Ocular formulations for drug-delivery to the posterior segment of the eye

Abstract

The present invention relates to topical formulations comprising a compound of the following formula: for treating ocular neovascularization. The Compound-I is present in a solution or a suspension in about 0.005% to about 5.0% w/v, such that the solution or suspension delivers the compound at the posterior segment of the eye for inhibiting VEGF in the retina and/or the choroid.

What is claimed is: 
     
         1 . A topical ocular formulation, the formulation comprising:
 a. an active agent of Formula II:   
       
         
           
           
               
               
           
         
         b. or a pharmaceutically acceptable salt thereof, and 
         c. and pharmaceutically acceptable excipients; 
         wherein the active agent or the pharmaceutically acceptable salt is present in about 0.005% to about 5.0% w/v such that the formulation forms a solution or a suspension. 
       
     
     
         2 . The formulation of  claim 1 , comprising a solubilizing agent. 
     
     
         3 . The formulation of  claim 2 , wherein the solubilizing agent is cyclodextrin selected from the group consisting of 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, trimethyl-γ-cyclodextrin, and combinations thereof. 
     
     
         4 . The formulation of  claim 3 , wherein the pharmaceutically acceptable salt is a hydrochloride salt provided by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The formulation of  claim 3 , wherein the solubilizing agent is 2-hydroxypropyl-β-cyclodextrin or β-cyclodextrin sulfobutyl ether. 
     
     
         6 . The formulation of  claim 3 , comprising about 0.005%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, or 5.0% w/v of the active agent or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The formulation of  claim 3 , comprising one or more of benzalkonium chloride (BAK), sodium chloride, and a pH adjusting agent. 
     
     
         8 . The formulation of  claim 1 , comprising about 0.005%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, or 5.0% w/v of the active agent or a pharmaceutically acceptable salt thereof, and about 0.3%-1% w/v tromethamine. 
     
     
         9 . The formulation of  claim 1 , comprising about 0.005%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, or 5.0% w/v of the active agent or a pharmaceutically acceptable salt thereof, about 0.3%-1% w/v tromethamine, and about 0.005% w/v benzalkonium chloride (BAK). 
     
     
         10 . The formulation of  claim 1 , having a pH value of about 4.5 to 7.5 at or under about 40° C. 
     
     
         11 . The formulation of  claim 1 , having a pH value of about 6.0 at or under about 40° C. 
     
     
         12 . The formulation of  claim 1 , having a pH value of about 5.0 to 7.0 at or under about 40° C. 
     
     
         13 . The formulation of  claim 1 , wherein the formulation is suitable for treating ocular neovascularization. 
     
     
         14 . A method of treating a subject with a posterior segment disease of the eye with the formulation of  claim 1 , wherein the disease is selected from the group consisting of: diabetic retinopathy, age-related macular degeneration (AMD), pathologic choroidal neovascularization (CNV), pathologic retinal neovascularization, uveitis, retinal vein occlusion, ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, retinopathy of prematurity, Coat's disease, sickle cell retinopathy, and neovascular glaucoma. 
     
     
         15 . The method according to  claim 14 , wherein the diabetic retinopathy is background diabetic retinopathy, proliferative diabetic retinopathy, or diabetic macular edema. 
     
     
         16 . The method according to  claim 14 , wherein the AMD is neovascular AMD, dry AMD, or Geographic Atrophy. 
     
     
         17 . The method according to  claim 16 , wherein the neovascular AMD is wet or exudative AMD. 
     
     
         18 . The method according to  claim 14 , wherein the CNV is related to high myopia, trauma, sickle cell disease, ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, drusen of the optic nerve, or some retinal dystrophies. 
     
     
         19 . The method according to  claim 14 , wherein the pathologic retinal neovascularization is related to sickle cell retinopathy, Eales disease, ocular ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteriolitis; birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis. 
     
     
         20 . The method according to  claim 14 , wherein retinal vein occlusion is central or branch occlusion. 
     
     
         21 . The method according to  claim 14 , comprising administering the formulation 1, 2, 3, or 4 times daily. 
     
     
         22 . The method according to  claim 14 , comprising administering the formulation 2 or 3 times daily. 
     
     
         23 . The method according to  claim 14 , comprising administering twice daily the formulation containing 0.005%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, or 5.0% w/v of the active agent. 
     
     
         24 . The method according to  claim 23 , wherein the formulation is administered to one eye or both eyes. 
     
     
         25 . The method according to  claim 23 , wherein the formulation comprises a solubilizing agent. 
     
     
         26 . The method according to  claim 25 , wherein the solubilizing agent is cyclodextrin selected from the group consisting of selected from the group consisting of 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, trimethyl-γ-cyclodextrin, and combinations thereof. 
     
     
         27 . The method according to  claim 26 , wherein the solubilizing agent is 2-hydroxypropyl-β-cyclodextrin or β-cyclodextrin sulfobutyl ether.