PHARMACEUTICAL FORMULATIONS COMPRISING 9-CIS-RETINYL ESTERS IN A LIPID VEHICLE
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.