Ophthalmic compositions

Abstract

The present disclosure provides an ophthalmic composition comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.

1 . An ophthalmic formulation, consisting essentially of:
 A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.02 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.8; or 
   F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.008 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.9. 
   
     
     
         2 . The ophthalmic formulation of  claim 1 , wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate. 
     
     
         3 . The ophthalmic formulation of  claim 1 , wherein the mannitol is D-mannitol. 
     
     
         4 . The ophthalmic formulation of  claim 1 , wherein the polyoxyl 40 stearate is Myrj-52. 
     
     
         5 . The ophthalmic formulation of  claim 1 , wherein the polyethoxylated castor oil is Cremophor RH 40. 
     
     
         6 . The ophthalmic formulation of  claim 1 , which is a topical ophthalmic formulation. 
     
     
         7 . The ophthalmic formulation of  claim 1 , which is packaged in a unit dose form. 
     
     
         8 . The ophthalmic formulation of  claim 1 , which is packaged in a multidose form. 
     
     
         9 . The ophthalmic formulation of  claim 1 , which is in a plastic storage container. 
     
     
         10 . The ophthalmic formulation of  claim 1 , consisting of:
 A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.02 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
   4.7 weight/volume % of mannitol,
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.8; or 
   F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.008 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.9. 
   
     
     
         11 . A method of treating an ophthalmic disease in a subject in need thereof, comprising topically administering to an eye of the subject an ophthalmic formulation consisting essentially of:
 A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.02 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.8; or 
   F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.008 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.9. 
   
     
     
         12 - 24 . (canceled) 
     
     
         25 . The method of  claim 11 , wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate. 
     
     
         26 . The method of  claim 11 , wherein the mannitol is D-mannitol. 
     
     
         27 . The method of  claim 11 , wherein the polyoxyl 40 stearate is myrj-52. 
     
     
         28 . The method of  claim 11 , wherein the polyethoxylated castor oil is cremophor RH 
     
     
         40 . 
     
     
         29 . The method of  claim 11 , wherein the ophthalmic formulation is a topical ophthalmic formulation. 
     
     
         30 . The method of  claim 11 , wherein the ophthalmic formulation is packaged in a unit dose form. 
     
     
         31 . The method of  claim 11 , wherein the ophthalmic formulation is packaged in a multidose form. 
     
     
         32 . The method of  claim 11 , wherein the ophthalmic formulation is in a plastic storage container. 
     
     
         33 . The method of  claim 11 , wherein the ophthalmic formulation consists of:
 A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.02 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.8; or 
   F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.008 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.9. 
   
     
     
         34 . A method of treating glaucoma in a subject in need thereof, comprising topically administering to an eye of the subject an ophthalmic formulation consisting essentially of:
 A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.02 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.8; or 
   F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.008 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.9. 
   
     
     
         35 . The method of  claim 34 , wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate. 
     
     
         36 . The method of  claim 34 , wherein the mannitol is D-mannitol. 
     
     
         37 . The method of  claim 34 , wherein the polyoxyl 40 stearate is myrj-52. 
     
     
         38 . The method of  claim 34 , wherein the polyethoxylated castor oil is cremophor RH 40. 
     
     
         39 . The method of  claim 34 , wherein the ophthalmic formulation is a topical ophthalmic formulation. 
     
     
         40 . The method of  claim 34 , wherein the ophthalmic formulation is packaged in a unit dose form. 
     
     
         41 . The method of  claim 34 , wherein the ophthalmic formulation is packaged in a multidose form. 
     
     
         42 . The method of  claim 34 , wherein the ophthalmic formulation is in a plastic storage container. 
     
     
         43 . The method of  claim 34 , wherein the ophthalmic formulation consists of:
 A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.005 weight/volume % of latanoprost, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.02 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 5; 
   E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.015 weight/volume % of benzalkonium chloride, water, and 
 a pH of 4.8; or 
   F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
 0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, 
 0.05 weight/volume % of boric acid, 
 4.7 weight/volume % of mannitol, 
 0.008 weight/volume % of benzalkonium chloride, 
 water, and 
 a pH of 4.9.