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AssigneeShire Laboratories, Inc.
InventorsLikan Liang, Amir H. Shojaei, Scott A. Ibrahim, Beth A. Burnside
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A fibrate self-emulsifying oral formulation with improved bioavailability when compared to commercially available formulations containing a therapeutically effective dose of fenofibrate, derivative of fenofibrate or mixtures thereof dissolved in a fibrate solubilizer selected from N-alkyl derivative of 2-pyrrolidone, mono- or di- or polyethylene glycol monoethers, C8-12 fatty acid mono- or di-esters of propylene glycol, or combinations thereof, one or more surfactants and optionally one or more stabilizers useful in the treatment of hypercholesterolaemia or hypertriglyceridaemia in mammals in the fed or fasted state.
1-An oral self-emulsifying pharmaceutical formulation of a fibrate with improved oral bioavailability comprising a fibrate selected from fenofibrate, derivative of fenofibrate or mixtures thereof dissolved in one or more fibrate solubilizers selected from n-alkyl derivative of 2-pyrrolidone, mono- or di- or polyethylene glycol monoethers, C8-12 fatty acid mono- or diesters of propylene glycol, or combinations thereof;
2-A formulation according to claim 1 that further contains one or more stabilizers in sufficient amounts to prevent the crystal growth of the fibrate, wherein fibrate remains in solution and no crystallization of fibrate is observed for at least 24 hours.
3-A formulation according to claim 2 wherein the stabilizers are selected from fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidones, polyvinylethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers.
4-A formulation according to claim 2 wherein the weight ratio of the fibrate to the stabilizer is between about 50:1 to about 1:10.
5-A formulation according to claim 1 wherein the amount of solubilizers is between about 20% to about 80% by weight of the formulation.
6-A formulation according to claim 1 wherein fibrate solubilizer is selected from N—C1-4 alkyl derivative of 2-pyrrolidone, mono- or di- or polyethylene glycol monoethers, C8-12 fatty acid mono- or diesters of propylene glycol, or combinations thereof.
7-A formulation according to claim 1 wherein the surfactant is between about 2% to about 25% by weight of the formulation.
8-A formulation according to claim 3 wherein the stabilizer is between about 0% to about 30% by weight of the formulation.
9-A formulation according to claims 1 to 8 wherein the solubilizer is selected from N—C1-4 alkyl derivative of 2-pyrrolidones, mono- or di- or polyethylene glycol monoethers, C8-12 fatty acid mono- or diesters of propylene glycol, or combinations thereof.
10-A formulation according to claim 9 wherein the weight ratio of the N—C1-4alkyl derivative of 2-pyrrolidone or a mono- or di- or polyethylene glycol monoethers or combinations thereof to one or more C8-12 fatty acid mono- or diesters of propylene glycol is between about 100:1 to about 1:100.
11-A formulation according to claim 9 wherein the solubilizer is C8-12 fatty acid monoesters of propylene glycol, C8-12 fatty acid diesters of propylene glycol, or combinations thereof.
12-A formulation according to claim 1 wherein the N—C1-4 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.
13-A formulation according to claim 12 wherein the N—C1-4 alkyl derivative of 2-pyrrolidone is N-methyl-2-pyrrolidone.
14-A formulation according to claim 1 wherein the mono- or di- or polyethylene glycol monoethers is selected from diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monobutyl ether and other higher-ethylene glycol monoethers.
15-A formulation according to claim 1 wherein the fibrate solubilizer is a combination of N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether wherein the weight ratios of N-methyl-2-pyrrolidone to diethylene glycol monoethyl ether is between about 100:1 and about 1:100.
16-A formulation according to claim 9 wherein the stabilizer is ethanol, oleic acid, caprylic acid, capric acid, polyvinylpyrrolidone, waxes, or combinations thereof.
17-A self-emulsifying oral pharmaceutical formulation with improved bioavailability comprising:
18-A formulation according to claim 1, 9 or 17 wherein the Cmax is at least 1.2 times that of Lipanthyl® or TriCor® or the AUC0-∞ is at least 1.5 times that of Lipanthyl® or TriCor® when dosed mammals in the fasted state.
19-A method of treating endogenous hyperlipidaemias, hypercholesterolaemias and hypertriglyceridaemias in mammals comprising the administration of a fibrate formulation of any of claims 1, 9 or 17.
20-A pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a fibrate dissolved in a fibrate solubilizer composed selected from N-alkyl derivative of 2-pyrrolidone, mono- or di- or polyethylene glycol monoethers, C8-12 fatty acid mono- or diesters of propylene glycol, or combinations thereof;
21-An oral self-emulsifying pharmaceutical formulation of a fibrate with improved oral bioavailability comprising a fibrate dissolved in a fibrate solubilizer selected from N-alkyl derivative of 2-pyrrolidone, mono- or di- or polyethylene glycol monoethers, C8-12 fatty acid mono- or diesters of propylene glycol, or combinations thereof;
22-An oral self-emulsifying pharmaceutical formulation of a fibrate with improved oral bioavailability comprising a fibrate dissolved in a fibrate solubilizer selected from N-alkyl derivative of 2-pyrrolidone, mono- or di- or polyethylene glycol monoethers, C8-12 fatty acid mono- or diesters of propylene glycol, or combinations thereof;