Cai-based systems and methods for the localized treatment of ocular and other diseases

Abstract

The subject invention provides CAI compounds and formulations thereof, and methods for their use in the localized treatment of non-life threatening diseases. Formulations of CAI compounds of the subject invention include CAI free base and CAI prodrug microcrystallines, microparticles, emulsions, and the like. The subject invention further provides methods for treating non-life threatening diseases using the CAI compounds of the invention (i.e., novel delivery systems and combination therapies), that are effective and are associated with little or no adverse side effects.

1 - 32 . (canceled) 
     
     
         33 . A method for treating a patient suffering from inflammatory optic neuropathies comprising:
 diagnosing inflammatory optic neuropathies in a patient; and   local ocularly administering to said patient a sterile, aqueous suspension formulation comprising a therapeutically effective amount of suspended solid microparticulates of 5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) (CAI) in free base form.   
     
     
         34 . The method of  claim 33 , wherein the patient further suffers from ocular diseases or symptoms selected from the group consisting of: retinal vascular occlusion, choroidal and retinal angiomatous proliferation, chronic glaucoma, retinal detachment, sickle cell retinopathy, rubeosis iritis, neoplasms, Fuch's heterochromic iridocyclitis, neovascular glaucoma, corneal neovascularization, neovascularization resulting from combined vitrectomy and lensectomy, contusive ocular injury, retinopathy of prematurity, retinitis pigmentosa, endophthalmitis, infectious diseases, inflammatory but non-infectious diseases, peripheral retinal degenerations, retinal degenerations and tumors, choroidal disorders and tumors, vitreous disorders, retinal detachment, non-penetrating and penetrating trauma, post-cataract complications, inflammatory optic neuropathies, hereditary degenerative retinal and vitreoretinal diseases, primary pigmented retinopathies, Autosomal dominant retinitis pigmentosa, Autosomal recessive retinitis pigmentosa, Leber's amaurosis congenital, X-linked recessive pigmented retinopathies, secondary pigmented retinopathies, autosomal dominant pigmented retinopathies, Autosomal dominant pigmented retinopathies, Refsum's disease, Usher syndrome, X-linked recessive pigmented retinopathies, corneal ulceration disease, and von Hippel-Lindau syndrome, choroidal neovascularization, retinal neovascularization, iris neovascularization, corneal vascularization and ocular tumors. 
     
     
         35 . The method of  claim 33 , wherein the local ocular administration is by topical administration or ocular injection. 
     
     
         36 . The method of  claim 35 , wherein the ocular injection is any one or combination of routes selected from the group consisting of periocular injection, subtenon's injection, juxtascleral injection, intravitreal injection, subconjuctival injection, subretinal injection, and retrobulbar injection. 
     
     
         37 . The method of  claim 33 , wherein the local ocular administration is assisted by sonophoresis or iontophoresis. 
     
     
         38 . The method of  claim 33 , wherein the therapeutically effective amount of the CAI compound is from 0.1 mg/mL to 100 mg/mL of formulation. 
     
     
         39 . The method of  claim 33 , wherein the CAI compound is a solid particle suspended in the formulation, wherein the therapeutically effective amount of the CAI compound is 0.1 to 10 mg of the CAI compound. 
     
     
         40 . The method of  claim 33 , wherein the sterile, aqueous suspension_formulation is a time-release formulation. 
     
     
         41 . The method of  claim 33 , wherein the CAI compound is solubilized with excipient materials selected from the group consisting of: pure triglyceride oils, diglycerides, monoglycerides, mixed glycerides, lipophilic surfactants, hydrophilic surfactants, and water-soluble cosolvents, and wherein said formulation consists of 0.1 mg/mL to 100 mg/mL of the CAI compound. 
     
     
         42 . The method of  claim 41 , wherein the CAI compound is an organic or inorganic acid addition salt form of CAI selected from the group consisting of: borate, hydrobromide, hydrochloride, nitrate, phosphate, dihydrogenphosphate, sulfate, hydrogensulfate, citrate, fumarate, gluconate, glutamate, lactate, maleate, mandelate, mesylate, oxalate, succinate tartrate, valerate, benzenesulfonate, benzoate, cholate, hydroxynaphthoate, laurate, napsylate, oleate, palmoate, palmitate, salicylate, stearate, tosylate, and taurocholate. 
     
     
         43 . The method of  claim 33 , wherein the formulation further comprises any one or combination of substances selected from the group consisting of: pharmaceutically acceptable carriers, pharmaceutically acceptable auxiliary substances, diluents, surfactants, detergents, stabilizers, excipients, carriers, and delivery-enhancing agents. 
     
     
         44 . The method of  claim 33 , wherein the formulation is a solid, liquid, emulsion, or ointment cream. 
     
     
         45 . The method of  claim 33 , wherein the formulation is an aqueous suspension of surface stabilized particles. 
     
     
         46 . The method of  claim 45 , wherein the formulation is a liposomal formulation or an emulsion based formulation. 
     
     
         47 . The method of  claim 45 , wherein the surface stabilized particles are stabilized by a pharmaceutically acceptable surface active agent selected from the group consisting of: lecithin, charged or uncharged phospholipids, polymeric surfactants, non-polymeric surfactants, charged surfactants, uncharged surfactants, and one or more of bile acids and their salts. 
     
     
         48 . The method of  claim 45 , wherein the formulation further comprises any one or combination of materials selected from the group consisting of: a pharmaceutically acceptable carrier, diluents, viscosity-modifiers, stabilizers, erodible matrices, and a concentrated vehicle that forms an oil-in-water microemulsion upon mixing with body tissue after delivery. 
     
     
         49 . The method of  claim 33 , wherein the formulation further comprises an inclusion host compound material. 
     
     
         50 . The method of  claim 49 , wherein the inclusion host compound material is hydroxypropyl β-cyclodextrin, and wherein the therapeutically effective amount of the CAI compound is 0.1 mg to 10 mg. 
     
     
         51 . The method of  claim 33 , wherein the microparticulate size is 10 micrometers or less. 
     
     
         52 . The method of  claim 33 , wherein the formulation further comprises an ocular therapeutic substance selected from the group consisting of: a VEGF binding molecule and a tyrosine receptor kinase inhibitor. 
     
     
         53 . The method of  claim 33 , wherein the VEGF binding molecule is selected from the group consisting of ranibizumab (Lucentis®) and pegatanib (Macugen®). 
     
     
         54 . The method of  claim 33 , wherein the formulation comprises CAI in emulsion with 25 to 45% of a glyceride, 10 to 20% of a hydrophilic co-surfactant and 25 to 45% of a hydrophobic surfactant. 
     
     
         55 . The method of  claim 33 , wherein the glyceride is soybean oil or sesame oil, wherein the co-surfactant is Tween® 20, Tween® 40, or Tween® 80, and wherein the hydrophobic surfactant is glyceryl monostearate, Pluronic® F68, or Pluronic® F127. 
     
     
         56 . The method of  claim 33 , wherein CAI is in a molecular complex with 1 to 60 wt % hydroxypropyl β-cyclodextrin in formulation, and wherein the formulation further comprises glutamate, a cellulosic polymer, a surfactant, and a pH from about 3.0 to about 8.0