.
  • Applications of the methods include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery bypass procedures, or to improve outcomes following stent implantation (i.e., to prevent thromboembolism on device insertion). It may also be used to treat patients with acute coronary ischemic syndromes including unstable angina and subsequent myocardial infarction.
  • compositions containing, procedures for making, and methods for using low molecular weight heparin are described in various patent publications, the contents of which are hereby incorporated by reference, including US 4281108, US 4687765, US 5106734, US 4977250, US 5576304, and EP 372 969.
  • Commercially available low molecular weight heparin are described in various patent publications, the contents of which are hereby incorporated by reference, including US 4281108, US 4687765, US 5106734, US 4977250, US 5576304, and EP 372 969.
  • -6- molecular weight heparin includes FRAGMINTM (dalteparin sodium injection, available from Pharmacia, Inc. (Columbus, OH)) and LOVENOX® (enoxaparin sodium injection, available from Rhone- Poulenc Rorer Pharmaceuticals, Inc. (Collegeville, PA), described in EP 040 144).
  • FRAGMINTM salteparin sodium injection, available from Pharmacia, Inc. (Columbus, OH)
  • LOVENOX® enoxaparin sodium injection, available from Rhone- Poulenc Rorer Pharmaceuticals, Inc. (Collegeville, PA), described in EP 040 144).
  • FRAGMINTM dalteparin sodium injection is a sterile low molecular weight heparin produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chroma to graphic purification process. It is composed of strongly acidic sulphated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000-9000. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. It is available in a strength of 2500 anti- Factor Xa IU/0.2 mL.
  • FRAGMINTM is used for prophylaxis against deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing abdominal surgery who are at risk for thromboembolic complications, including those over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary embolism.
  • thromboembolic complications including those over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary embolism.
  • LOVENOX® enoxaparin sodium injection is a sterile, low molecular weight heparin produced by alkaline degradation of heparin derived from porcine intestinal mucosa. Its structure is characterized by a 2-0-sulfo-4-enepyranosuronic end group at the non-reducing end of the chain. The substance is the sodium salt. The average molecular weight is 4500.
  • LOVENOX® is used for prevention of deep vein thrombosis, which may lead to pulmonary embolism, following hip or knee replacement surgery. It contains 30 mg enoxaparin sodium in 0.3 mL of Water for Injection, and has an anti-Factor Xa activity of approximately 3000 IU. In patients undergoing hip replacement, or
  • Antagonists for the glycoprotein Ilb/IIIa fibrinogen receptor have been described in United States Patents 5,470,849, 5,463,011, 5,455,243, 5,451,578, 5,446,056,
  • the GP Ilb/IIIa receptor antagonist is selected from: [3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-l]acetyl-3(R)-
  • xemlofiban also known as xemilofiban
  • SB 2144857 from SmithKline Beecham
  • ZD2486 from Zeneca
  • TAK 029 described in J. Pharmacology and Experimental Therapeutics. 1996, 277 :502-510, from Takeda; orbofiban and SC-58635 from Searle; SC54684, described in Cook et al.. ibid, and Cox et al..
  • Suitable intravenous compositions of GP Ilb/IIIa receptor antagonists, and compositions of low molecular weight heparin include bolus or extended infusion compositions. Such intravenous compositions are well known to those of ordinary skill in the
  • 2- S-(n-butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid or pharmaceutically acceptable salts thereof and low molecular weight heparin can be administered to the patient together, e.g. in one intravenous solution, or in two separate simultaneously administered solutions.
  • Intravenous administration of the GP Ilb/IIIa receptor antagonist and low molecular weight heparin, whether administered together in one solution, or together in two separate solutions involves preparation of suitable infusion solutions according to procedures well known in the art.
  • the dosage regimen utilizing the active drugs is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the therapeutically effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • the active drug can be administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • GP Ilb/IIIa receptor antagonists e.g., 2-S-(n-butylsulfonylamino)-3-[4-(4-(piperidin- 4-yl)butyloxy)phenyl]propionic acid or pharmaceutically acceptable salts
  • pH buffers e.g. sodium citrate
  • tonicity adjusting agents e.g. tonicity adjusting agents
  • other components providing a storage stable and therapeutically effective intravenous solution.
  • Tonicity adjusting agents including sodium chloride are used to adjust tonicity for osmotic pressure and prevent blood cell lysing. These agents minimize pain and thrombophlebitis often experienced by patients receiving intravenous administrations of pharmaceutical compositions.
  • the amount used is that which makes the formulation isotonic with osmotic pressure of the biological system of the patient.
  • the preferred amount of tonicity adjusting agent suitable for the present invention e.g., sodium chloride, is between about 50-500 milliosmoles, more preferably about 290 milliosmoles.
  • compositions of the invention can be achieved by formulating with an amount of sodium chloride of between about 1.5 and 15 mg/ml, preferably about 9 mg/ml. Such osmolality can also be achieved by using an amount of mannitol of between about 7 and 75 mg/ml, preferably about 50 mg/ml.
  • Other tonicity adjusting agents which can be used to adjust tonicity include, but are not limited to, dextrose and other sugars.
  • the compositions are not limited to the GP Ilb/IIIa receptor antagonist, citrate buffer and tonicity adjusting agent, however, and may also include other pharmaceutically acceptable diluents, excipients or carriers.
  • the formulations are suitable for long-term storage in glass containers commonly used in the pharmaceutical industry, e.g., in concentrated form in standard USP Type I borosilicate glass containers.
  • the procedure for preparing GPIIb/IIIa receptor antagonist compositions of the invention involves combining the various ingredients in a mixing vessel, e.g., at room temperature.
  • the active ingredient in salt or free base form
  • buffer sources e.g., citric acid and sodium citrate
  • tonicity adjusting agent are combined to obtain an active ingredient concentration of between about 0.01 mg/ml and 0.5 mg/ml.
  • a substantial portion of the finished product amount of water (e.g., between about 60 and 100%) is introduced into a standard
  • -11- pharmaceutical mixing vessel An amount of active ingredient suitable for obtaining the desired finished product concentration is dissolved in the water. Amounts of sodium citrate and citric acid sufficient to obtain a finished citrate concentration of between about 2 and 20 mM, are added. A pharmaceutically acceptable amount of tonicity adjusting agent in the isotonic range, is added. Any remaining portion of water is then added to achieve the desired final concentrations of ingredients. The amount of water initially used in preparing the formulation, and the amount of the remaining portion of water added at the end of the procedure, does not affect the properties of the finished product. Such amounts are a matter of choice for the skilled artisan, allowing for pH adjustment during formulation.
  • Concentrated formulations of the compositions can be diluted at the time of administration with a suitable diluent to obtain a finished concentration, for example, of about 0.05 mg/ml, which is suitable for transfer to an infusion bag and use by the patient in need of the desired active ingredient.
  • the most preferred doses of 2-S-(n- butylsulfonylamino)-3-[4-(4-(piperidin-4-yl)butyloxy)phenyl]propionic acid hydrochloride will range from about 0.001 to about 2 ⁇ g/kg/minute during a constant rate of infusion, e.g., 0.1, 0.15, 0.2, and 0.4 ⁇ g/kg/minute.
  • an intravenous composition having 0.05 mg/ml of active ingredient can be administered at rates of 0.002, 0.003, 0.004 or 0.008 ml/kg/min, respectively.
  • Compositions of the invention containing higher concentrations of active ingredients should be administered at correspondingly lower rates.
  • 2-S-(n-butylsulfonylamino)-3-[4-(4- (piperidin-4-yl)butyloxy)phenyl]propionic acid hydrochloride (tirofiban) is administered intravenously at an initial infusion rate of 0.4 ⁇ g/kg/minute for 30 minutes or as a bolus of 10 ⁇ g/kg over 3 minutes.
  • tirofiban is continued at a maintenance infusion rate of 0.10 ⁇ g/kg/minute.
  • Administration may be continued as needed, e.g. for 48 hours or more (through angiography,
  • tirofiban should be administered intravenously as an initial bolus of 10 ⁇ g/kg administered over 3 minutes followed by a maintenance infusion rate of 0.15 ⁇ g/kg/minute.
  • GP Ilb/IIIa receptor antagonists which are orally active are also suitable for purposes of the present method. Dosages of such antagonists, when used for the indicated effects, will range between about 0.005 mg per kg of body weight per day (mg/kg/day) to about 50 mg/kg/day and preferably 0.005-20 mg/kg/day and most preferably 0.005- 10 mg/kg/day.
  • Suitable oral tablets contain between 0.5 mg and 5 g, preferably between 0.5 mg and 2 g, most preferably between 0.5 mg and lg, e.g. 50 mg, 150 mg, 250 mg, or 500 mg. Oral administration may be in one or divided doses of two, three, or four times daily.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Oral compositions of the GP Ilb/IIIa receptor antagonists with enteric coatings may be prepared by mixing the antagonist with an excipient to form a spheroid, and coating the spheroid with a thin
  • the antagonist is mixed with non-water swellable microcrystalline cellulose to form a spheroid which is then coated with a film of hydroxypropyl methyl cellulose phthalate and or a plasticizer which prevents any release of the antagonist in the stomach. When the composition reaches the intestine, the antagonist is released.
  • the oral compositions may also be prepared by mixing the antagonist with a wetting agent such as fatty acid esters, lecithin, sucrose, mannitol or sorbitol and then spheronizing or granulating the mixture into microgranules.
  • compositions are then coated with a microporous membrane polymer such as Eudragit ® E30D (Rohm Pharma GmbH, Rothstadt, Germany), hydroxypropyl methyl cellulose phthalate and other wetting agents, plasticizers and the like.
  • the formulations are enteric by nature and the antagonist does not become bioavailable until the system reaches the intestine.
  • the compositions may also be prepared by mixing the antagonist and an acid such as fumeric or tartaric acid which is compressed into a spherical tablet and coated with lacquers that are insoluble in gastric juices and soluble in intestinal juices. These lacquers include copolymers of acrylic acid and methacrylic acid esters.
  • compositions may also be prepared by coating a solid dosage form of the antagonist with hydroxypropyl methyl cellulose phthalate or acidic succinyl and acetyl esters of hydroxypropyl methyl cellulose.
  • Triethylcitrate is added as a plasticizer which aids in the binding of the coating material to the core pellet. The coating resists dissolution in the stomach but completely dissolves in the small intestine.
  • Suitable materials for providing enteric coatings include, for example, hydroxypropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose hexahydrophthalate, shellac, cellulose acetate, cellulose acetate phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, methacrylic acid copolymers, methacrylic ester copolymers and the like.
  • solid dosage forms comprising the antagonist may be coated using conventional coating techniques such as conventional pan coating techniques or column spray coating techniques.
  • coating pans e.g. subglobular, pear shaped or hexagonal pans, which are inclined are set to rotate at an appropriate setting sufficient to allow uncoated tablets to be exposed to spray solutions of the polymer used to form the coat. The pan is heated to a sufficient temperature to allow the coat to dry soon after contact with the outside of the tablet.
  • pans have a cylindrical shape, are rotated horizontally, and have at least some regions of the walls perforated by small holes or slots. This design permits a one-way air flow through the pan. In other designs the flow of air is through the tablet bed and out through the perforated wall of the pan. In others the air flows from the perforated pan wall through the tablet bed into the central region, i.e., countercurrent to the coating spray direction. Still others permit either co- or counter-current air flow to suit particular products.
  • the coating is sprayed in one of several methods.
  • One method relies entirely on hydraulic pressure to produce a spray when material is forced through a nozzle (airless spraying).
  • atomization of the spray is assisted by turbulent jets of air. This method tends to produce a more easily controlled spray pattern and is therefore better for small-scale operations, although both are capable of giving the flat jet profile preferred for pan operation.
  • the thickness of coating required on the granules depends on the dissolution profile of the particular coating materials.
  • the coating can contain a plasticizer and possibly other coating additives such as coloring agents, gloss producers, talc and/or magnesium stearate.
  • the antagonists can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Antagonists may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Antagonists may also be coupled with soluble polymers as targe table drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide- phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
  • antagonists may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • ocular formulations such as eyedrops
  • from about 0.01- 5.0% (w/v) of antagonist can be employed, e.g., from about 0.01-2.0% (w/v) of antagonist.
  • Suitable eyedrop volume is, for example, 20, 30, 35, 50 or 100 ml.
  • the objective is to administer a dose of between about 0.005-0.5 mg/kg per day to each eye, for a total dosage of between about 0.01-1.0 mg/kg/day, e.g. a dose of about 0.05 mg/kg per day to each eye, for a total dosage of about 0.1 mg/kg/day.
  • the eyedrops can be used to provide doses of 1 mg, 10 mg, or 50 mg.
  • Suitable eyedrop formulations are those which are isotonic and maintain sufficient contact with the eye surface to systemically deliver the active agent to the patient. Such formulations advantageously have a pH approximating neutrality and are non- irritating to the eye, e.g. they do not induce tearing and consequential flow of active agent out of the eye.
  • Pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, hydroxy ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic,
  • water mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, hydroxy ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic,
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1000, 1500, 4000, 6000 and 10000, antibacterial compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethyl enediamine tetraacetic acid, and the
  • formulations are rendered sterile by appropriate means, such as starting the preparation procedure with sterile components and proceeding under sterile conditions, irradiating or autoclaving the finished formulation, and the like.
  • Suitable anti microbial agents are also useful for maintaining sterility of the eyedrop.
  • the ocular preparation may also be a solid insert such as one which, after dispensing the antagonist, remains essentially intact, or a bioerodible insert that is soluble in lacrimal fluids, or otherwise disintegrates.
  • a solid insert such as one which, after dispensing the antagonist, remains essentially intact, or a bioerodible insert that is soluble in lacrimal fluids, or otherwise disintegrates.
  • a solid water soluble polymer as the carrier for the antagonist.
  • the polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, acrylates such as polyacrylic acid salts, ethylacrylates, polyacrylamides, natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia, starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, as
  • the ocular preparation may also be an ointment which is compounded, for example, by mixing finely milled powdered ingredients with a small amount of white petrolatum and levigating or otherwise mixing until a uniform distribution is achieved. The balance of white petrolatum is added by geometric addition until the desired dosage form is made.
  • the present invention is demonstrated in a study of patients with acute coronary ischemic syndromes. Such patients may undergo early coronary revascularization with percutaneous coronary angioplasty or atherectomy.
  • Acute coronary ischemic syndrome is associated with unstable angina, nonfatal myocardial infarction, and death, and subsequent follow-up procedures such as coronary artery bypass grafting, repeat percutaneous intervention for acute ischemia, and insertion of a coronary endovascular stent. Because of unstable plaque with thrombus, percutaneous revascularization procedures in these patients carry with them considerable higher morbidity than procedures performed in patients with stable coronary disease.
  • patients receive 2-S-(n- butylsulfonylamino)-3-[4-(4-(piperidin-4-yl)butyloxy)phenyl]propionic acid or pharmaceutically acceptable salts thereof with low molecular weight heparin and optionally aspirin.
  • the following examples show that therapeutic levels of unfractionated heparin combined with tirofiban elicit prolongation in bleeding time that is greater than prolongation in bleeding time resulting from administration of therapeutic levels of low molecular weight heparin combined with tirofiban.
  • a patient is treated for unstable angina by intravenously receiving tirofiban in an amount of 0.4 ⁇ g/kg/min for 30 minutes followed by 0.1 ⁇ g/kg/min for 47.5-107.5 hours.
  • tirofiban therapy is administered to a patient.
  • -18- LOVENOX® enoxaparin is subcutaneously administered in an amount of 1 mg/kg every 12 hours.
  • a patient is treated for non-Q wave myocardial infarction by intravenously receiving tirofiban in an amount of 0.4 ⁇ g/kg/min for 30 minutes followed by 0.1 ⁇ g/kg/min for 47.5-107.5 hours.
  • tirofiban therapy LOVENOX® enoxaparin is subcutaneously administered in an amount of 1 mg/kg every 12 hours.
  • Activated partial thromboplastin times (APTT, ex vivo measurement of intrinsic coagulation pathway in plasma) and activated clotting times (ACT, ex vivo measurement of intrinsic coagulation pathway in whole blood) were determined as an indication of the function of the clotting factors. Following blood collection and centrifugation, plasma for APTT determination was removed and stored on ice for later assay. APTTs were determined using an automated clot timer (ELECTRA 900, Medical Laboratory Automation, Mt. Vernon, NY) and commercially available reagents (American Dade, Aquada, Puerto Rico), ACTs were measured and determined immediately using fresh, unanticoagulated whole blood (ACT II, Medtronic HemoTec, Inc., Parker, Colorado). AntiXa activity was determined using a colorimetric assay with the Stachrom® Heparin kit (MLA Electra 900C). Whole blood platelet counts were determined using an automated hematology analyzer (Biochem
  • Intravenous formulations An intravenous dosage form of tirofiban is prepared as follows:
  • the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.
  • a pharmaceutical composition was prepared at room temperature using tirofiban, a citrate buffer, and sodium chloride, to obtain a concentration of tirofiban of 0.25 mg/ml.
  • aqueous formulation had the following concentrations:
  • the finished concentrated formulation is stored in a standard USP Type I borosilicate glass container at 30-40 degrees C. Prior to compound administration, the concentrated formulation is diluted in a 4:1 ratio resulting in a finished concentration of 0.05 mg/ml and transferred to an infusion bag.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un procédé relatif à l'inhibition de l'agrégation plaquettaire chez un mammifère, qui consiste à administrer à ce mammifère une quantité sûre et thérapeutiquement efficace d'antagoniste de récepteur de GP IIb/IIIa ou un sel pharmaceutiquement acceptable dudit antagoniste, en combinaison avec une quantité sûre et thérapeutiquement efficace d'héparine à faible poids moléculaire. L'invention concerne également un procédé relatif à l'inhibition de l'agrégation plaquettaire chez un mammifère, qui consiste à administrer à ce mammifère une quantité sûre et thérapeutiquement efficace d'acide propionique-(2-S-(n-butylsulfonylamino)-3[4-(pipéridine-4-yl)butyloxyphényl] ou un sel pharmaceutiquement acceptable dudit produit, en combinaison avec une quantité sûre et thérapeutiquement efficace d'héparine à faible poids moléculaire.
PCT/US1999/002035 1998-02-02 1999-01-29 INHIBITION DE L'AGREGATION PLAQUETTAIRE AU MOYEN D'UNE COMBINAISON D'HEPARINE A FAIBLE POIDS MOLECULAIRE ET D'ANTAGONISTE DE RECEPTEUR DE GP IIb/IIIa WO1999038827A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000530066A JP2002501936A (ja) 1998-02-02 1999-01-29 低分子量ヘパリンをＧＰＩＩｂ／ＩＩＩａ拮抗物質と組合わせて使用する血小板凝集の抑制
CA002318215A CA2318215A1 (fr) 1998-02-02 1999-01-29 Inhibition de l'agregation plaquettaire au moyen d'une combinaison d'heparine a faible poids moleculaire et d'antagoniste de recepteur de gp iib/iiia
EP99903499A EP1068172A4 (fr) 1998-02-02 1999-01-29 INHIBITION DE L'AGREGATION PLAQUETTAIRE AU MOYEN D'UNE COMBINAISON D'HEPARINE A FAIBLE POIDS MOLECULAIRE ET D'ANTAGONISTE DE RECEPTEUR DE GP IIb/IIIa
AU23506/99A AU740941B2 (en) 1998-02-02 1999-01-29 Platelet aggregation inhibition using low molecular weight heparin in combination with a GP IIb/IIIa antagonist

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US7342698P 1998-02-02 1998-02-02
US60/073,426 1998-02-02
GBGB9809793.4A GB9809793D0 (en) 1998-05-07 1998-05-07 Platelet aggregation inhibition
GB9809793.4 1998-05-07

Publications (1)

Publication Number Publication Date
WO1999038827A1 true WO1999038827A1 (fr) 1999-08-05

Family

ID=26313621

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/002035 WO1999038827A1 (fr) 1998-02-02 1999-01-29 INHIBITION DE L'AGREGATION PLAQUETTAIRE AU MOYEN D'UNE COMBINAISON D'HEPARINE A FAIBLE POIDS MOLECULAIRE ET D'ANTAGONISTE DE RECEPTEUR DE GP IIb/IIIa

Country Status (5)

Country Link
EP (1) EP1068172A4 (fr)
JP (1) JP2002501936A (fr)
AU (1) AU740941B2 (fr)
CA (1) CA2318215A1 (fr)
WO (1) WO1999038827A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000053168A2 (fr) * 1999-03-11 2000-09-14 Du Pont Pharmaceuticals Company Synergie entre l'heparine a faible masse moleculaire et des inhibiteurs d'agregation plaquettaire permettant d'elaborer une polytherapie pour la prevention et le traitement de divers troubles thromboemboliques
WO2000053264A1 (fr) * 1999-03-11 2000-09-14 Du Pont Pharmaceuticals Company Traitement de la thrombose au moyen d'une combinaison d'un inhibiteur du facteur xa et d'aspirine, d'un activateur tissulaire du plasminogene (tpa), d'un antagoniste de gpiib/iiia, d'heparine a faible masse moleculaire ou d'heparine
WO2002072132A1 (fr) * 2001-03-09 2002-09-19 Celsus Biopharmaceuticals, Inc. Combinaisons d'un agoniste du cofacteur ii de l'heparine et d'un antagoniste plaquettaire iib/iiia et leurs applications
JP2003531854A (ja) * 2000-05-02 2003-10-28 シャーロット‐メクレンバーグ・ホスピタル・オーソリティ，ドゥーイング・ビジネス・アズ・キャロライナズ・メディカル・センター アポトーシスの予防方法
US6770660B2 (en) 2002-05-06 2004-08-03 Artery Llc Method for inhibiting platelet aggregation
US6794412B1 (en) 1999-03-11 2004-09-21 Bristol-Myers Squibb Pharma Company Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin
EP1574516A1 (fr) * 2004-03-05 2005-09-14 Sanofi-Aventis Composés antithrombotiques
WO2007042470A2 (fr) * 2005-10-10 2007-04-19 N.V. Organon Compose antithrombotique
US7875596B2 (en) 2004-05-19 2011-01-25 Celsus Biopharmaceuticals, Inc. Use of dermatan sulfates and/or desulfated heparins to treat or prevent heparinoid-induced autoimmune responses
DE102014108210A1 (de) 2014-06-11 2015-12-17 Dietrich Gulba Rodentizid
CN112569184A (zh) * 2020-12-30 2021-03-30 山东裕欣药业有限公司 一种盐酸替罗非班注射液及制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4533549A (en) * 1983-01-04 1985-08-06 Lasker Sigmund E Antithrombotic agent
US4977165A (en) * 1987-08-24 1990-12-11 Eisai Co., Ltd. Piperidine derivative and therapeutic and preventive agents for arrhythmia containing same
US5763427A (en) * 1995-03-31 1998-06-09 Hamilton Civic Hospitals Research Development Inc. Compositions and methods for inhibiting thrombogenesis
US5880136A (en) * 1990-09-27 1999-03-09 Merck & Co., Inc. Sulfonamide fibrinogen receptor antagonists

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035579A1 (fr) * 1996-03-27 1997-10-02 Merck & Co., Inc. Procede d'inhibition de la formation de caillots

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4533549A (en) * 1983-01-04 1985-08-06 Lasker Sigmund E Antithrombotic agent
US4977165A (en) * 1987-08-24 1990-12-11 Eisai Co., Ltd. Piperidine derivative and therapeutic and preventive agents for arrhythmia containing same
US5880136A (en) * 1990-09-27 1999-03-09 Merck & Co., Inc. Sulfonamide fibrinogen receptor antagonists
US5763427A (en) * 1995-03-31 1998-06-09 Hamilton Civic Hospitals Research Development Inc. Compositions and methods for inhibiting thrombogenesis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1068172A4 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6794412B1 (en) 1999-03-11 2004-09-21 Bristol-Myers Squibb Pharma Company Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin
WO2000053264A1 (fr) * 1999-03-11 2000-09-14 Du Pont Pharmaceuticals Company Traitement de la thrombose au moyen d'une combinaison d'un inhibiteur du facteur xa et d'aspirine, d'un activateur tissulaire du plasminogene (tpa), d'un antagoniste de gpiib/iiia, d'heparine a faible masse moleculaire ou d'heparine
WO2000053168A3 (fr) * 1999-03-11 2002-01-24 Du Pont Pharm Co Synergie entre l'heparine a faible masse moleculaire et des inhibiteurs d'agregation plaquettaire permettant d'elaborer une polytherapie pour la prevention et le traitement de divers troubles thromboemboliques
US6346517B1 (en) 1999-03-11 2002-02-12 Bristol-Myers Squibb Pharma Company Synergy between low molecular weight heparin and platelet aggregation inhibitors, providing a combination therapy for the prevention and treatment of various thromboembolic disorders
WO2000053168A2 (fr) * 1999-03-11 2000-09-14 Du Pont Pharmaceuticals Company Synergie entre l'heparine a faible masse moleculaire et des inhibiteurs d'agregation plaquettaire permettant d'elaborer une polytherapie pour la prevention et le traitement de divers troubles thromboemboliques
US6518244B2 (en) 2000-03-09 2003-02-11 Intimax Corporation Combinations of heparin cofactor II agonist and platelet IIb/IIIa antagonist, and uses thereof
JP2003531854A (ja) * 2000-05-02 2003-10-28 シャーロット‐メクレンバーグ・ホスピタル・オーソリティ，ドゥーイング・ビジネス・アズ・キャロライナズ・メディカル・センター アポトーシスの予防方法
WO2002072132A1 (fr) * 2001-03-09 2002-09-19 Celsus Biopharmaceuticals, Inc. Combinaisons d'un agoniste du cofacteur ii de l'heparine et d'un antagoniste plaquettaire iib/iiia et leurs applications
US6770660B2 (en) 2002-05-06 2004-08-03 Artery Llc Method for inhibiting platelet aggregation
EP1574516A1 (fr) * 2004-03-05 2005-09-14 Sanofi-Aventis Composés antithrombotiques
WO2005090382A1 (fr) 2004-03-05 2005-09-29 Sanofi-Aventis Compose antithrombotique
AU2005223339B2 (en) * 2004-03-05 2011-06-23 Sanofi-Aventis Antithrombotic compound
US7875596B2 (en) 2004-05-19 2011-01-25 Celsus Biopharmaceuticals, Inc. Use of dermatan sulfates and/or desulfated heparins to treat or prevent heparinoid-induced autoimmune responses
WO2007042470A2 (fr) * 2005-10-10 2007-04-19 N.V. Organon Compose antithrombotique
WO2007042470A3 (fr) * 2005-10-10 2007-11-29 Organon Nv Compose antithrombotique
DE102014108210A1 (de) 2014-06-11 2015-12-17 Dietrich Gulba Rodentizid
US11678659B2 (en) 2014-06-11 2023-06-20 Dietrich Gulba Use as rodenticides of compounds that inhibit blood coagulation
CN112569184A (zh) * 2020-12-30 2021-03-30 山东裕欣药业有限公司 一种盐酸替罗非班注射液及制备方法

Also Published As

Publication number Publication date
EP1068172A1 (fr) 2001-01-17
CA2318215A1 (fr) 1999-08-05
EP1068172A4 (fr) 2006-09-27
JP2002501936A (ja) 2002-01-22
AU740941B2 (en) 2001-11-15
AU2350699A (en) 1999-08-16

Similar Documents

Publication Publication Date Title
US6136804A (en) Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
EP1392329B1 (fr) Utilisation de sulodexide pour le traitement d'une maladie enterique inflammatoire
US6403571B2 (en) Combination therapy for reducing the risks associated with cardiovascular disease
AU2002304265A1 (en) Use of sulodexide for the treatment of inflammatory bowel disease
AU740941B2 (en) Platelet aggregation inhibition using low molecular weight heparin in combination with a GP IIb/IIIa antagonist
RU2252783C2 (ru) Фармацевтический препарат, содержащий низкомолекулярный ингибитор тромбина и его пролекарство
WO1998011896A1 (fr) Traitement combine destine a reduire les risques de maladies cardio-vasculaires
US6251852B1 (en) Combination therapy for reducing the risks associated with cardiovascular disease
US6136794A (en) Platelet aggregation inhibition using low molecular weight heparin in combination with a GP IIb/IIIa antagonist
US6518244B2 (en) Combinations of heparin cofactor II agonist and platelet IIb/IIIa antagonist, and uses thereof
WO1997035579A1 (fr) Procede d'inhibition de la formation de caillots
EP1061908A1 (fr) Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes
GB2332373A (en) Treatment of coronary and/or peripheral ischemia using an antithrombotic agent and an angiogenesis promoter
ZA200106360B (en) Treatment of thrombosis by combined use of a factor XA inhibitor and aspirin, tissue plasminogen activator (TPA), a GPIIb/IIIa antagonist, low molecular weight heparin or heparin.
US5978698A (en) Angioplasty procedure using nonionic contrast media
WO1997035615A1 (fr) Compositions et techniques d'inhibition de la formation de caillots
US5980951A (en) Oral coated active drugs
EP0914099A1 (fr) Medicaments actifs enrobes a administration orale
AU2002248566A1 (en) Combinations of heparin cofactor II agonist and platelet IIB/IIIA antagonist, and uses thereof
GB2318053A (en) Angioplasty procedure using nonionic contrast media

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 23506/99

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2318215

Country of ref document: CA

Kind code of ref document: A

Ref document number: 2318215

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2000 530066

Country of ref document: JP

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 1999903499

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1999903499

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: KR

WWP Wipo information: published in national office

Ref document number: 1999903499

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 23506/99

Country of ref document: AU