Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability

Abstract

A fibrate oral formulation with improved bioavailability when compared to commercially available formulations containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C 8-12 fatty acid ester of polyethylene glycol, fatty acids, or combinations thereof useful for the treatment of hypercholesterolaemia or hypertriglyceridaemia in mammals.

1 —A pharmaceutical formulation of a fibrate with improved oral bioavailability comprising a fibrate selected from fenofibrate , derivative of fenofibrate or mixtures thereof dissolved in a water miscible fibrate solubilizer selected from N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C 8-12  fatty acid ester of polyethylene glycol, fatty acids and combinations thereof; wherein the fibrate to solubilizer weight ratio is between about 1:1 and about 1:100.  
     
     
         2 —A formulation according to  claim 1  wherein the formulation further includes at least one surfactant.  
     
     
         3 —A formulation according to  claim 1  wherein the formulation further includes a gelling agent.  
     
     
         4 —A formulation according to  claim 2  wherein the formulation is a self-emulsifying formulation wherein the water miscible fibrate solubilizer is selected from N-C 1-4  alkyl derivative of 2-pyrrolidone or C 6-8  ethylene glycol monoether and mixtures thereof, in combination with at least one C 8-12  fatty acid ester of polyethylene glycol and at least one non-ionic surfactant with a HLB value lower than or equal to 10.  
     
     
         5 —A formulation according to  claim 2  wherein the solubilizer comprises a non-oily component selected from N-C 1-4  alkyl derivative of 2-pyrrolidone, C 6-8  ethylene glycol monoether and combinations thereof; and an oily component selected from C 8-12  fatty acid ester of polyethylene glycol, fatty acids and mixtures thereof.  
     
     
         6 —A formulation according to  claim 2  wherein the surfactant is nonionic hydrophobic surfactant.  
     
     
         7 —A formulation according to claims  1  or  5  wherein the solubilizer is selected from mixtures of N-C 1-4  alkyl derivative of 2-pyrrolidones, C 6-8  ethylene glycol monoethers or combinations thereof; with one or more polyethylene glycol mono- and diester of C 8-12  fatty acids or combinations of polyethylene glycol mono- and diester of C 8-12  fatty acids and fatty acids.  
     
     
         8 —A formulation according to  claim 7  wherein the weight ratio of the N-C 1-4  alkyl derivative of 2-pyrrolidone or a C 6-8  ethylene glycol monoethers or combinations thereof to one or more polyethylene glycol mono- and diester of C 8-12  fatty acids or combinations of polyethylene glycol mono- and diester of C 8-12  fatty acids and fatty acids is between about 100:1 to about 1:4.  
     
     
         9 —A formulation according to  claim 1  wherein the N-C 1-4  alkyl derivative of 2-pyrrolidone is selected from N-Methyl-2-Pyrrolidone, N-Ethyl-2-pyrrolidone, N-Propyl-2-pyrrolidone, N-Isopropyl-2-pyrrolidone, N-Butyl-2-pyrrolidone, and N-(2-Hydroxyethyl)-2-pyrrolidone or mixtures thereof.  
     
     
         10 —A formulation according to  claim 9  wherein the N-C 1-4  alkyl derivative of 2-pyrrolidone is N-methyl-2-pyrrolidone.  
     
     
         11 —A formulation according to  claim 1  wherein the ethylene glycol monoether is diethylene glycol monoethyl ether.  
     
     
         12 —A formulation according to  claim 6  wherein the surfactant has a HBL value lower than or equal to 10.  
     
     
         13 —A formulation according to  claim 2  wherein the formulation further includes at least one co-surfactant.  
     
     
         14 —A formulation according to  claim 13  wherein the surfactant/co-surfactant combination has a HLB value lower than or equal to 10.  
     
     
         15 —A formulation according to  claim 14  wherein the formulation further includes a surfactant selected from non-ionic surfactants with HLB values greater than 10 and at least one non-ionic co-surfactant with low HLB values lower than or equal to 6.  
     
     
         16 —A formulation according to  claim 15  wherein the co-surfactant is at least one non-ionic surfactants with HLB value between 10 and 18, one or more non-ionic co-surfactant with a HLB value between 2 and 6, provided that the HBL value of the combination is less than or equal to 10.  
     
     
         17 —A self-emulsifying oral pharmaceutical formulation with improved bioavailability comprising: a therapeutically effective amount of the fenofibrate or a fenofibrate derivative; at least one non-ionic hydrophobic surfactant; and a water miscible fibrate solubilizer selected from N-C 1-4  alkyl derivative of 2-pyrrolidone, C 3-8  ethylene glycol monoether, or combinations thereof; mixed with at least one of C 8-12  fatty acid ester of polyethylene glycol, fatty acids or mixtures thereof.  
     
     
         18 —A method of treating endogenous hyperlipidaemias, hypercholesterolaemias and hypertriglyceridaemias in mammals comprising the administration of a fibrate formulation of any of claims  1  or  5 .  
     
     
         19 —A process for improving the bioavailability of fenofibrate or a fenofibrate derivative comprising dissolving the fenofibrate or a fenofibrate derivative in N-methyl-2-pyrrolidone.  
     
     
         20 —A pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C 8-12  fatty acid ester of polyethylene glycol, fatty acids, or combinations thereof.  
     
     
         21 —A pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and one or more N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether and mixtures thereof in combination with at least one of C 8-12  fatty acid ester of polyethylene glycol, fatty acids and mixtures thereof, and at least one non-ionic hydrophobic surfactant or surfactant combinations.