Ophthalmic formulations

Abstract

The present invention relates to an ophthalmic formulation which comprises a fine particle of Compound A in an aqueous suspension and a manufacturing process thereof. More specifically, the present invention relates to a topically applied ophthalmic aqueous suspension which is obtainable by suspending fine particles of Compound A in an aqueous vehicle containing a surfactant and boric acid. The invention also provides processes for making the ophthalmic formulations and to methods of use thereof.

1 - 67 . (canceled) 
     
     
         68 . An ophthalmic formulation comprising:
 (a) an aqueous suspension of micronized Compound A (((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate),   (b) boric acid from about 0.5 to about 1.0% (w/v),   (c) a second therapeutic ophthalmic agent,   (d) a surfactant,   (e) a phosphate buffer that maintains the pH from about 6.0 to about 7.0; and   wherein the formulation is stable for at least 6 months at 5° C. and has an X 90  particle size of less than about 25 microns.   
     
     
         69 . The ophthalmic formulation of  claim 68 , wherein Compound A is present in the ophthalmic formulation between about 0.5 to about 5% (w/v). 
     
     
         70 . The ophthalmic formulation of  claim 69 , wherein Compound A is present in the ophthalmic formulation at about 5% (w/v). 
     
     
         71 . The ophthalmic formulation of  claim 68 , wherein the boric acid is present at about 0.8% (w/v). 
     
     
         72 . The ophthalmic formulation of  claim 68 , wherein the second ophthalmic agent is a prostaglandin analog. 
     
     
         73 . The ophthalmic formulation of  claim 72 , wherein the prostaglandin analog is latanoprost between about 1-200 μg/ml. 
     
     
         74 . The ophthalmic formulation of  claim 73 , wherein the latanoprost is present in about 50 μg/ml. 
     
     
         75 . The ophthalmic formulation of  claim 68 , wherein the surfactant is selected from polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, wherein the surfactant is between about 0.01 to about 0.1%, w/v. 
     
     
         76 . The ophthalmic formulation of  claim 68 , wherein the surfactant is polysorbate 80. 
     
     
         77 . The ophthalmic formulation of  claim 68 , wherein the formulation further includes a preservative between about 0.005 and about 0.05% (w/v). 
     
     
         78 . The ophthalmic formulation according to  claim 77 , wherein the preservative is benzalkonium chloride between about 0.005 and about 0.02% (w/v). 
     
     
         79 . The ophthalmic formulation according to  claim 68 , wherein the phosphate buffer is present at about 10 mM. 
     
     
         80 . The ophthalmic formulation according to  claim 68 , further comprising a suspending agent selected from the group consisting of sodium carboxymethylcellulose (NaCMC), hydroxyethylcellulose, hypromellose, polyvinyl alcohol, povidone, carbomers, hyaluronic acid and its salts, chondroitin sulfate and its salts, natural gums, and other pharmaceutically acceptable polymers. 
     
     
         81 . The ophthalmic formulation according to  claim 80 , wherein the suspending agent is selected from sodium carboxymethylcellulose (NaCMC) or hypromellose. 
     
     
         82 . The ophthalmic formulation according to  claim 68 , wherein the pH is about 6.5±0.1. 
     
     
         83 . The ophthalmic formulation according to  claim 68 , further comprising edetate disodium between 0.01-0.08% (w/v). 
     
     
         84 . The ophthalmic formulation of  claim 68 , wherein the formulation is stable for at least 3 to 6 months at 25° C. 
     
     
         85 . The ophthalmic formulation of  claim 68 , wherein the formulation is stable for at least 2 years at 5° C. 
     
     
         86 . The ophthalmic formulation according to  claim 68 , comprising the following ingredients: 
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Compound A, micronized 
                   0.5-5% 
                   (w/v) 
                 
                     
                   A prostaglandin analog 
                   1-200 
                   μg/ml 
                 
                     
                   A suspending agent 
                   0.5-1.5% 
                   (w/v) 
                 
                     
                   Boric acid 
                   0.05-2% 
                   (w/v) 
                 
                     
                   A preservative 
                   0.01-0.05% 
                   (w/v) 
                 
                     
                   A surfactant 
                   0.01-0.1% 
                   (w/v) 
                 
                     
                   A phosphate buffering agent 
                   0.05-0.5% 
                   (w/v), and 
                 
                 
                 
                 
               
                     
                   NaOH/HCl (pH adjustment) 
                   pH 6.0-7.0 ± 0.1; 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
               
            
             
                
                
               
            
           
         
         wherein Compound A is ((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate, and the formulation is stable for at least 12 months at 5° C. 
       
     
     
         87 . The ophthalmic formulation according to  claim 86 , wherein the formulation comprises about 5.0% (w/v) Compound A. 
     
     
         88 . The ophthalmic formulation according to  claim 86 , wherein the prostaglandin analog is latanoprost. 
     
     
         89 . The ophthalmic formulation according to  claim 88 , wherein the formulation comprises about 50 μg/ml latanoprost. 
     
     
         90 . A kit or packaged formulation comprising a topically applicable ophthalmic formulation of  claim 68 . 
     
     
         91 . An ophthalmic formulation consisting essentially of:
 (a) an aqueous suspension of micronized Compound A (((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate),   (b) latanoprost,   (c) boric acid from about 0.5 to about 1.0% (w/v) in the ophthalmic formulation,   (d) a surfactant,   (e) a suspending agent,   (f) a preservative,   (g) a chelating agent,   (h) a salt, and   (i) a phosphate buffer that maintains the pH from about 6.0 to about 7.0;   wherein the formulation is stable for at least 6 months at 5° C.   
     
     
         92 . An ophthalmic formulation consisting essentially of:
 (a) an aqueous suspension of micronized Compound A (((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate) at about 3% to about 5% (w/v),   (b) latanoprost at about 50 to 200 μg/ml,   (c) boric acid from about 0.5 to about 1.0% (w/v) in the ophthalmic formulation,   (d) Polysorbate 80 at about 0.01 to about 0.1%, w/v,   (e) Sodium carboxymethylcellulose,   (f) Benzalkonium Chloride at about 0.005 and about 0.02% (w/v),   (g) edetate disodium at 0.01-0.08% (w/v),   (h) NaCl, and   (i) a phosphate buffer that maintains the pH from about 6.0 to about 7.0;   wherein the formulation is stable for at least 6 months at 5° C.