WO2003049720A1 - Therapie combinee comprenant un inhibiteur de cyclo-oxygenase 2 - Google Patents

Therapie combinee comprenant un inhibiteur de cyclo-oxygenase 2 Download PDF

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Publication number
WO2003049720A1
WO2003049720A1 PCT/US2002/038376 US0238376W WO03049720A1 WO 2003049720 A1 WO2003049720 A1 WO 2003049720A1 US 0238376 W US0238376 W US 0238376W WO 03049720 A1 WO03049720 A1 WO 03049720A1
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Prior art keywords
cyclooxygenase
once
aspirin
dose
selective inhibitor
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PCT/US2002/038376
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English (en)
Inventor
Richard K. Murray
John Yates
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Merck & Co., Inc.
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Priority to AU2002357046A priority Critical patent/AU2002357046A1/en
Publication of WO2003049720A1 publication Critical patent/WO2003049720A1/fr

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

  • Inhibitors of cyclooxygenase-2 are a sub-class of the class of drugs known as non-steroidal antiinflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal antiinflammatory drugs
  • the NSAIDs are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process but are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process.
  • use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential.
  • An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
  • Previous NSAIDs have been found to prevent the production of prostaglandin by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway including the enzyme cyclooxygenase (COX).
  • COX cyclooxygenase
  • COX-2 inhibitors Many compounds which have activity as COX-2 inhibitors have been identified, including rofecoxib (VIOXX®), etoricoxib (ARCOX3ATM), celecoxib (CELEBREX®) and valdecoxib (BEXTRATM), and much research continues in this area.
  • thrombotic cardiovascular events such as stroke, myocardial ischemia, myocardial infarction, angina pectoris, transient ischemic attack (TIA; amaurosis fugax), reversible ischemic neurologic deficits, and any similar thrombotic event in any vascular bed (splanchnic, renal, aortic, peripheral, etc.).
  • TIA transient ischemic attack
  • reversible ischemic neurologic deficits reversible ischemic neurologic deficits
  • any similar thrombotic event in any vascular bed planchnic, renal, aortic, peripheral, etc.
  • chronic inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosis are at increased risk for thrombotic cardiovascular events.
  • aspirin 650 mg dosed every fourth day, either alone or in the presence of a COX-2 inhibitor, is associated with fewer gastric erosions or ulcers than 81 mg administered once daily, despite the doubling in cumulative dose.
  • the mean life span of human platelets is approximately 10 days (Patronon et al. CHEST 1998; 114: 470S-488S) and the effects of aspirin on individual platelets is irreversible, so that 5 to 6 days following dosing with aspirin, approximately 50% of the platelets function normally.
  • aspirin is administered together with a COX-2 inhibitor leading to several advantages: 1) The less-than-daily frequency of administration of aspirin reduces the risk of GI ulcers and bleeds (which is otherwise particularly increased when both a COX-2 inhibitor and aspirin are administered on a daily basis) while providing substantial antiplatelet efficacy;
  • COX-2 specific inhibitor provides symptom relief for the chronic cyclooxygenase-2 mediated disease or condition, such as chronic pain or arthritis;
  • the invention provides for a clearly superior profile than that hitherto obtainable in that it provides efficacy in treating chronic cyclooxygenase-2 mediated diseases or conditions, effectively inhibits platelets thus reducing the risk of thrombotic cardiovascular events and at the same time reduces the risk of GI ulceration or bleeding relative either to conventional NSAIDS or separate administration of a COX-2 inhibitor and low-dose daily aspirin, or than a NSAID plus ASA.
  • the present invention encompasses a method and kit for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the risk of a thrombotic cardiovascular event in a human patient in need of such treatment and at risk of a thrombotic cardiovascular event comprising orally administering to said patient a cyclooxygenase-2 selective inhibitor on a once or twice daily basis in an amount effective to treat the cyclooxygenase-2 mediated disease or condition and orally administering to said patient aspirin once every two to seven days in an amount effective to reduce the risk of the thrombotic cardiovascular event while maintaining a high level of upper gastrointestinal safety and tolerability.
  • the present invention encompasses a method and kit for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the risk of a thrombotic cardiovascular event in a human patient in need of such treatment and at risk of a thrombotic cardiovascular event comprising orally administering to said patient a cyclooxygenase-2 selective inhibitor on a once or twice daily basis in an amount effective to treat the cyclooxygenase-2 mediated disease or condition and orally administering to said patient aspirin once every two to seven days in an amount effective to reduce the risk of the thrombotic cardiovascular event while maintaining a high level of upper gastrointestinal safety and tolerability.
  • the invention encompasses a method for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the risk of a thrombotic cardiovascular event in a human patient in need of such treatment and at risk of a thrombotic cardiovascular event comprising orally administering to said patient a cyclooxygenase-2 selective inhibitor on a once or twice daily basis in an amount effective to treat the cyclooxygenase-2 mediated disease or condition and orally administering to said patient aspirin once every two to seven days in an amount effective to reduce the risk of the thrombotic cardiovascular event.
  • treating a chronic cylcooxygenase-2 mediated disease or condition means treating or preventing any chronic disease or condition that is advantageously treated or prevented by inhibiting the cyclooxygenase-2 enzyme.
  • the term includes the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back pain, neck pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout, ankylosing spondylitis, bursitis, burns, injuries, and pain and inflammation following surgical procedures.
  • such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
  • such a compound may inhibit the onset or progression of Altzheimer's disease or cognitive impairment.
  • the term also includes the treatment and/or prevention of cyclooxygenase-mediated proliferative disorders such as may occur in diabetic retinopathy and tumor angiogenesis.
  • treating encompasses not only treating a patient to relieve the patient of the signs and symptoms of the disease or condition but also prophylactically treating an asymptomatic patient to prevent the onset or progression of the disease or condition.
  • a "thrombotic cardiovascular event” is defined as any sudden event of a type known to be caused by platelet aggregation, thrombosis, and subsequent ischemic clinical events, including thrombotic or thromboembolic stroke, myocardial ischemia, myocardial infarction, angina pectoris, transient ischemic attack (TIA; amaurosis fugax), reversible ischemic neurologic deficits, and any similar thrombotic event in any vascular bed (splanchnic, renal, aortic, peripheral, etc.).
  • patient in need of such treatment and at risk of a thrombotic cardiovascular event means a patient in need of both treatment for a cyclooxygenase- 2 mediated disease and also at risk of a thrombotic cardiovascular event.
  • One skilled in the art can diagnose a patient that is in need of treatment for a cyclooxygenase-2 mediated disease or condition and also at risk of suffering a thrombotic cardiovascular event.
  • a patient may be a patient over the age of 50 with osteoarthritis and with a previous myocardial infarction.
  • Other risk factors for a thrombotic cardiovascular event include hypertension, hypercholesterolemia, diabetes mellitus, chronic renal impairment, smoking, and any prior personal or family history of such an event.
  • Administration of the drug combination to the patient includes both self-administration and administration to the patient by another person.
  • inhibitor of cyclooxygenase-2 means compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
  • the compounds have a cyclooxygenase-2 IC50 of less than about 2 ⁇ M in the human whole blood COX-2 assay, yet have a cyclooxygenase-1 IC50 of greater than about 5 ⁇ M in the human whole blood COX-1 assay.
  • the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, and more preferably of at least 40. The resulting selectivity may indicate an ability to reduce the incidence of common NS AID-induced side effects, especially erosions and ulceration of the upper gastrointestinal mucosa.
  • cyclooxygenase-2 selective inhibitors examples include rofecoxib (NIOXX®, see U.S. Patent No. 5,474,995, hereby incorporated by reference in its entirety), etoricoxib (ARCOXIATM see U.S. Patent No. 5,861,419, hereby incorporated by reference in its entirety), celecoxib (CELEBREX®, see U.S. Patent No. 5,466,823, hereby incorporated by reference in its entirety), valdecoxib (see U.S. No. 6,633,272, hereby incorporated by reference in its entirety), parecoxib (see U.S. No.
  • COX-189 Novartis
  • BMS347070 Bristol Myers Squibb
  • tiracoxib or JTE522 Japan Tobacco
  • ABT963 Abbott
  • CS502 Sankyo
  • GW406381 GaxoSmithKline
  • amounts that are effective to treat is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the term also encompasses the amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the inhibitor of cyclooxygenase-2 may be administered at a dosage level up to conventional dosage levels for NSAIDs.
  • Suitable dosage levels will depend upon the antiinflammatory effect of the chosen inhibitor of cyclooxygenase-2, but typically suitable levels will be about 0.001 to 50 mg/kg per day, preferably 0.005 to 30 mg/kg per day, and especially 0.05 to 10 mg/kg per day.
  • the compound may be administered on a regimen of once or twice per day.
  • the term "amount effective to reduce the risk of means the amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • Aspirin is administered at a dose of about 30 mg to about 1 g once every two to seven days, preferably at a dose of about 80 mg to about 650 mg.
  • An embodiment of the invention encompasses the above method wherein the cyclooxygenase-2 selective inhibitor is selected from the group consisting of: rofecoxib, etoricoxib, celecoxib, valdecoxib, COX-189, BMS347070, tiracoxib, ABT963, CS502 and GW406381.
  • a further embodiment of the invention encompasses the above method wherein the cyclooxygenase-2 selective inhibitor is rofecoxib.
  • rofecoxib is administered on a once or twice daily basis at a dose of about 12.5 mg or about 25 mg.
  • Another embodiment of the invention encompasses the above method wherein the cyclooxygenase-2 selective inhibitor is etoricoxib. Within this embodiment is encompassed the above method wherein rofecoxib is administered on a once or twice daily basis at a dose of about 60 mg, 90 mg or about 120 mg. Another embodiment of the invention encompasses the above method wherein the cyclooxygenase-2 selective inhibitor is celecoxib. Within this embodiment is encompassed the above method wherein celecoxib is administered on a once or twice daily basis at a dose of about 100 mg or about 200 mg. Another embodiment of the invention encompasses the above method wherein the cyclooxygenase-2 selective inhibitor is valdecoxib.
  • valdecoxib is administered on a once or twice daily basis at a dose of about 10 mg or about 20 mg.
  • An embodiment of the invention encompasses the above method wherein the cycloxygenase-2 selective inhibitor is administered orally on a once daily basis.
  • Another embodiment of the invention encompasses the above method the cycloxygenase-2 selective inhibitor is administered orally on a twice daily basis.
  • An embodiment of the invention encompasses the above method wherein the cycloxoygenase-2 selective mediated disease or condition is osteoarthritis.
  • Another embodiment of the invention encompasses the above method wherein the cycloxoygenase-2 selective mediated disease or condition is rheumatoid arthritis.
  • Another embodiment of the invention encompasses the above method wherein the cycloxoygenase-2 selective mediated disease or condition is chronic pain.
  • the invention encompasses the above method wherein aspirin is administered at a dose of about 30 mg to about 1 g.
  • unit dose or when aspirin is indicated to be dosed "once every three to seven days” means the indicated amount is administered at the time of dosing rather than the amount taken on average over a prolonged interval. For example a dose of 325 mg taken every 3 days delivers approximately 758 mg per week, but the dose administered every third day or unit dose is 325 mg.
  • aspirin is administered at a dose of about 80 to about 650 mg.
  • aspirin is administered at a dose of about 81 mg and wherein aspirin is administered at a dose of about 325 mg.
  • the invention encompasses the above method wherein aspirin is orally administered once every two days.
  • the invention further encompasses the above method wherein aspirin is orally administered once every three days.
  • the invention further encompasses the above method wherein aspirin is orally administered once every four days.
  • the invention further encompasses the above method wherein aspirin is orally administered once every five days.
  • aspirin is administered once every six days.
  • aspirin is orally administered once every seven days.
  • the invention encompasses a kit comprising a cyclooxygenase-2 selective inhibitor for oral administration on a once-daily or twice- daily basis and aspirin for oral administration once every two to seven days.
  • the kit may comprise a sequenced means of presenting the medication to the patient, such as a calendar pack, in which patients will be instructed to take either one or two tablets in a predefined order.
  • Aspirin may either be provided as a separate tablet copackaged to be taken at the same time as the cycloxoygenase-2 selective inhibitor or, alternatively, within a single tablet that contains both active moieties.
  • the kit may comprise a calendar pack wherein the patient is instructed to take a cyclooxygenase-2 selective inhibitor once a day, except every third, fourth, fifth or seventh day wherein the patient is instructed to take aspirin and the cycloxygenase-2 selective inhibitor as a single tablet.
  • the kit may comprise a calendar pack wherein the patient is instructed to take a cyclooxygenase-2 selective inhibitor once each day, while every third, fourth, fifth or seventh day the patient is instructed to concomitantly take aspirin that is copackaged with the cycloxygenase-2 selective inhibitor.
  • the invention encompasses the above kit wherein the medication is presented to the patient in a predefined sequenced order. Within this embodiment is encompassed the above method wherein the medication is presented to the patient as a calendar pack.
  • the invention also encompasses the above kit wherein the cyclooxygenase-2 selective inhibitor and aspirin are provided as a unit dosage for administration on the same day.
  • a "unit dosage form" means that both active moieties are combined together in the same pharmaceutical formulation.
  • the invention encompasses the above kit wherein the cyclooxygenase-2 selective inhibitor and aspirin are provided as separate dosage forms for concomitant administration on the same day.
  • the invention encompasses the above kit wherein the cyclooxygenase-2 selective inhibitor is rofecoxib. Within this embodiment is encompassed the above kit wherein rofecoxib is provided for administration on a once daily basis at a dose of about 12.5 mg or about 25 mg. In another embodiment, the invention encompasses the above kit wherein the cyclooxygenase-2 selective inhibitor is etoricoxib. Within this embodiment is encompassed the above kit wherein etoricoxib is provided for administration on a once daily basis at a dose of about 60 mg, 90 mg or about 120 mg. Another embodiment of the invention encompasses the above kit wherein the cyclooxygenase-2 selective inhibitor is celecoxib.
  • celecoxib is provided for administration on a once daily basis at a dose of about 100 mg or about 200 mg.
  • the cyclooxygenase-2 selective inhibitor is valdecoxib.
  • valdecoxib is provided for administration on a once daily basis at a dose of about 10 mg or about 20 mg.
  • the invention encompasses the above kit wherein aspirin is provided for administration once every two to seven days at a dose of about 30 mg to about 1 g. Within this embodiment is encompassed the above kit wherein aspirin is provided for administration once every two to seven days at a dose of about 80 mg to about 650 mg. Also within this embodiment is encompassed the above kit wherein aspirin is provided for administration once every two to seven days at a dose of about 81 mg. Also within this embodiment is encompassed the above kit wherein aspirin is provided for administration once every two to seven days at a dose of about 325 mg.
  • the present invention also encompasses a method for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the combined risk of death and nonfatal stroke in a human patient who has had ischemic stroke of transient ischemia of the brain due to fibrin platelet emboli and also in need of treatment for a chronic cyclooxygenase-2 mediated disease comprising orally administering to said patient a cyclooxygenase-2 selective inhibitor on a once or twice daily basis in an amount effective to treat the chronic cyclooxygenase-2 mediated disease or condition and orally administering to said patient aspirin once every two to seven days at a dose of about 30 mg to about 1 g.
  • the present invention also encompasses a method for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the combined risk of death and nonfatal myocardial infarction in a human patient with a previous myocardial infarction or unstable angina pectoris and also in need of treatment for a chronic cyclooxygenase-2 mediated disease comprising orally administering to said patient a cyclooxygenase-2 selective inhibitor on a once or twice daily basis in an amount effective to treat the chronic cyclooxygenase-2 mediated disease or condition and orally administering to said patient aspirin once every two to seven days at a dose of about 30 mg to about 1 g.
  • the present invention also encompasses a method for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the combined risk of death and nonfatal myocardial infarction in a human patient with chronic stable angina pectoris and also in need of treatment for a chronic cyclooxygenase-2 mediated disease comprising orally administering to said patient a cyclooxygenase-2 selective inhibitor on a once or twice daily basis in an amount effective to treat the chronic cyclooxygenase-2 mediated disease or condition and orally administering to said patient aspirin once every two to seven days at a dose of about 30 mg to about 1 g.
  • the invention encompasses a method for treating a chronic cyclooxygenase-2 mediated disease or condition and preventing a thrombotic cardiovascular event in a human patient in need of such treatment and prevention comprising orally administering to said patient a cyclooxygenase-2 selective inhibitor on a once or twice daily basis in an amount effective to treat the cyclooxygenase-2 mediated disease or condition and orally administering to said patient aspirin once every two to seven days in an amount effective to prevent the thrombotic cardiovascular event.
  • references to the compounds of use in this invention are meant to also include the pharmaceutically acceptable salts.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as argin
  • the compounds of use in this invention may have one or more chiral centers and the present compounds may occur as racemates, racemic mixtures and as individual diasteriomers or enantiomers with all such isomeric forms and mixtures thereof being included within the scope of this invention.
  • some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates and hydrates, as well as anhydrous compositions, are encompassed within the scope of this invention.
  • Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • COX-2 inhibitors that may be used with this invention encompass all pharmaceutically acceptable salt forms of the compounds.
  • Examples of such salt forms of COX-2 inhibitors include but are not limited to salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as arg
  • the instant pharmaceutical combination comprising aspirin in combination with a COX-2 inhibitor includes administration of a single pharmaceutical dosage formulation which contains both aspirin and the COX-2 inhibitor, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
  • aspirin and the COX-2 inhibitor can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially.
  • the instant pharmaceutical combination is understood to include all these regimens.
  • the dosage regimen utilizing aspirin in combination with COX-2 inhibitor 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 or ester thereof employed.
  • the active agents are typically 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
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage forms.
  • suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • the active drugs 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. Active drug may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drug may also be coupled with soluble polymers as targetable 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.
  • active drug 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.
  • the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining aspririn and the COX-2 inhibitor with a pharmaceutically acceptable carrier, as well as the pharmaceutical composition which is made by combining aspirin and the COX-2 inhibitor with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount of aspirin and a COX-2 inhibitor can be used together for the preparation of a medicament useful for treating or preventing the disease or conditions herein.
  • the medicament may be comprised of a COX-2 inhibitor in combination with about 30 mg to 1 g of aspirin, or more particularly about 80 mg to about 650 mg of aspirin.
  • the instant invention also encompasses the use of aspirin for the preparation of a medicament for the combined use with a cyclooxygenase-2 inhibitor for use as provided by the present invention; and the use of a cyclooxygenase-2 inhibitor for the preparation of a medicament for the combined use with aspirin for use as provided by the present invention.

Abstract

L'invention concerne une méthode et une trousse pour le traitement d'une maladie ou d'un état pathologique chronique dépendant de la cyclo-oxygénase 2, qui réduisent le risque d'événement cardio-vasculaire thrombotique chez un patient humain nécessitant un tel traitement et présentant un risque d'événement cardio-vasculaire thrombotique. La méthode consiste à administrer par voie orale à ce patient un inhibiteur sélectif de cyclo-oxygénase 2, une ou deux fois par jour, en quantité efficace pour traiter la maladie ou l'état pathologique dépendant de la cyclo-oxygénase 2 ; et à administrer à ce patient de l'aspirine par voie orale, une fois tous les deux à sept jours, en quantité efficace pour réduire le risque d'événement cardio-vasculaire thrombotique et maintenir en même temps un niveau élevé de sécurité et de tolérance pour le tractus gastro-intestinal supérieur.
PCT/US2002/038376 2001-12-07 2002-12-03 Therapie combinee comprenant un inhibiteur de cyclo-oxygenase 2 WO2003049720A1 (fr)

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WO2004058354A1 (fr) * 2002-12-20 2004-07-15 Pharmacia Corporation Compositions d'inhibiteurs selectifs de cyclooxygenase-2 et d'inhibiteurs selectifs de recaptage de serotonine dans le traitement ou dans la prevention d'un evenement vaso-occlusif
US7220749B2 (en) 2002-06-11 2007-05-22 Nitromed, Inc. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
CN104173359A (zh) * 2014-09-05 2014-12-03 罗国安 一种降低罗非考昔副作用的消炎镇痛复方药物及其应用

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WO2001091750A1 (fr) * 2000-05-26 2001-12-06 Pharmacia Corporation Utilisation d'une composition de celecoxibe pour soulagement rapide de la douleur
US20020071857A1 (en) * 2000-08-18 2002-06-13 Kararli Tugrul T. Rapidly disintegrating oral formulation of a cyclooxygenase-2 inhibitor

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US7220749B2 (en) 2002-06-11 2007-05-22 Nitromed, Inc. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7589124B2 (en) 2002-06-11 2009-09-15 Nicox, S.A. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2004058354A1 (fr) * 2002-12-20 2004-07-15 Pharmacia Corporation Compositions d'inhibiteurs selectifs de cyclooxygenase-2 et d'inhibiteurs selectifs de recaptage de serotonine dans le traitement ou dans la prevention d'un evenement vaso-occlusif
CN104173359A (zh) * 2014-09-05 2014-12-03 罗国安 一种降低罗非考昔副作用的消炎镇痛复方药物及其应用

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