Therapeutic agent for keratoconjunctive disorders

Abstract

The present invention addresses the problem of providing a novel therapeutic agent for keratoconjunctive disorders. As a means for solving the problem, a therapeutic agent for keratoconjunctive disorders which contains a RARγ agonist as an active ingredient is provided. The therapeutic agent exhibits an excellent ameliorating effect in a keratoconjunctive disorder model, and is therefore useful as a therapeutic agent for keratoconjunctive disorders such as corneal ulcer, corneal epithelial abrasion, keratitis, dry eye, conjunctivitis, chronic superficial keratitis, corneal erosion, persistent corneal disorders, superficial punctate keratopathy, corneal epithelial defects, conjunctival epithelial defects, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis, filamentary keratoconjunctivitis, infectious keratitis, noninfectious keratitis, infectious conjunctivitis and noninfectious conjunctivitis. The therapeutic agent is also useful as a therapeutic agent for corneal scarring and conjunctival scarring both associated with keratoconjunctive disorders.

1 . An ophthalmic ointment comprising 0.3% (w/w) (E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoic acid (R667), or an ester or salt thereof, 10% (w/w) liquid paraffin, and white petrolatum. 
     
     
         2 . A method of preventing or treating keratoconjunctivitis sicca in a subject in need thereof, comprising administering to an eye of the subject an RARγ agonist, or an ester or salt thereof, in an amount effective to prevent or treat keratoconjunctivitis sicca, wherein said RARγ agonist is (E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoic acid (R667), 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene acid (CD437), 3-fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)acetylamino]benzoic acid (BMS961), (2E)-3-(4-carboxyphenyl)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-2-propene-1-one oxime (NRX204647), 4-[7-(1-adamantyl)-6-hydroxynaphthalene-2-yl] benzoic acid (CD1530), an ester thereof, or a salt thereof. 
     
     
         3 . The method of  claim 2 , wherein said RARγ agonist is 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene acid (CD437), an ester thereof, or a salt thereof. 
     
     
         4 . The method of  claim 2 , wherein said RARγ agonist is 3-fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)acetylamino]benzoic acid (BMS961), an ester thereof, or a salt thereof. 
     
     
         5 . The method of  claim 2 , wherein said RARγ agonist is (2E)-3-(4-carboxyphenyl)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-2-propene-1-one oxime (NRX204647), an ester thereof, or a salt thereof. 
     
     
         6 . The method of  claim 2 , wherein said RARγ agonist is 4-[7-(1-adamantyl)-6-hydroxynaphthalene-2-yl] benzoic acid (CD1530), an ester thereof, or a salt thereof. 
     
     
         7 . The method of  claim 2 , wherein the RARγ agonist is in the form of a powder, syrup, granule, liquid formulation, suspension, emulsion, ointment, or instillation. 
     
     
         8 . The method of  claim 7 , wherein the ointment is an ophthalmic ointment. 
     
     
         9 . The method of  claim 8 , wherein the ointment comprises a solubilizer. 
     
     
         10 . The method of  claim 9 , wherein the solubilizer is selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol 4000. 
     
     
         11 . The method of  claim 10 , wherein the solubilizer is polysorbate 80. 
     
     
         12 . The method of  claim 8 , wherein the concentration of the RARγ agonist in the ophthalmic ointment is from 0.00001 to 10% (w/w), from 0.0001% to 3% (w/w), or from 0.001% to 1% (w/w). 
     
     
         13 . The method of  claim 7 , wherein the RARγ agonist is in the form of a liquid formulation. 
     
     
         14 . The method of  claim 13 , wherein the liquid formulation comprises a solubilizer. 
     
     
         15 . The method of  claim 14 , wherein the solubilizer is selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol 4000. 
     
     
         16 . The method of  claim 15 , wherein the solubilizer is polysorbate 80. 
     
     
         17 . The method of  claim 13 , wherein the concentration of the RARγ agonist in the liquid formulation is from 0.000001-10% (w/v), from 0.00001% to 3% (w/v), from 0.0001% to 1% (w/v), 0.3% (w/v), 0.5% (w/v), or 1% (w/v). 
     
     
         18 . The method of  claim 2 , wherein the RARγ agonist is administered to the subject in one or more daily doses. 
     
     
         19 . The method of  claim 2 , wherein the administering is administering by instillation.