CA2263998A1 - Compositions and methods for administering integrin receptor antagonists - Google Patents

Abstract

The 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.

Description

?W0 98/08518l015202530CA 02263998 l999-02- l9-1-TITLE OF THE INVENTIONCOMPOSITIONS AND METHODS FOR ADIVHNISTERINGINTEGRIN RECEPTOR ANTAGONISTSBACKGROUND OF THE INVENTIONThe invention concerns a means for delivering to a patienta therapeutically effective amount of an integrin receptor antagonistsuch as a fibrinogen receptor (OLIIB3, also referred to as GP Hb/IIIa)antagonist or a vitronectin receptor (OLVB3) antagonist.Integrins constitute an extended family ("superfamily") ofmembrane receptors interacting with adhesive proteins in plasma andextracellular matrix and with other membrane receptors (counter-receptors). The name "integrin" implies that they integrate the ligandson the outside of the cell with the cytoskeletal apparatus in the inside ofthe cell. Integrin receptors consist of a noncovalently lined Ca2"'~dependent, heterodimeric glycoprotein complex composed of on and [3subunits.The eight known integrin [3 subunits give rise to eightfamilies in which one "founder" [3 subunit forms heterodimers withdifferent ot subunits. There are at least 14 known on subunits. Amongthem Otv ("v" stands for association with the vitronectin receptor) seemsto be most promiscuous, forming liaisons with six different [3 subunits.Receptors belonging to the B1 and [53 families are expressed inendothelial cells. The B1 family, also named Very Late Antigens(VLA), is represented by the fibronectin receptor (oc5B1, or VLA-5),the collagen receptor (OLZB1, or VLA-2) and the larninin receptor(0c6B1). The [33 family is represented by the vitronectin receptor(OLVB3), which is structurally similar (the same [33 subunit) to theplatelet integrin receptor for fibrinogen, glycoprotein IIb—IIIa complex(0c1]b[53). The functional difference between these two receptors is thatthe platelet receptor recognizes the 7 chain domain(I-IHLGGAKQAGDV) of human fibrinogen and the endothelialvitronectin receptor does not. Both recognize the sequence R-G-Didentified as the cell adhesion site of fibronectin, vitronectin, vWf, andPCT/US97/ 14908 "?WO 98/085181015202530CA 02263998 l999-02- 19PC T/U S97/ 14908-2-the oc chain of human fibrinogen. Therefore, synthetic peptidescontaining the R—G—D sequence cause detachment of endothelial cellsfrom the extracellular in matrix in vitro.The final obligatory step in platelet aggregation is thebinding of fibrinogen to an activated membrane-bound glycoproteincomplex, GP Ilb/Illa (oc11B3). Platelet activators such as thrombin,collagen, epinephrine or ADP, are generated as an outgrowth of tissuedamage. During activation, GP IIb/IIIa undergoes changes inconformation that result in exposure of occult binding sites forfibrinogen. There are six putative recognition sites within fibrinogenfor GP IIb/Illa and thus fibrinogen can potentially act as a hexavalentligand to crossing GP IIb/Illa molecules on adjacent platelets. Adeficiency in either fibrinogen or GP IIb/Illa prevents normal plateletaggregation regardless of the agonist used to activate the platelets. Sincethe binding of fibrinogen to its platelet receptor is an obligatorycomponent of normal aggregation, GP IIb/IIla is an attractive target foran antithrombotic agent.The snake venom proteins, termed disintegrins, haveprovided important structural information for identifying fibrinogenreceptor antagonists, but their antigenicity has limited their developmentas therapeutic agents (Cook et al. ibid.; and Cox et al. ibid.). Integrilinis a cyclic peptide that is based on the KGD sequence in the snake venomprotein barbourin (Cook et al. ibid.; and Cox et al. ibid.). It inhibitsligand binding to GPHa/IIIa but has very little effect on ligand bindingto OLVB3. Among the non—peptide compounds are Ro 44-9883 and MK-383, which are administered intravenously, and are also selective forGPIIb/Illa (Cook et al. ibid.; and Cox et al. ibid.). Orally active agentsinclude SC54684, which is a prodrug (i.e., it requires biotransforrnationin vivo to its active form) with high oral bioavailability and R0 43-8857, GRl44053, and DMP728, which are themselves the activeinhibitors (Cook et al. ibid.; and Cox et al. ibid.). Literally thousandsof other compounds have been synthesized in an attempt to obtainoptimal potency, metabolic stability, receptor specificity, and favorableintravascular survival. Despite variations in these compounds, virtually?W0 98/085181015202530CA 02263998 l999-02- l9PCT/U S97/ 14908 ’-3-of all of them retain the basic charge relations of the RGD sequencewith a positive charge separated from a negative charge byapproximately 10-20 A (Cook et al. ibid.; and Cox et al. ibid.).Since ocv[33 is found on endothelial cells, and perhapssmooth muscle cells (Felding—Haberma1m et al. Curr. Opin. Cell Biol.1993; 51864-868), there are many potential sites of action. RecentlyChoi et al. demonstrated that a peptide that blocks OLVB3 preventedintimal hyperplasia after vascular injury in the rat (Choi et al. J. Vasc.Surg. 1994; 19: 125-134), and Matsuno er al. demonstrated that a peptidethat reacts with GP[IIb/IIIa and at/B3 prevents neointima formation inthe hamster (Matsuno et al. Circulation 1994; 90:2203-2206). Whetherthe peptide used by Choi et al. also inhibited rat platelet GPIIb/Hla isnot known.Vitronectin (serum spreading factor or S protein) is a 75-kDa glycoprotein found in plasma (500 ug/rnL) and in extracellularmatrix, including endothelial cell subendothelium (Barnes et al. J. Biol.Chem. 258; 12548 (1983); Hayman et al. Proc. Natl. Acad. Sci. USA80; 4003, (1983); and Preissner et al. Blood 71; 1381 (1986)).Endothelial cells express a surface receptor for vitronectin and bindvitronectin (Fitzgerald et al. Biochemistry 26: 8158 (1987); Cheresh etal. Proc. Natl. Acad. Sci. USA 84; 6471 (1989); Cheng et al. J. CellPhysiol. 139; 275 (1989); Preissner et al. ibid.; and Polack et al. Blood73; 1519 (1989)). Vitronectin mediates attachment and spreading ofendothelial cells, the development of focal adhesion plaques, andclustering of the vitronectin receptor (Dejana et al. Blood 75; 1509(1990); Dejana et al. J. Cell Biol. l07;l2l5 (1988); Dejana et al. Blood7l;566 (1988); Charo et al. J. Biol. Chem. 262;9935 (1987); Cheresh etal. Proc. Natl Acad. Sci. USA 84;6471, (1987); Cheng et al. J. CellPhysiol. l39;275 (1989); Barnes et al. J. Biol. Chem. 258:l2548 (1983);I-layman et al. J. Cell Biol. 95;2O (1982)). Vitronectin is also found inplatelets and is released when platelets are activated; vitronectin thenbinds to platelets, probably to GP IIb-Illa (Barnes et al. Proc. Natl.Acad. Sci. USA 80;l362 (1983)). Vitronectin thus acts as asubendothelial attachment factor for both endothelial cells and platelets.?WO 98/085181015202530CA 02263998 l999-02- l9-4-Vitronectin also mediates the adherence of group A and G streptococcito endothelial cells.Compounds which are otvB3 antagonists are useful forinhibiting bone resorption, treating and preventing osteoporosis, andinhibiting vascular restenosis, diabetic retinopathy, angiogenesis,artherosclerosis and tumor metastasis.Osteoclasts are multinucleated cells of up to 400 um indiameter that resorb mineralized tissue, chie?y calcium carbonate andcalcium phosphate, in vertebrates. They are actively motile cells thatmigrate along the surface of bone. They can bind to bone, secretenecessary acids and proteases and thereby cause the actual resorption ofmineralized tissue from the bone.More specifically, osteoclasts are believed to exist in at leasttwo physiological states. In the secretory state, osteoclasts are ?at,attach to the bone matrix via a tight attachment zone (sealing zone),become highly polarized, form a ruf?ed border, and secrete lysosomalenzymes and acids to resorb bone. The adhesion of osteoclasts to bonesurfaces is an important initial step in bone resorption. In themigratory or motile state, the osteoclasts migrate across bone matrixand do not take part in resorption until they attach again to bone.Integrins are transmembrane, heterodimeric, glycoproteinswhich interact with extracellular matrix and are involved in osteoclastattachment, activation and migration. The most abundant integrin inosteoclasts (rat, chicken, mouse and human) is the vitronectin receptor,or ocvB3, thought to interact in bone with matrix proteins that containthe RGD sequence. Antibodies to ocv[33 block bone resorption in ?tmindicating that this integrin plays a key role in the resorptive process.There is increasing evidence to suggest that otv[33 ligands can be usedeffectively to inhibit osteoclast mediated bone resorption in vivo inmammals.The current major bone diseases of public concern areosteoporosis, hypercalcemia of malignancy, osteopenia due to bonemetastases, periodontal disease, hyperparathyroidism, periarticularPCT/U S97/ 14908 »?WO 98/085181015202530CA 02263998 l999-02- l9PCT/U S97/ 14908-5-erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment.Additionally, OLVB3 ligands have been found to be useful intreating and/or inhibiting restenosis (recurrence of stenosis afterangioplasty or corrective surgery on the heart valve), artherosclerosis,diabetic retinopathy and angiogenesis (formation of new blood vessels).Moreover, it has been postulated that the growth of tumors depends onan adequate blood supply, which in turn is dependent on the growth ofnew vessels into the tumor; thus, inhibition of angiogenesis can causetumor regression in animal models. (See, Harrison's Principles ofInternal Medicine, 12th ed., 1991): OLVB3 antagonists, which inhibitangiogenesis, are therefore useful in the treatment of cancer forinhibiting tumor growth. (See e.g., Brooks et al., Cell, 7911157-1164(1994)).Oral integrin receptor antagonists are readily absorbedwhen a patient consumes them on an empty stomach. However, it hasbeen recently observed that absorption and bioavailability of oralintegrin receptor antagonists, when taken with food, may be reduced bythe presence of food in the stomach. The present compositions andmethods provide a means for systemically delivering to a patienttherapeutically effective amounts of integrin receptor antagonists.SUMMARY OF THE INVENTIONThe compositions and methods of the invention provide aconvenient means for systemically administering an integrin receptorantagonist or a pharrnaceutically effective amount thereof to a patient byintroducing the antagonist, in an ophthalmic formulation, to the patient'seye. In accordance with the compositions and methods of the invention,the integrin receptor antagonist or a pharrnaceutically acceptable saltthereof is formulated, along with suitable carriers, excipients andpreservatives, into an ophthalmic preparation. Such preparationsinclude ophthalmic solutions (e.g. eyedrop formulations), ophthalmicsuspensions, ophthalmic solid inserts, and ophthalmic ointments.?WO 98/085181015202530CA 02263998 l999-02- l9-6-The invention also includes the use of a fibrinogen receptorantagonist in the manufacture of an ophthalmic medicament forprevention of platelet thrombosis, thromboembolism and reocclusionduring and after thrombolytic therapy and prevention of plateletthrombosis, thromboembolism and reocclusion after angioplasty orcoronary artery bypass procedures, to treat patients with unstableangina, and to prevent subsequent myocardial infarction.The invention also includes the use of a vitronectin receptorantagonist in the manufacture of an ophthalmic medicament for treatingin?ammation, 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 whichinhibits the binding of fibrinogen to the glycoprotein Hb/IIIa receptor,or a pharmaceutically acceptable salt thereof, or a compound whichinhibits the binding of vitronectin to the OLVB3 receptor, or apharmaceutically acceptable salt thereof, in the manufacture of anophthalmic medicament for reducing the risk of acute coronaryischemic syndrome, or inhibiting osteoclast cellular adhesion,solubilization of mammalian bone minerals by osteoclast cells, inhibitingdiabetic retinopathy, or inhibiting macular degeneration in a mammal.DETAILED DESCRIPTION OF THE INVENTIONIn eyedrop formulations, from about 0.0l—5.0% (w/v) ofactive ingredient can be employed. In one class of eyedropformulations, from about 0.01-2.0% (w/v) of active ingredient can beemployed. In a subclass of the class, from about 0.1-1.0% (w/v) ofactive ingredient can be employed. Suitable eyedrop volume is, forexample, 20, 30, 35, 50 or 100 pl. The objective is to administer a doseof between about 0.005-0.5 mg/kg per day to each eye, for a totaldosage of between about 0.01-1.0 mg/kg/day, e.g. a dose of about 0.05mg/kg per day to each eye, for a total dosage of about 0.1 mg/kg/day.For example, the eyedrops can be used to provide doses of 1 mg, 10mg, or 50 mg. These dosage values are based on known and presentlyPCT/US97/ 14908 *?W0 98/085181015202530CA 02263998 l999-02- l9PCT/US97/14908 '-7-understood pharmacology of the integrin receptor antagonists, Dosagerequirements are variable and must be individualized on the basis of thedisease and the response of the patient.Suitable eyedrop formulations are those which are isotonicand maintain sufficient contact with the eye surface to systemicallydeliver the active agent to the patient. Such formulationsadvantageously have a pH approximating neutrality and are non-irritating to the eye, e.g. they do not induce tearing and consequentialflow of active agent out of the eye. Pharmaceutically acceptablecarriers are, for example, water, mixtures of water and water—miscib1esolvents such as lower alkanols orarylalkanols, vegetable oils,polyalkylene glycols, petroleum based jelly, ethyl cellulose, hydroxyethyl cellulose, ethyl oleate, carboxymethylcellulose,polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharrnaceutically acceptable organic and inorganiccarriers. The pharmaceutical preparation may also contain non-toxicauxiliary 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, phenylrnercuric salts known to have coldsterilizing properties and which are non—injurious in use, thimerosal,methyl and propyl paraben, benzyl alcohol, phenyl ethanol, bufferingingredients such as sodium chloride, sodium borate, sodium acetates,gluconate buffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetraacetic acid, and the like.Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic sodium chloride vehicles,isotonic sodium borate vehicles and the like.In the procedure for making eyedrops, formulations arerendered sterile by appropriate means, such as starting the preparationprocedure with sterile components and proceeding under sterile?W0 98/085181015202530CA 02263998 l999-02- l9PCT/US97/ 14908-3-conditions, irradiating or autoclaving the finished formulation, and thelike. Suitable anti microbial agents are also useful for maintainingsterility of the eyedrop.The ophthalmic preparation may also be an ophthalmicsolid insert such as one which, after dispensing the integrin receptorantagonist, remains essentially intact, or a bioerodible insert that isI soluble in lacrimal ?uids, or otherwise disintegrates. For example, onemay use a solid water soluble polymer as the carrier for the integrinreceptor antagonist. The polymer used to form the insert may be anywater soluble non-toxic polymer, for example, cellulose derivativessuch as methylcellulose, sodium carboxymethyl cellulose,hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylrnethylcellulose, acrylates such as polyacrylic acid salts, ethylacrylates,polyacrylamides, natural products such as gelatin, alginates, pectins,tragacanth, karaya, chondrus, agar, acacia, starch derivatives such asstarch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, aswell as other synthetic derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralizedcarbopol, gellan gum and xanthan gum, and mixtures of said polymers.The ophthalmic preparation may also be an ophthalmicointment which is compounded, for example, by mixing finely milledpowdered ingredients with a small amount of white petrolatum andlevigating or otherwise mixing until a uniform distribution is achieved.The balance of white petrolatum is added by geometric addition untilthe desired dosage form is made.8 Integrin receptor antagonists suitable for administrationusing compositions of the invention include fibrinogen receptorantagonists and vitronectin receptor antagonists.Antagonists for the glycoprotein IIb/IIIa fibrinogenreceptor have been described in, for example, United States Patents5,470,849, 5,463,011, 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. cyclic heptapeptides?W0 98/085181015202530CA 02263998 l999-02- l9-9-Mpr—(Acetimidyl—Lys)-Gly-Asp-Trp-Phe-Cys-NH2, Mpr-(Acetimidyl-Lys)—Gly-Asp—Trp—Phe-Pen—NH2, Mpr-(Phenylimidyl-Lys)—Gly-Asp-Trp—Phe—Pen~NH2, and Mpr-(Phenylimidyl—Lys)-Gly-Asp—Trp—Phe—Cys-NH2, wherein Mpr is mercapto propionyl), 5,312,923, 5,294,616,5,292,756 (e.g. 2-S~(n-Butylsu1fony1amino)—3[4-piperidin-4-yl)buty1oxyphenyl]propionic acid hydrochloride), 5,281,585 5,272,158,5,264,420, 5,260,307, 5,239,113 (e.g. Ethyl 3—[[4—[[4—(aIninoiminomethy1)pheny1]amino]— l ,4-dioxobuty1]amino]-4-pentynoate), 5,227,490, 5,206,373, 4,703,036 (e.g. N-Methyl-D-phenylalanyl-N—[(lS)-1-forrnyl-4-guanidinobutyl]-1.-prolinamide), EP505 868 (e.g. ((1-(2-((4 (aminoiminomethyl)benzoy1)amino)-3-(4-hydroxyphenyl)-1—oxopropyl)-4-piperidinyl)oxy)—(S)—acetic acid), W0931 1 152 (e.g. N-(2-(2-(((3-((aminoiminomethyl)amino)propyl)amino)—carbony1)—1-piperidnyl)-1-(cyclohexylmethyl)-2—oxoethyl)—(R,S)-glycine), W0 9418981 (e.g. 2(S)-[(p-To1uenesu1fony1)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo—5-[2—(piperidin-4-y1)ethyl]~4H—pyrazolo—[1 ,5-a][1,4]diazepin—2—yl]carbonyl]-amino]propionic acid), W0 9514683(e. g. methy1—N3—[2- { 3-(4—formamidinophenyl)-isoxazolin-5(R)-yl }—acetyl]—N2—(n-butyloxycarbonyl)-2,3—(S)—dia.minopropionate acetatesalt), EP 333 356 and W0 9422820. They are desciibed as useful forinhibiting fibrinogen binding and inhibiting clot formation.Antagonists for the OLVB3 vitronectin receptor have beendescribed in, for example, W0 9723451, W0 9708145, Japanese Patent6128289, W0 9600730, W0 9600574, and United States Patent5,229,366. These are generally described as useful for treatingin?ammation, cancer, atherosclerosis, restenosis, osteoporosis,hyperparathyroidism, Paget's disease, malignant hypercalcemia,metastatic osteolytic lesions, and bone loss.Antagonists for integrin receptors that are described asuseful for treating thrombosis and osteoporosis are described in, forexample, European Publications 710 657, 683 173, 741 133, 668 278,645 376, 643 072, 623 615 in W0 9532710, WO 9701549, W09626190, W0 9606087, W0 9523811, United States Patent 5,565,449,and Japanese Patent 7206860.PCT/U S97! 14908 A?WO 98/0851810202530CA 02263998 l999-02- l9PCT/U S97! 14908-10-Glycoprotein Hb/Illa receptor antagonists and theirpharmaceutically acceptable salts, and ocV[33 receptor antagonists andtheir pharmaceutically acceptable salts, are useful in the presentinvention. The term "phannaceutically 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, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tarmate, tartrate, teoclate,tosylate, triethiodide, valerate.Pharmaceutically effective amounts of the glycoproteinIIb/IIIa receptor antagonists and the on/B3 receptor antagonists aresuitable for use in the compositions and methods of the presentinvention. The term "pharmaceutically effective amount" means thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system or animal that is being sought bya researcher or clinician.The compositions and methods of the present inventioncomprising fibrinogen receptor antagonists are useful in combinationwith procedures for treating patients with other anticoagulants (e.g.thrombin inhibitors such as heparin and Factor Xa inhibitors such aswarfarin), thrombolytic agents (e.g. streptokinase and tissueplasminogen activator), and platelet antiaggregation agents (e.g. aspirinand dipyridamole). ‘The fibrinogen receptor antagonist may be administered topatients where prevention of thrombosis by inhibition of binding offibrinogen to the platelet membrane glycoprotein complex IIb/IIIareceptor is desired. Such administration is useful in surgery on?W0 98/085181015202530CA 02263998 l999-02- l9PCT/U S97/ 14908-11-peripheral arteries (arterial grafts, carotid endarterectomy), incardiovascular surgery where manipulation of arteries and organs,and/or the interaction of platelets with artificial surfaces, leads toplatelet aggregation and potential formation of thrombi andthromboemboli, and for treating patients where inhibition of human ormammalian acute coronary ischemic syndrome is desired. Theaggregated platelets may form thrombi and thromboemboli. Thefibrinogen receptor antagonists may be administered to these surgicalpatients to prevent the formation of thrombi and thromboemboli.Other applications of the fibrinogen receptor antagonistsinclude prevention of platelet thrombosis, thromboembolism andreocclusion during and after thrombolytic therapy and prevention ofplatelet thrombosis, thromboembolism and reocclusion after angioplastyor coronary artery bypass procedures. It may also be used to treatpatients with unstable angina and prevent subsequent myocardialinfarction.The compositions and methods of the present inventioncomprising vitronectin receptor antagonists elicit an OLVB3 antagonizingeffect in a mammal in need thereof. The OCVB3 antagonizing effect is,for example, inhibition of bone resorption, inhibition of restenosis,inhibition of artherosclerosis, inhibition of angiogenesis, inhibition ofdiabetic retinopathy or inhibition of tumor growth.The compositions and methods of the present inventioncomprising vitronectin receptor antagonists are useful for treatingand/or preventing a condition mediated by an on/B3 receptor in amammal in need thereof, such as osteoporosis, cancer, bone resorption,restenosis, diabetic retinopathy, artherosclerosis, angiogenesis or tumorgrowth.The compositions and methods of the present inventioncomprising vitronectin receptor antagonists are useful for treatinghypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, and immobilization-inducedosteopenia.?W0 98/0851 810152025CA 02263998 l999-02- 19-12-The dosage regimen is selected in accordance with a varietyof factors including type, species, age, weight, sex and medicalcondition of the patient; the severity of the condition to be treated; therenal and hepatic function of the patient; and the particular compoundor salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter, or arrest the progress of thecondition.EXAMPLE 1Eye dropsSolution compositions for topical administration containing0.64% w/v 2(S)-[(p—To1uenesulfonyl)amino]-3-[[[5,6,7,8—tetrahydro-4-ox0-5-[2-(piperidin—4-y1)ethyl]-4H—pyrazo1o-[1,5-a][l ,4]diazepin-2-y1]carbony1]—amino]propionic acid (compound 1-1) are prepared asillustrated below:Compound 1-1 6400 mg0.5% hydroxyethylcellulose 1 LCompound 1-1 was dissolved directly into 0.5% hydroxyethylcelluloseto form a solution. The formulation was rendered sterile by starting thepreparation procedure with sterile components and proceeding understerile conditions.PCT/US97/14908 "?CA 02263998 l999-02- l9wo 98/08518 PCT/US97/14908- 13 _EXAMPLE 2Eye dropsAdditional eyedrop formulations are prepared having the5 following composition:l0152025Compound 1-1 0.5%Benzalkonium chloride solution 0.02% v/vDisodium edetate 0.05%NaCl 0.8%Water to 100%EXAMPLE 3Ophthalmic insertsOphthalmic inserts are manufactured from compressionmolded ?lms which are prepared on a Carver Press by subjecting thepowdered mixture of 1 mg Compound 1-1 and 12 mghydroxymethylcellulose to a compression force of 12,000 lbs. (gauge) at300 degrees F. for one to four minutes. The film is cooled underpressure by having cold water circulate in the platen. Ophthalmicinserts 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 humiditycabinet (88% R.H. at 30 degrees C.) for two or four days. Afterremoval from the humidity cabinet, the vials are stoppered from thehumidity cabinet, the vials are stoppered and then capped. The vialscontaining the hydrate insert are then autoclaved at 250 degrees F. forone-half hour.?W0 98/08518101520CA 02263998 l999-02- l9PCT/US97/14908-14-EXAMPLE 4Eyedrop administrationOne drop (100 1.11) of the eyedrop prepared in Example 1was instilled into each eye of a conscious purpose-bred mongrel dog(HHCMLH). Ex vivo inhibition of platelet aggregation as compared tobaseline predose aggregatory response induced by 10 },LM ADP + 1 uMepinephrine was measured over a period of 4 hours and shown toachieve over 50% inhibition:Time (minutes) % Inhibition0 O1 95 -15 2030 1445 1460 2075 3990 8120 42180 30240 57?W0 98/08518101520CA 02263998 l999-02- l9PCT/US97/14908-15-EXAMPLE 5Eyedrop administrationOne drop (100 pl) of the eyedrop prepared in Example 1was instilled into each eye of a conscious purpose—bred mongrel dog(HIAMGV). Ex vivo inhibition of platelet aggregation as compared tobaseline predose aggregatory response induced by 10 },LM ADP + 1 },LMepinephrine was measured over a period of 4 hours and shown toachieve 100% inhibition:Time (minutes) % Inhibition0 O1 165 3215 630 3845 3060 6875 7890 62120 68180 88240 lOO?CA 02263998 l999-02- 19WO 98/08518101520Eyedrop administrationEXAMPLE 6PCTIU S97! 14908One drop (100 pl) of the eyedrop prepared in Example 1was instilled into each eye of a conscious purpose-bred mongrel dog(41309). Ex vivo inhibition of platelet aggregation as compared tobaseline predose aggregatory response induced by 10 p.M ADP + 1 p.Mepinephrine was measured over a period of 24 hours and shown toachieve 100% inhibition:Time (minutes 1O3060901201802403003604204801440% Inhibition0847490901008710010010010088?CA 02263998 l999-02- 19W0 98/08518101520Eyedrop administrationOne drop (100 pl) of the eyedrop prepared in Example 1was instilled into each eye of a conscious purpose-bred mongrel dogEXAMPLE 7PCT/US97/14908(HGFMKC). Ex vivo inhibition of platelet aggregation as compared tobaseline predose aggregatory response induced by 10 },tM ADP + 1 uMepinephrine was measured over a period of 24 hours and shown toachieve over 50% inhibition:Time gminuteszO3060901201802403003604204801440% Inhibition021922831234357414956

Claims (10)

WHAT IS CLAIMED IS:

1. A composition comprising a carrier suitable for topical ophthamological administration and between about 0.01-5% w/v of an integrin receptor antagonist or pharmaceutically acceptable salt thereof or a prodrug thereof.

2. A composition of Claim 1 wherein the amount of integrin receptor antagonist is between about 0.01-2% w/v.

3. A composition of Claim 2 wherein the amount of integrin receptor antagonist is between about 0.1-1% w/v.

4. A composition of Claim 1 wherein the integrin receptor antagonist is a fibrinogen receptor antagonist.

5. A composition of Claim 1 wherein the integrin receptor antagonist is a vitronectin receptor antagonist.

6. A method for administering an integrin receptor antagonist to a patient in need of such antagonist comprising topically applying to the patient's eye an effective amount of a composition of Claim 1.

7. A method for inhibiting platelet aggregation in a patient comprising topically applying to the patient's eye an effective amount of the composition of Claim 4.

8. A method for reducing the risk of acute coronary ischemic syndrome in patients at risk to acute coronary ischemic syndrome comprising topically applying to the patient's eye a safe and effective amount of a glycoprotein IIb/IIIa receptor antagonist composition of Claim 4.

9. A method for inhibiting of bone resorption, inhibiting restenosis, inhibiting angiogenesis, inhibiting diabetic retinopathy or inhibiting tumor growth in a patient comprising topically applying to the patient's eye a therapeutically effective amount of the composition of Claim 5.

10. The use of a compound which inhibits the binding of fibrinogen to the glycoprotein IIb/IIIa receptor, or a pharmaceutically acceptable salt thereof, or a compound which inhibits the binding of vitronectin to the .alpha.v.beta.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.