WO1998008518A1 - Compositions and methods for administering integrin receptor antagonists - Google Patents

Compositions and methods for administering integrin receptor antagonists Download PDF

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Publication number
WO1998008518A1
WO1998008518A1 PCT/US1997/014908 US9714908W WO9808518A1 WO 1998008518 A1 WO1998008518 A1 WO 1998008518A1 US 9714908 W US9714908 W US 9714908W WO 9808518 A1 WO9808518 A1 WO 9808518A1
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Prior art keywords
inhibiting
composition
receptor antagonist
patient
integrin receptor
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PCT/US1997/014908
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English (en)
French (fr)
Inventor
Michael F. Sugrue
Robert J. Gould
George D. Hartman
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Merck & Co., Inc.
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Priority claimed from GBGB9619583.9A external-priority patent/GB9619583D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002263998A priority Critical patent/CA2263998A1/en
Priority to AU40862/97A priority patent/AU729488B2/en
Priority to EP97938565A priority patent/EP0928194A4/en
Priority to JP10511782A priority patent/JP2001501597A/ja
Publication of WO1998008518A1 publication Critical patent/WO1998008518A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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

  • the invention concerns a means for delivering to a patient a therapeutically effective amount of an integrin receptor antagonist such as a fibrinogen receptor ( ⁇ 3, also referred to as GP Ilb/IIIa) antagonist or a vitronectin receptor ( ⁇ y ⁇ 3) antagonist.
  • an integrin receptor antagonist such as a fibrinogen receptor ( ⁇ 3, also referred to as GP Ilb/IIIa) antagonist or a vitronectin receptor ( ⁇ y ⁇ 3) antagonist.
  • Integrins constitute an extended family ("superfamily") of membrane receptors interacting with adhesive proteins in plasma and extracellular matrix and with other membrane receptors (counter- receptors).
  • the name "integrin” implies that they integrate the ligands on the outside of the cell with the cytoskeletal apparatus in the inside of the cell.
  • Integrin receptors consist of a noncovalently lined Ca ⁇ +- dependent, heterodimeric glycoprotein complex composed of and ⁇ subunits.
  • the eight known integrin ⁇ subunits give rise to eight families in which one "founder" ⁇ subunit forms heterodimers with different subunits. There are at least 14 known subunits. Among them ocv (“v” stands for association with the vitronectin receptor) seems to be most promiscuous, forming liaisons with six different ⁇ subunits. Receptors belonging to the ⁇ l and ⁇ 3 families are expressed in endothelial cells.
  • the ⁇ l family also named Very Late Antigens (VLA), is represented by the fibronectin receptor ( ⁇ 5 ⁇ l , or VLA-5), the collagen receptor (cc2 ⁇ l , or VLA-2) and the laminin receptor ( ⁇ 6 ⁇ l ).
  • the ⁇ 3 family is represented by the vitronectin receptor ( ⁇ ⁇ 3), which is structurally similar (the same ⁇ 3 subunit) to the platelet integrin receptor for fibrinogen, glycoprotein Ilb-IIIa complex (oc_Ib ⁇ 3)-
  • the functional difference between these two receptors is that the platelet receptor recognizes the ⁇ chain domain (HHLGGAKQAGDV) of human fibrinogen and the endothelial vitronectin receptor does not.
  • Both recognize the sequence R-G-D identified as the cell adhesion site of fibronectin, vitronectin, vWf, and the oc chain of human fibrinogen. Therefore, synthetic peptides containing the R-G-D sequence cause detachment of endothelial cells from the extracellular in matrix in vitro.
  • the final obligatory step in platelet aggregation is the binding of fibrinogen to an activated membrane-bound glycoprotein complex, GP Ilb/IIIa ( ⁇ 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 antithro mbotic agent.
  • the snake venom proteins termed disintegrins, have provided important structural information for identifying fibrinogen receptor antagonists, but their antigenicity has limited their development as therapeutic agents (Cook et al. ibid.; and Cox et al. ibid.).
  • 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 GPHa/IIIa but has very little effect on ligand binding to ⁇ v ⁇ 3.
  • non-peptide compounds are Ro 44-9883 and MK- 383, which are administered intravenously, and are also selective for GPIIb/I ⁇ a (Cook et al. ibid.; and Cox et al. ibid.).
  • Orally active agents include SC54684, which is a prodrug (i.e., it requires biotransformation in vivo to its active form) with high oral bioavailability and Ro 43- 8857, GR 144053, and DMP728, which are themselves the active inhibitors (Cook et al. ibid.; and Cox et al. ibid.).
  • Vitronectin serum spreading factor or S protein
  • S protein serum spreading factor
  • endothelial cell subendothelium endothelial cell subendothelium
  • Endothelial cells express a surface receptor for vitronectin and bind vitronectin (Fitzgerald et al. Biochemistry 26: 8158 (1987); Cheresh et al. Proc. Natl. Acad.
  • Vitronectin mediates attachment and spreading of endothelial cells, the development of focal adhesion plaques, and clustering of the vitronectin receptor (Dejana et al. Blood 75; 1509 (1990); Dejana et al. J. Cell Biol. 107; 1215 (1988); Dejana et al. Blood 71 ;566 (1988); Charo et al. J. Biol. Chem. 262;9935 (1987); Cheresh et al.
  • Vitronectin is also found in platelets and is released when platelets are activated; vitronectin then binds to platelets, probably to GP Ilb-IIIa (Barnes et al. Proc. Natl. Acad. Sci. USA 80; 1362 (1983)). Vitronectin thus acts as a subendothelial attachment factor for both endothelial cells and platelets. Vitronectin also mediates the adherence of group A and G streptococci to endothelial cells.
  • Compounds which are v ⁇ 3 antagonists are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, angiogenesis, artherosclerosis and tumor metastasis.
  • Osteoclasts are multinucleated cells of up to 400 ⁇ m in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
  • osteoclasts are believed to exist in at least two physiological states.
  • the secretory state osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and acids to resorb bone.
  • the adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption.
  • the osteoclasts migrate across bone matrix and do not take part in resorption until they attach again to bone.
  • Integrins are transmembrane, heterodimeric, glycoproteins which interact with extracellular matrix and are involved in osteoclast attachment, activation and migration.
  • the most abundant integrin in osteoclasts (rat, chicken, mouse and human) is the vitronectin receptor, or ⁇ v ⁇ 3, thought to interact in bone with matrix proteins that contain the RGD sequence.
  • Antibodies to ⁇ v ⁇ 3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process.
  • v ⁇ 3 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals.
  • osteoporosis hypercalcemia of malignancy
  • osteopenia due to bone metastases
  • periodontal disease hyperparathyroidism
  • periarticular erosions in rheumatoid arthritis Paget's disease
  • immobilization- induced osteopenia and glucocorticoid treatment.
  • ctv ⁇ 3 ligands have been found to be useful in treating and/or inhibiting restenosis (recurrence of stenosis after angioplasty or corrective surgery on the heart valve), artherosclerosis, diabetic retinopathy and angiogenesis (formation of new blood vessels).
  • restenosis currence of stenosis after angioplasty or corrective surgery on the heart valve
  • artherosclerosis CAD
  • diabetic retinopathy formation of new blood vessels
  • angiogenesis formation of new blood vessels.
  • ⁇ v ⁇ 3 antagonists which inhibit angiogenesis, are therefore useful in the treatment of cancer for inhibiting tumor growth.
  • compositions and methods provide a means for systemically delivering to a patient therapeutically effective amounts of integrin receptor antagonists.
  • compositions and methods of the invention provide a convenient means for systemically administering an integrin receptor antagonist or a pharmaceutically effective amount thereof to a patient by introducing the antagonist, in an ophthalmic formulation, to the patient's eye.
  • the integrin receptor antagonist or a pharmaceutically acceptable salt thereof is formulated, along with suitable carriers, excipients and preservatives, into an ophthalmic preparation.
  • suitable carriers, excipients and preservatives into an ophthalmic preparation.
  • Such preparations include ophthalmic solutions (e.g. eyedrop formulations), ophthalmic suspensions, ophthalmic solid inserts, and ophthalmic ointments.
  • the invention also includes the use of a fibrinogen receptor antagonist in the manufacture of an ophthalmic medicament for 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, to treat patients with unstable angina, and to prevent subsequent myocardial infarction.
  • the invention also includes the use of a vitronectin receptor antagonist in the manufacture of an ophthalmic medicament for treating inflammation, cancer, atherosclerosis, restenosis, osteoporosis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, and bone loss.
  • the invention also includes the use of a compound which inhibits the binding of fibrinogen to the glycoprotein Ilb/IIIa receptor, or a pharmaceutically acceptable salt thereof, or a compound which inhibits the binding of vitronectin to the otv ⁇ 3 receptor, or a pharmaceutically acceptable salt thereof, in the manufacture of an ophthalmic medicament for reducing the risk of acute coronary ischemic syndrome, or inhibiting osteoclast cellular adhesion, solubilization of mammalian bone minerals by osteoclast cells, inhibiting diabetic retinopathy, or inhibiting macular degeneration in a mammal.
  • eyedrop formulations from about 0.01-5.0% (w/v) of active ingredient can be employed. In one class of eyedrop formulations, from about 0.01-2.0% (w/v) of active ingredient can be employed. In a subclass of the class, from about 0.1-1.0% (w/v) of active ingredient can be employed. Suitable eyedrop volume is, for example, 20, 30, 35, 50 or 100 ⁇ l.
  • 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. These dosage values are based on known and presently understood pharmacology of the integrin receptor antagonists, Dosage requirements are variable and must be individualized on the basis of the disease and the response of the patient.
  • 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 conventional ly- employed non-toxic, pharmaceutically acceptable organic and inorganic carriers.
  • 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 conventional ly- employed non-toxic, pharmaceutically acceptable organic and inorganic carriers.
  • 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, ethylenediamine tetraacetic acid, and the like.
  • suitable ophthalmic vehicles can be used as carrier media
  • 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 ophthalmic preparation may also be an ophthalmic solid insert such as one which, after dispensing the integrin receptor antagonist, remains essentially intact, or a bioerodible insert that is soluble in lacrimal fluids, or otherwise disintegrates.
  • an ophthalmic solid insert such as one which, after dispensing the integrin receptor 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 integrin receptor 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, hydro xypropylmethyl 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 well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol, gellan gum and xanthan gum, and mixtures of said polymers.
  • cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose
  • the ophthalmic preparation may also be an ophthalmic 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.
  • Integrin receptor antagonists suitable for administration using compositions of the invention include fibrinogen receptor antagonists and vitronectin receptor antagonists.
  • Antagonists for the glycoprotein Ilb/IIIa fibrinogen receptor have been described in, for example, United States Patents 5,470,849, 5,463,01 1 , 5,455,243, 5,451,578, 5,446,056, 5,441 ,952, 5,422,249, 5,416,099, 5,405,854, 5,397,791 , 5,393,760, 5,389,631 , 5,380,713, 5,374,622, 5,358,956, 5,344,783, 5,340,798, 5,338,7235,334,596, 5,321,034, 5,318,899 (e.g.
  • EP 505 868 e.g. ((l -(2-((4 (aminoiminomethyl)benzoyl)amino)-3-(4- hydroxyphenyl)- 1 -oxopropyl)-4-piperidinyl)oxy)-(S)-acetic acid
  • WO 931 1 152 e.g.
  • Antagonists for the ocy ⁇ 3 vitronectin receptor have been described in, for example, WO 9723451, WO 9708145, Japanese Patent 6128289, WO 9600730, WO 9600574, and United States Patent 5,229,366. These are generally described as useful for treating inflammation, cancer, atherosclerosis, restenosis, osteoporosis, hype ⁇ arathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, and bone loss.
  • Antagonists for integrin receptors that are described as useful for treating thrombosis and osteoporosis are described in, for example, European Publications 710 657, 683 173, 741 133, 668 278, 645 376, 643 072, 623 615 in WO 9532710, WO 9701549, WO 9626190, WO 9606087, WO 952381 1, United States Patent 5,565,449, and Japanese Patent 7206860.
  • Glycoprotein Ilb/IIIa receptor antagonists and their pharmaceutically acceptable salts, and otv ⁇ 3 receptor antagonists and their pharmaceutically acceptable salts, are useful in the present invention.
  • pharmaceutically acceptable salts means non- toxic salts of the compounds 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, methylsulfate, mucate, napsylate, nitrate,
  • compositions and methods of the present invention are suitable for use in the compositions and methods of the present invention.
  • pharmaceutically 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.
  • compositions and methods of the present invention comprising fibrinogen receptor antagonists are useful in combination with procedures for treating patients with other anticoagulants (e.g. thrombin inhibitors such as heparin and Factor Xa inhibitors such as warfarin), thrombolytic agents (e.g. streptokinase and tissue plasminogen activator), and platelet anti aggregation agents (e.g. aspirin and dipyridamole).
  • anticoagulants e.g. thrombin inhibitors such as heparin and Factor Xa inhibitors such as warfarin
  • thrombolytic agents e.g. streptokinase and tissue plasminogen activator
  • platelet anti aggregation agents e.g. aspirin and dipyridamole
  • the fibrinogen receptor antagonist may be administered to 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), in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and potential formation of thrombi and thromboemboli, and for treating patients where inhibition of human or mammalian acute coronary ischemic syndrome is desired.
  • the aggregated platelets may form thrombi and thromboemboli.
  • the fibrinogen receptor antagonists may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
  • Other applications of the fibrinogen receptor antagonists include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thro mbolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery bypass procedures. It may also be used to treat patients with unstable angina and prevent subsequent myocardial infarction.
  • compositions and methods of the present invention comprising vitronectin receptor antagonists elicit an 0Cy ⁇ 3 antagonizing effect in a mammal in need thereof.
  • the ccv ⁇ 3 antagonizing effect is, for example, inhibition of bone reso ⁇ tion, inhibition of restenosis, inhibition of artherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy or inhibition of tumor growth.
  • compositions and methods of the present invention comprising vitronectin receptor antagonists are useful for treating and/or preventing a condition mediated by an ccv ⁇ 3 receptor in a mammal in need thereof, such as osteoporosis, cancer, bone reso ⁇ tion, restenosis, diabetic retinopathy, artherosclerosis, angiogenesis or tumor growth.
  • a condition mediated by an ccv ⁇ 3 receptor such as osteoporosis, cancer, bone reso ⁇ tion, restenosis, diabetic retinopathy, artherosclerosis, angiogenesis or tumor growth.
  • compositions and methods of the present invention comprising vitronectin receptor antagonists are useful for treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hype ⁇ arathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, and immobilization-induced osteopenia.
  • the dosage regimen 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 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 effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Compound 1-1 was dissolved directly into 0.5% hydroxyethylcellulose to form a solution.
  • the formulation was rendered sterile by starting the preparation procedure with sterile components and proceeding under sterile conditions.
  • Additional eyedrop formulations are prepared having the following composition:
  • Ophthalmic inserts are manufactured from compression molded films which are prepared on a Carver Press by subjecting the powdered mixture of 1 mg Compound 1 -1 and 12 mg hydroxymethylcellulose to a compression force of 12,000 lbs. (gauge) at 300 degrees F. for one to four minutes. The film is cooled under pressure by having cold water circulate in the platen. Ophthalmic inserts are then individually cut from the film with a rod-shaped punch. Each insert is placed into a vial, which is then placed in a humidity cabinet (88% R.H. at 30 degrees C.) for two or four days. After removal from the humidity cabinet, the vials are stoppered from the humidity cabinet, the vials are stoppered and then capped. The vials containing the hydrate insert are then autoclaved at 250 degrees F. for one-half hour. EXAMPLE 4
  • Example 2 One drop (100 ⁇ l) of the eyedrop prepared in Example 1 was instilled into each eye of a conscious pu ⁇ ose-bred mongrel dog (HHCMLH). Ex vivo inhibition of platelet aggregation as compared to baseline predose aggregatory response induced by 10 ⁇ M ADP + 1 ⁇ M epinephrine was measured over a period of 4 hours and shown to achieve over 50% inhibition:
  • Example 2 One drop (100 ⁇ l) of the eyedrop prepared in Example 1 was instilled into each eye of a conscious pu ⁇ ose-bred mongrel dog (HIAMGV). Ex vivo inhibition of platelet aggregation as compared to baseline predose aggregatory response induced by 10 ⁇ M ADP + 1 ⁇ M epinephrine was measured over a period of 4 hours and shown to achieve 100% inhibition:
  • Example 2 One drop (100 ⁇ l) of the eyedrop prepared in Example 1 was instilled into each eye of a conscious pu ⁇ ose-bred mongrel dog (41309). Ex vivo inhibition of platelet aggregation as compared to baseline predose aggregatory response induced by 10 ⁇ M ADP + 1 ⁇ M epinephrine was measured over a period of 24 hours and shown to achieve 100% inhibition:
  • Example 2 One drop (100 ⁇ l) of the eyedrop prepared in Example 1 was instilled into each eye of a conscious pu ⁇ ose-bred mongrel dog (HGFMKC). Ex vivo inhibition of platelet aggregation as compared to baseline predose aggregatory response induced by 10 ⁇ M ADP + 1 ⁇ M epinephrine was measured over a period of 24 hours and shown to achieve over 50% inhibition:

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PCT/US1997/014908 1996-08-29 1997-08-25 Compositions and methods for administering integrin receptor antagonists WO1998008518A1 (en)

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CA002263998A CA2263998A1 (en) 1996-08-29 1997-08-25 Compositions and methods for administering integrin receptor antagonists
AU40862/97A AU729488B2 (en) 1996-08-29 1997-08-25 Compositions and methods for administering integrin receptor antagonists
EP97938565A EP0928194A4 (en) 1996-08-29 1997-08-25 COMPOSITIONS AND METHODS FOR ADMINISTERING INTEGRIN RECEPTOR ANTAGONISTS
JP10511782A JP2001501597A (ja) 1996-08-29 1997-08-25 インテグリンレセプターアンタゴニストを投与するための組成物と方法

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US2580896P 1996-08-29 1996-08-29
US60/025,808 1996-08-29
GBGB9619583.9A GB9619583D0 (en) 1996-09-19 1996-09-19 Compositions and methods for administering integrin receptor antagonists
GB9619583.9 1996-09-19

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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2002067972A1 (en) * 2001-02-28 2002-09-06 Duke University Method of inducing vitreous detachment
US7618226B2 (en) 2005-06-24 2009-11-17 Asm Japan K.K. Semiconductor substrate transfer apparatus and semiconductor substrate processing apparatus equipped with the same

Citations (2)

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CA2263998A1 (en) 1998-03-05
AU4086297A (en) 1998-03-19
EP0928194A1 (en) 1999-07-14
EP0928194A4 (en) 2001-01-17
AU729488B2 (en) 2001-02-01
JP2001501597A (ja) 2001-02-06

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