Pharmaceutical compositions comprising an integrin alpha4 antagonist for use in treating ocular inflammatory conditions

Abstract

The invention relates to antagonists of integrin α4 and their use in pharmaceutical compositions, primarily topically administered ophthalmic compositions. The pharmaceutical compositions are useful for treating ocular inflammatory conditions, such as dry eye disease, non-infectious uveitis (e.g., anterior, intermediate, posterior, pan-uveitis), non-infectious conjunctivitis, iritis, or scleritis in animals, and particularly mammals, including humans.

1 . A method of treatment, comprising:
 ocularly administering a pharmaceutical composition comprising an effective amount of a compound of formula I   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, hydrate, solvate, polymorph, optical isomer, racemate, diastereoisomer or enantiomer thereof, to a human subject suffering from an ocular inflammatory condition,
 wherein the pharmaceutical composition is administered with an individual dose of the compound in the range of from 0.01 mg to 5 mg, in each affected eye. 
 
     
     
         2 . The method of  claim 1 , wherein the ocular inflammatory condition is selected from the group consisting of dry eye disease, noninfectious uveitis, non-infectious conjunctivitis, iritis, and scleritis. 
     
     
         3 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is a potassium salt. 
     
     
         4 . The method of  claim 1 , wherein the pharmaceutical composition is administered in a volume between 10 μL and 100 μL. 
     
     
         5 . The method of  claim 4 , wherein the pharmaceutical composition contains between 1 mg/mL and 100 mg/mL of the compound of formula I or the pharmaceutically acceptable salt, hydrate, solvate, polymorph, optical isomer, racemate, diastereoisomer or enantiomer thereof. 
     
     
         6 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound in the range from 1 mg to 5 mg, in each affected eye. 
     
     
         7 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound in the range from 0.1 mg to 5 mg, in each affected eye. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound in the range from 1 mg to 2 mg, in each affected eye. 
     
     
         9 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound in the range from 0.5 mg to 2 mg, in each affected eye. 
     
     
         10 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound in the range from 0.1 mg to 2 mg, in each affected eye. 
     
     
         11 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound in the range from 0.01 mg to 2 mg, in each affected eye. 
     
     
         12 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound that is 0.01 mg, 0.1 mg, 0.5 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg, 2.4 mg, 2.6 mg, 2.8 mg, 3.0 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, or 4.0 mg, in each affected eye. 
     
     
         13 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound at 1.4 mg, in each affected eye. 
     
     
         14 . The method of  claim 1 , wherein the pharmaceutical composition is administered with an individual dose of the compound at 0.8 mg, in each affected eye. 
     
     
         15 . The method of  claim 1 , wherein the pharmaceutical composition is administered topically. 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutical composition is administered subconjunctivally, intracamerally, intravitreally, subtenon, subretinally, subchoroidally, or suprachoroidally. 
     
     
         17 . The method of  claim 1 , wherein the pharmaceutical composition is administered in the form of an eye drop, gel, ointment, spray, or mist. 
     
     
         18 . The method of  claim 1 , further comprising co-administering one or more additional therapeutic agents selected from the group consisting of (a) cyclosporin A; (b) a steroid selected from the group consisting of dexamethasone base, dexamethasone phosphate, difluprednate, fluocinolone, fluorometholone base, fluorometholone acetate, loteprednol, prednisolone acetate, prednisolone phosphate, rimexolone, and triamcinolone acetonide; (c) a non-steroidal anti-inflammatory agent selected from the group consisting of bromfenac, diclofenac, flurbiprofen, ketorolac, and nepafenac; and (d) an LFA-1 antagonist. 
     
     
         19 . The method of  claim 18 , wherein the co-administration is in a same or separate pharmaceutical composition.