Combination treatment of ocular inflammatory disorders and diseases

Abstract

The present disclosure provides a combination of a fused bicyclic amine compound and an anti-inflammatory agent for treating ocular inflammatory disorders and diseases. Further provided are pharmaceutical compositions of the compound and the anti-inflammatory agent.

We claim: 
     
         1 . A method of treating an ocular inflammatory disorder or disease, comprising administering to a subject with an ocular inflammatory disorder or disease a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 X, Y and X are each independently N, CH or C with the NH 2  attached, wherein one of X, Y and Z is N; 
 R 1  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein
 R a  is each independently a C 1-6  alkyl, and 
 R b  is a substituted or unsubstituted C 1-6  alkyl; 
 
         R 2  is each independently a halogen, hydroxyl, carbamoyl, amino or unsubstituted or substituted aryl; and 
         p is 0, 1, 2 or 3; and 
         an anti-inflammatory agent; 
         wherein the ocular inflammatory disorder or disease is ocular rosacea, with or without meibomian gland dysfunction; and 
         the anti-inflammatory agent is prednisolone or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I) is the compound of structural formula (1a): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 R 1  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           wherein 
           R a  is each independently a C 1-6  alkyl, and 
           R b  is a substituted or unsubstituted C 1-6  alkyl; 
         
         R 2  is each independently a halogen, hydroxyl, carbamoyl, amino or unsubstituted or substituted aryl; and 
         p is 0, 1, or 2. 
       
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) is Compound (2): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 - 7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the anti-inflammatory agent is prednisolone. 
     
     
         9 . The method of  claim 1 , wherein the anti-inflammatory agent is prednisolone acetate. 
     
     
         10 - 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the compound is formulated with a cyclodextrin. 
     
     
         27 . The method of  claim 26 , wherein the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatives thereof, and combinations thereof. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the compound and the anti-inflammatory agent are administered concurrently by the same route. 
     
     
         30 . The method of  claim 1 , wherein the compound and the anti-inflammatory agent are administered concurrently by different routes. 
     
     
         31 . The method of  claim 1 , wherein the compound and the anti-inflammatory agent are administered sequentially by the same route. 
     
     
         32 . The method of  claim 1 , wherein the compound and the anti-inflammatory agent are administered sequentially by different routes. 
     
     
         33 - 37 . (canceled) 
     
     
         38 . The method of  claim 1 , wherein the anti-inflammatory agent is administered topically to the eye at least once per day, twice per day, three times per day, four times per day or more to achieve a therapeutic benefit. 
     
     
         39 . The method of  claim 1 , wherein the compound of formula (I) and anti-inflammatory agent are administered in alternating doses. 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the compound of formula (I) is present at a concentration of about 0.1% w/v to about 5% w/v. 
     
     
         42 - 92 . (canceled) 
     
     
         93 . The method of  claim 26 , wherein the cyclodextrin comprises a β-cyclodextrin or a derivative thereof. 
     
     
         94 . The method of  claim 26 , wherein the cyclodextrin is selected from carboxyalkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, sulfoalkylether-β-cyclodextrin, alkyl-β-cyclodextrin, and combinations thereof. 
     
     
         95 . The method of  claim 26 , wherein the cyclodextrin is sulfoalkylether-β-cyclodextrin or hydroxyalkyl-β-cyclodextrin. 
     
     
         96 . The method of  claim 95 , wherein the sulfoalkylether-β-cyclodextrin is sulfobutylether-β-cyclodextrin present at about 0.5% w/v to about 10% w/v.