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-3-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-3-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-3-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.