Formulations for treatment of dry eye disease

Abstract

The present invention provides a reproxalap ophthalmic solution, and methods of using the same for treating dry eye disease.

1 - 10 . (canceled) 
     
     
         11 . A method of treating dry eye disease in a subject, comprising topically administering to an eye of a subject with dry eye disease a therapeutically effective amount of an ophthalmic solution of claim  1  comprising reproxalap, or a pharmaceutically acceptable salt thereof, at about 0.2% w/v to about 0.3% w/v, and a pharmaceutically acceptable excipient comprising a cyclodextrin, wherein the cyclodextrin is selected from a hydroxyalkyl derivative of β-or γ-cyclodextrin, randomly methylated β-cyclodextrin, sulfobutylether β-cyclodextrin, sulfobutylether γ-cyclodextrin, a branched β- or γ-cyclodextrin derivative, and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein the reproxalap and cyclodextrin are present in a ratio of about 1:2, about 1:3, about 1:4, or about 1:5 on a mole:mole basis, wherein the ophthalmic solution is topically administered to the eye with dry eye disease four times a day in an initiation phase or exacerbation phase followed by three times a day, twice a day, or once a day, or as needed in a maintenance phase. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein the ophthalmic solution is topically administered to the eye with dry eye disease three times a day in the maintenance phase. 
     
     
         14 . The method of  claim 11 , wherein the ophthalmic solution is topically administered to the eye with dry eye disease two times a day in the maintenance phase. 
     
     
         15 . The method of  claim 11 , wherein the ophthalmic solution is topically administered to the eye with dry eye disease once a day in the maintenance phase. 
     
     
         16 . The method of  claim 11 , wherein the treatment is for at least 12 weeks. 
     
     
         17 . The method of  claim 11 , wherein the ophthalmic solution is topically administered to the eye with dry eye disease four times a day for about 2 to 6 weeks in an initiation phase or exacerbation phase followed by administration three times a day, two times a day, once a day, or as needed in a maintenance phase. 
     
     
         18 . The method of  claim 17 , wherein the maintenance phase is administration three times a day, two times a day, once a day, or as needed for about 6 to 10 weeks. 
     
     
         19 . The method of  claim 18 , wherein the maintenance phase is administration two times a day. 
     
     
         20 . A method of treating dry eye disease in a subject, comprising:
 topically administering to an eye of a subject with dry eye disease a therapeutically effective amount of an ophthalmic solution comprising reproxalap, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient comprising a cyclodextrin,   wherein the reproxalap is at about 0.2% w/v to about 0.3% w/v, and the cyclodextrin is selected from a hydroxyalkyl derivative of β- or γ-cyclodextrin, randomly methylated β-cyclodextrin, sulfobutylether β-cyclodextrin, sulfobutylether γ-cyclodextrin, and a branched β- or γ-cyclodextrin derivative, and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein the reproxalap and cyclodextrin are present in a ratio of about 1:2, about 1:3, about 1:4, or about 1:5 on a mole:mole basis, and   wherein the ophthalmic solution is administered four times a day.   
     
     
         21 . The method of  claim 20 , wherein reproxalap is at about 0.25% w/v and the pharmaceutically acceptable excipient comprises sulfobutylether-β-cyclodextrin hydroxypropyl-β-cyclodextrin, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is at about 7% w/v. 
     
     
         22 . The method of  claim 20 , wherein reproxalap is at a concentration of 0.25% w/v and the pharmaceutically acceptable excipient comprises sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is at about 11% w/v. 
     
     
         23 . A method of treating dry eye disease in a subject, comprising topically administering to an eye of a subject with dry eye disease a therapeutically effective amount of an ophthalmic solution comprising reproxalap, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient comprising a cyclodextrin,
 wherein the reproxalap is at about 0.2% w/v to about 0.3% w/v, and the cyclodextrin is selected from a hydroxyalkyl derivative of β- or γ-cyclodextrin, randomly methylated β-cyclodextrin, sulfobutylether β-cyclodextrin, sulfobutylether γ-cyclodextrin, and a branched β- or γ-cyclodextrin derivative, and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein the reproxalap and cyclodextrin are present in a ratio of about 1:2, about 1:3, about 1:4, or about 1:5 on a mole:mole basis, and   wherein the ophthalmic solution is administered at least four times a day in an initiation phase or exacerbation phase, followed by three times a day, two times a day, once a day, or as needed in a maintenance phase.   
     
     
         24 . The method of  claim 23 , wherein the ophthalmic solution is administered two times a day in the maintenance phase. 
     
     
         25 . The method of  claim 23 , wherein reproxalap is at about 0.25% w/v and the pharmaceutically acceptable excipient comprises sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof; or a pharmaceutically acceptable salt thereof of, is at about 7% w/v. 
     
     
         26 . The method of  claim 23 , wherein reproxalap is at a concentration of 0.25% w/v and the pharmaceutically acceptable excipient comprises sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is at about 11% w/v. 
     
     
         27 . The method of  claim 23 , wherein the ophthalmic solution is administered at a dose strength to achieve an early onset of effect. 
     
     
         28 . The method of  claim 27 , wherein the early onset effect is for dry eye symptoms of one or more of: ocular dryness, itchiness, tearing, burning, stinging, grittiness, cloudy vision, sensitivity to environment, and stringy ocular secretion. 
     
     
         29 . The method of  claim 27 , wherein the early onset of effect is for dry eye signs of one or more of: ocular vital staining, tear film break-up time, tear osmolarity, and tear volume. 
     
     
         30 . The method of  claim 11 , wherein the ophthalmic solution further comprises a tonicity agent selected from the group consisting of dextrose, potassium chloride, propylene glycol, and sodium chloride. 
     
     
         31 . The method of  claim 30 , wherein the tonicity agent is at a concentration of about 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, or 0.1% w/v. 
     
     
         32 . The method of  claim 30 , wherein the tonicity agent comprises about 0.2 to about 0.3% w/v sodium chloride. 
     
     
         33 . The method of  claim 11 , wherein the reproxalap and cyclodextrin are present in a ratio of about 1:3 on a mole:mole basis. 
     
     
         34 . The method of  claim 11 , wherein the reproxalap and cyclodextrin are present in a ratio of about 1:4 on a mole:mole basis. 
     
     
         35 . The method of  claim 11 , wherein reproxalap, or a pharmaceutically acceptable salt thereof, is at about 0.25% w/v, and the cyclodextrin comprises sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof; or a pharmaceutically acceptable salt thereof, at about 7% w/v. 
     
     
         36 . The method of  claim 11 , wherein reproxalap, or a pharmaceutically acceptable salt thereof, is at about 0.25% w/v, and the cyclodextrin comprises sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a mixture thereof; or a pharmaceutically acceptable salt thereof, at about 11% w/v. 
     
     
         37 . The method of  claim 30 , wherein the reproxalap and cyclodextrin are present in a ratio of about 1:4 on a mole:mole basis. 
     
     
         38 . The method of  claim 11 , wherein the cyclodextrin is selected from a hydroxyethyl or hydroxypropyl derivative of β-cyclodextrin or γ-cyclodextrin, glucosyl-β-cyclodextrin, glucosyl-γ-cyclodextrin, sulfobutylether-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin; or a pharmaceutically acceptable salt thereof.