Methods and compositions for enhanced drug delivery to the eye and extended delivery formulations

Abstract

The present invention comprises compounds and compositions thereof for enhanced drug delivery. Pro-drug and double pro-drug derivatives of corticosteroids non-steroid anti-inflammatory drugs (NSAIDs), and ruboxistaurin for delivery to the eye are provided. The compounds and compositions are useful for treating various ocular diseases, including ocular diseases effecting the posterior segments of the eye. In addition, the present invention is directed to particle in particle carrier formulations for sustained release of therapeutic agents.

What is claimed is: 
     
         1 . A corticosteroid prodrug, comprising:
 i) a corticosteroid; and   ii) a modification to the corticosteroid on either the A, B, C, or D ring;   wherein the modification increases the hydrophilicity of the corticosteroid.   
     
     
         2 . The prodrug according to  claim 1 , wherein the modification is capable of having at least one negatively charged terminal groups. 
     
     
         3 . The prodrug according to  claim 2 , wherein the modification is chosen from sulphates, sulfphones, sulfoxides, sulphonic acids, citrates, phosphates, phosphines, phosphodiesters, phosphonic acids succinates, or salts thereof. 
     
     
         4 . The prodrug according to  claim 1 , wherein the modification is chosen from:
 i) —COCH 2 COOH;   ii) —COCH 2 CH 2 COOH;   iii) —COCH 2 CH 2 CH 2 COOH;   iv) —COCH 2 CH 2 CH 2 CH 2 COOH; or   v) —COCH 2 CH(OH)COOH.   
     
     
         5 . The compound according to  claim 1 , wherein the modification has the formula:
   —PO(OH) 2.  
   
     
     
         6 . A therapeutic agent of the formula: 
       
         
           
           
               
               
           
         
         wherein R is a unit that increases the hydrophilicity of the compound. 
       
     
     
         7 . The compound according to  claim 6 , wherein R is chosen from sulphate, sulfphone, sulfoxide, sulphonic acis, citrate, phosphate, phosphine, phosphodiester, phosphonic acid succinate, or salts thereof. 
     
     
         8 . The compound according to  claim 6 , wherein R provides an ester of a di-carboxylic acid. 
     
     
         9 . The compound according to  claim 8 , wherein R is chosen from:
 i) —COCH 2 COOH;   ii) —COCH 2 CH 2 COOH;   iii) —COCH 2 CH 2 CH 2 COOH;   iv) —COCH 2 CH 2 CH 2 CH 2 COOH; or   v) —COCH 2 CH(OH)COOH.   
     
     
         10 . The compound according to  claim 6 , wherein the —COOH unit is further linked to a taurine. 
     
     
         11 . A composition for drug delivery, the composition comprising:
 a) an inner particle; and   b) an outer particle;   wherein the composition comprises a therapeutic agent of the formula:   
       
         
           
           
               
               
           
         
         wherein R is a unit that increases the hydrophobicity of the compound; wherein further the inner particle has a diameter of approximately 1 nm to approximately 999 nm, and wherein the outer particle has a diameter of approximately 1 to approximately 500 μm; and wherein the therapeutic agent is bound to the surface of the inner particle, bound to the surface of the outer particle, encapsulated in the inner particle, encapsulated in the outer particle, present in the pores of the outer particle or a combination thereof. 
       
     
     
         12 . The composition according to  claim 11 , wherein the inner particle comprises polylactide (PLA), poly(glycolic acid) (PGA), co-polymer of lactic and glycolic acid (PLGA), cellulose derivatives, or chitosan. 
     
     
         13 . The composition according to  claim 12 , wherein the inner particle comprises polylactide (PLA). 
     
     
         14 . The compositon according to  claim 11 , wherein the outer particle comprises polyamides, polycarbonates, polyalkylene glycols, polyalkylene oxides, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinylpyrrolidone, polyglycolides, and copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose poly(methyl methacrylate), poly(ethylmethacrylate), poly(butylmethacrylate), poly(vinyl alcohols), poly(vinyl acetate), or polyvinylpryrrolidone. 
     
     
         15 . The composition according to  claim 11 , wherein the outer particle comprises lactide-co-glycolide. 
     
     
         16 . The compound according to  claim 11 , wherein R is chosen from sulphate, sulfphone, sulfoxide, sulphonic acis, citrate, phosphate, phosphine, phosphodiester, phosphonic acid succinate, or salts thereof. 
     
     
         17 . The compound according to  claim 11 , wherein R provides an ester of a di-carboxylic acid. 
     
     
         18 . The compound according to  claim 17 , wherein R is chosen from:
 i) —COCH 2 COOH;   ii) —COCH 2 CH 2 COOH;   iii) —COCH 2 CH 2 CH 2 COOH;   iv) —COCH 2 CH 2 CH 2 CH 2 COOH; or   v) —COCH 2 CH(OH)COOH.   
     
     
         19 . A method for treating degenerative, vascular, infectious, angiogenic, and inflammatory diseases, comprising administering to a subject a prodrug according to  claim 1 . 
     
     
         20 . A method for treating degenerative, vascular, infectious, angiogenic, and inflammatory diseases, comprising administering to a subject a composition according to  claim 11 .