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 . A method for treating a patient suffering from an ocular disease or symptom comprising: 
 diagnosing an ocular disease or symptom in a patient;    local ocularly administering to said patient a sterile, aqueous formulation comprising a therapeutically effective amount of a CAI compound.    
   
   
       2 . The method of  claim 1 , wherein the CAI compound is selected from the group consisting of CAI free base; CAI acid addition salt, and CAI prodrug.  
   
   
       3 . The method of  claim 1 , wherein said ocular disease or symptom is selected from the group consisting of: age-related macular degeneration, diabetic retinopathy, retinal vascular occlusion, choroidal and retinal angiomatous proliferation, chronic glaucoma, retinal detachment, sickle cell retinopathy, rubeosis iritis, uveitis, neoplasms, Fuch's heterochromic iridocyclitis, neovascular glaucoma, corneal neovascularization, neovascularization resulting from combined vitrectomy and lensectomy, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia, retinal artery/vein occlusion, contusive ocular injury, retinopathy of prematurity, retinitis pigmentosa, endophthalmitis, infectious diseases, inflammatory but non-infectious diseases, ocular ischemia syndrome, 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, Auto somal recessive retinitis pigmentosa, Leber's amaurosis congenital, X-linked recessive pigmented retinopathies, secondary pigmented retinopathies, autosomal dominant pigmented retinopathies, Paget's disease, Charcot-Marie-Tooth disease, Steinert's disease, Pierre-Marie syndrome, Autosomal dominant pigmented retinopathies, mannosidoses, mucopolysccharidoses, Batten's disease, Refsum's disease, Usher syndrome, X-linked recessive pigmented retinopathies, Hunter syndrome, conjunctivitis, allergic conjunctivitis, chronic conjunctivitis, contact lens-associated conjunctivitis, conjunctival ulceration, drug-related conjunctivitis, uveitis, uveoretinitis, age-related macular panuveitis, retinitis, degeneration diabetes mellitus, infectious choroiditis, vitreitis, tuberculosis syphilis, cytomegalo-Scleritis/Episcleritis, virus retinitis, UV Iridocyclitis, sarcoidosis, and inflammatory bowel disease, corneal ulceration disease, and von Hippel-Lindau syndrome.  
   
   
       4 . The method of  claim 1 , wherein the local ocular administration is by topical administration or ocular injection.  
   
   
       5 . The method of  claim 4 , 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.  
   
   
       6 . The method of  claim 1 , wherein the therapeutically effective amount of the CAI compound is from 0.1 mg/mL to 100 mg/mL of formulation.  
   
   
       7 . The method of  claim 6 , wherein the therapeutically effective amount of the CAI compound is from 1 mg/mL to 60 mg/mL of formulation.  
   
   
       8 . The method of  claim 1 , 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.  
   
   
       9 . The method of  claim 1 , wherein the sterile, aqueous formulation is a time-release formulation.  
   
   
       10 . An aqueous, sterile formulation comprising a CAI compound, wherein said 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.  
   
   
       11 . The formulation of  claim 10 , wherein the CAI compound is selected from the group consisting of CAI free base; CAI acid addition salt, and CAI prodrug.  
   
   
       12 . The formulation of  claim 11 , 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.  
   
   
       13 . The formulation of  claim 10 , further comprising 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.  
   
   
       14 . The formulation of  claim 10 , wherein said formulation is selected from the group consisting of: Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5, and Formulation 6.  
   
   
       15 . The formulation of  claim 10 , wherein the formulation consists of 1 mg/mL to 60 mg/mL of the CAI compound.  
   
   
       16 . A method for preparing a sterile, aqueous formulation comprising a therapeutically effective amount of a CAI compound, wherein the therapeutically effective amount is from about 0.1 mg/mL to 100 mg/mL of the CAI compound in the formulation; said method comprising: 
 (a) in a solvent, mixing said CAI compound with any or combination of excipients selected from the group consisting of: pure triglyceride oils, diglycerides, monoglycerides, mixed glycerides, lipophilic surfactants, hydrophilic surfactants, and water-soluble cosolvents, to form a soluble CAI compound;    (b) adding an aqueous solution to the soluble CAI compound; and    (c) subjecting the aqueous solution to heating.    
   
   
       17 . The method of  claim 16 , wherein the CAI compound is selected from the group consisting of CAI free base; CAI acid addition salt, and CAI prodrug.  
   
   
       18 . The method of  claim 16 , wherein the CAI compound is mixed with oleic acid, soybean oil, and Tween-80.  
   
   
       19 . The method of  claim 16 , wherein the heating is performed at 121° C.  
   
   
       20 . The method of  claim 16 , further comprising the step of subjecting the aqueous solution to pressure.  
   
   
       21 . The method of  claim 20 , wherein the pressure is at 15 psi.  
   
   
       22 . The method of  claim 16 , wherein the solvent is absolute ethanol.  
   
   
       23 . The method of  claim 16 , wherein the aqueous solution is water, wherein said method further comprises the step of removing the solvent.  
   
   
       24 . The method of  claim 16 , further comprising the step of adding any one or combination of the following to the aqueous solution: pharmaceutically acceptable carriers, pharmaceutically acceptable auxiliary substances, diluents, surfactants, detergents, stabilizers, carriers, and delivery-enhancing agents.  
   
   
       25 . The method of  claim 16 , wherein the therapeutically effective amount of the CAI compound is 1 mg/mL to 60 mg/mL.