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.

We claim: 
     
         1 . A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:
 (a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and   (b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation with hydroxypropyl β-cyclodextrin.   
     
     
         2 . A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:
 (a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and   (b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation.   
     
     
         3 . The method of  claim 1 , wherein the local ocular administration is assisted by sonophoresis or iontophoresis. 
     
     
         4 . The method of  claim 1 , wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound. 
     
     
         5 . The method of  claim 1 , wherein the local ocular administration is intravitreal injection. 
     
     
         6 . The method of  claim 5 , wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound. 
     
     
         7 . The method of  claim 1 , wherein the aqueous suspension formulation further comprises any one or combination of substances selected from the group consisting of pharmaceutically acceptable carriers, auxiliary substances, diluents, surfactants, detergents, stabilizers, buffers, excipients, isotonicity adjusting auxiliary substances, preservatives, antioxidants, and delivery-enhancing agents. 
     
     
         8 . The method of  claim 1 , wherein the aqueous formulation further comprises one or more polymeric surfactants, sterile water, saline or phosphate buffered saline. 
     
     
         9 . The method of  claim 8 , wherein the polymeric surfactants are polysorbates, cellulosic polymers, polyethylene glycols and polyoxyethylene-polyoxypropylene block copolymers. 
     
     
         10 . The method of  claim 1 , wherein the aqueous formulation is formulated to be isotonic with said patient's blood. 
     
     
         11 . The method of  claim 1 , wherein the aqueous formulation further comprises any one or combination of anionic, cationic or zwitterionic detergents. 
     
     
         12 . The method of  claim 1 , wherein the microparticulates of CAI are surface stabilized particles. 
     
     
         13 . The method of  claim 12 , wherein the surface stabilization of the surface stabilized particles of CAI is provided 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. 
     
     
         14 . The method of  claim 13 , wherein the aqueous suspension formulation further comprises any one or combination of materials selected from the group consisting of pharmaceutically acceptable diluents, viscosity-modifiers, and stabilizers. 
     
     
         15 . The method of  claim 1 , 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, wherein the ocular disease is neovascular disease. 
     
     
         16 . The method of  claim 1 , wherein the VEGF binding molecule is selected from the group consisting of ranibizumab (Lucentis®) and pegatanib (Macugen®). 
     
     
         17 . The method of  claim 2 , wherein the local ocular administration is assisted by sonophoresis or iontophoresis. 
     
     
         18 . The method of  claim 2 , wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound. 
     
     
         19 . The method of  claim 2 , wherein the local ocular administration is intravitreal injection. 
     
     
         20 . The method of  claim 19 , wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound. 
     
     
         21 . The method of  claim 2 , wherein the aqueous suspension formulation further comprises any one or combination of substances selected from the group consisting of pharmaceutically acceptable carriers, auxiliary substances, diluents, surfactants, detergents, stabilizers, buffers, excipients, isotonicity adjusting auxiliary substances, preservatives, antioxidants, and delivery-enhancing agents. 
     
     
         22 . The method of  claim 2 , wherein the aqueous formulation further comprises one or more polymeric surfactants, a sterile water, saline or phosphate buffered saline. 
     
     
         23 . The method of  claim 22 , wherein the polymeric surfactants are polysorbates, cellulosic polymers, polyethylene glycols and polyoxyethylene-polyoxypropylene block copolymers. 
     
     
         24 . The method of  claim 2 , wherein the aqueous formulation is formulated to be isotonic with said patient's blood. 
     
     
         25 . The method of  claim 2 , wherein the aqueous formulation further comprises any one or combination of anionic, cationic or zwitterionic detergents. 
     
     
         26 . The method of  claim 2 , wherein the microparticulates of CAI are surface stabilized particles. 
     
     
         27 . The method of  claim 26 , wherein the surface stabilization of the surface stabilized particles of CAI is provided 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. 
     
     
         28 . The method of  claim 27 , wherein the aqueous suspension formulation further comprises any one or combination of materials selected from the group consisting of pharmaceutically acceptable diluents, viscosity-modifiers, and stabilizers. 
     
     
         29 . The method of  claim 2 , 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, wherein the ocular disease is neovascular disease. 
     
     
         30 . The method of  claim 2 , wherein the VEGF binding molecule is selected from the group consisting of ranibizumab (Lucentis®) and pegatanib (Macugen®).