Pharmaceutical formulations comprising 9-cis-retinyl esters in a lipid vehicle

Abstract

Pharmaceutical formulations comprising 9-cis-retinyl esters in a lipid vehicle are described as retinoid replacement therapies for treating retinal degenerations in humans.

1 . A pharmaceutical formulation comprising a lipid vehicle and one or more 9-cis-retinyl esters of Formula (I): 
       
         
           
           
               
               
           
         
         wherein R is an alkyl group or an alkenyl group; and the lipid vehicle comprises more than 50 w/w % polyunsaturated fatty acids, the polyunsaturated fatty acids including an omega-6 fatty acid and an omega-3 fatty acid in a ratio (by weight) of less than 15. 
       
     
     
         2 . The pharmaceutical formulation of  claim 1  wherein R is C 12-17  alkyl, C 12-17  alkenyl, C 1-8  alkyl, C 1-6  alkyl or C 1-4  alkyl. 
     
     
         3 . The pharmaceutical formulation of  claim 1  wherein R is methyl and the 9-cis-retinyl ester of Formula (I) is 9-cis-retinyl acetate. 
     
     
         4 . The pharmaceutical formulation of  claim 1  wherein R is C 15  alkyl and the 9-cis-retinyl ester of Formula (I) is 9-cis-retinyl palmitate. 
     
     
         5 . The pharmaceutical formulation of any one of  claims 1 - 4  wherein the lipid vehicle comprises triglyceride linoleate and triglyceride linolenate in a ratio (by weight) of less than 15, which collectively are more than 50% of the total weight of the lipid vehicle. 
     
     
         6 . The pharmaceutical formulation of any one of  claims 1 - 4  wherein the lipid vehicle comprises soybean oil. 
     
     
         7 . The pharmaceutical formulation of any one of  claims 1 - 4  wherein the lipid vehicle comprises walnut oil. 
     
     
         8 . The pharmaceutical formulation of any one of  claims 1 - 4  wherein the lipid vehicle comprises wheat germ oil. 
     
     
         9 . The pharmaceutical formulation of any one of  claims 1 - 8 , further comprising an anti-oxidant. 
     
     
         10 . The pharmaceutical formulation of  claim 9  wherein the anti-oxidant is α-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbyl palmitate, propyl gallate, tert-butyl hydroquinone (TBHQ), or a chelating agent, or a combination thereof. 
     
     
         11 . The pharmaceutical formulation of any one of  claims 1 - 10 , further comprising one or more flavoring agents or flavoring oils. 
     
     
         12 . A dosage formulation suitable for daily dosing of a 9-cis-retinyl ester to a subject in need thereof, the dosage formulation comprising about 1.25-20 mg/mL of 9-cis-retinyl acetate in soybean oil, wherein the dosage formulation provides about 1.25-40 mg/m 2  of the 9-retinyl acetate by body surface area of the subject over a 24-hour period. 
     
     
         13 . The dosage formulation of  claim 12  wherein a maximum plasma concentration of metabolic 9-cis-retinyl esters is reached at about 3-6 hours following oral or gavage administration of the dosage formulation. 
     
     
         14 . A dosage formulation suitable for a single dosing by intravitreal administration of 9-cis-retinyl acetate to a subject, the dosage formulation comprising about 18-40% mg/mL of 9-cis-retinyl acetate in soybean oil. 
     
     
         15 . The formulation of any of  claims 1 - 14 , wherein the formulation is a beverage comprising 9-cis-retinyl acetate, soybean oil and an emulsion. 
     
     
         16 . The formulation of  claim 15  wherein the emulsion is soymilk, or milk, or a mixture thereof. 
     
     
         17 . A method of treating Leber congenital amaurosis in a human subject in need thereof, comprising administering to the subject a pharmaceutical formulation having a lipid vehicle and one or more 9-cis-retinyl esters of Formula (I): 
       
         
           
           
               
               
           
         
         in an amount effective for treatment of the subject, wherein the lipid vehicle comprises more than 50 w/w % polyunsaturated fatty acids, the polyunsaturated fatty acids including an omega-6 fatty acid and an omega-3 fatty acid in a ratio (by weight) of less than 15. 
       
     
     
         18 . The method of  claim 17  wherein the 9-cis-retinyl esters of Formula (I) is 9-cis-retinyl acetate and the lipid vehicle is soybean oil. 
     
     
         19 . A method of treating a subject deficient in 11-cis-retinal, comprising administering to the subject a pharmaceutical formulation having a lipid vehicle and one or more 9-cis-retinyl esters of Formula (I): 
       
         
           
           
               
               
           
         
         in an amount effective for treatment of the subject, wherein the lipid vehicle comprises more than 50 w/w % polyunsaturated fatty acids, the polyunsaturated fatty acids including an omega-6 fatty acid and an omega-3 fatty acid in a ratio (by weight) of less than 15. 
       
     
     
         20 . The method of  claim 19  wherein the 9-cis-retinyl esters of Formula (I) is 9-cis-retinyl acetate and the lipid vehicle is soybean oil.