초록

Fenofibrate microparticles are prepared using a combination of surface modifiers with a phospholipid. Particle size growth and stability are controlled while significantly smaller sized fenofibrate particles are produced.

대표청구항 ▼

What is claimed is: 1. A method of preparing fenofibrate microparticles, comprising the steps of: (1) mixing the fenofibrate particles with (a) a natural or synthetic phospholipid and (b) at least one non-ionic, anionic, or cationic surfactant to form a mixture, prior to or during a reduction of pa

What is claimed is: 1. A method of preparing fenofibrate microparticles, comprising the steps of: (1) mixing the fenofibrate particles with (a) a natural or synthetic phospholipid and (b) at least one non-ionic, anionic, or cationic surfactant to form a mixture, prior to or during a reduction of particle size, said mixture comprising an alkyl aryl polyether sulfonate, a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene stearate, a polyethylene glycol, benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, or a combination of any thereof; and (2) subjecting the mixture of step (1) to size reduction by an energy input procedure selected from one or more of sonication, milling, homogenization, microfluidization, or precipitation from solution using antisolvent and solvent precipitation in the presence of the mixture to produce fenofibrate microparticles having a volume-weighted mean particle size that is about 50% smaller than particles produced without the presence of the surfactant using the same energy input procedure. 2. A method of preparing fenofibrate microparticles, comprising the steps of: (1) mixing the fenofibrate particles with (a) a natural or synthetic phospholipid selected from the group consisting of phosphatidyicholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidyiglycerol, sphingomyelin, dimyristoyl phosphatidyiglycerol sodium salt, phosphatidic acid, lysophospholipids and combinations thereof, and (b) at least one non-ionic, anionic, or cationic surfactant to form a mixture, prior to or during a reduction of particle size; and (2) subjecting the mixture of step (1) to size reduction by an energy input procedure selected from one or more of sonication, milling, homogenization, microfluidization, or precipitation from solution using antisolvent and solvent precipitation in the presence of the mixture to produce fenofibrate microparticles having a volume-weighted mean particle size that is about 50% smaller than particles produced without the presence of the surfactant using the same energy input procedure. 3. A method of preparing fenofibrate microparticles, comprising the steps of: (1) mixing the fenofibrate particles with (a) a natural or synthetic phospholipid and (b) at least one non-ionic, anionic, or cationic surfactant to form a mixture, prior to or during a reduction of particle size; and (2) subjecting the mixture of step (1) to size reduction by an energy input procedure selected from one or more of sonication, milling, homogenization, microfluidization, or precipitation from solution using antisolvent and solvent precipitation in the presence of the mixture to produce fenofibrate microparticles, wherein the fenofibrate microparticles are 5-100 μm in size, said fenofibrate microparticles having a volume-weighted mean particle size value that is about 80% smaller than particles produced without the presence of the surfactant using the same energy input procedure. 4. A method of preparing fenofibrate microparticles, comprising the steps of: (1) mixing the fenofibrate particles with (a) a natural or synthetic phospholipid and (b) at least one non-ionic, anionic, or cationic surfactant to form a mixture, prior to or during a reduction of particle size, wherein the mixture comprises the surfactant in a concentration above its critical micelle concentration; and thereafter (2) subjecting the mixture of step (1) to size reduction by an energy input procedure selected from one or more of sonication, milling, homogenization, microfluidization, or precipitation from solution using antisolvent and solvent precipitation in the presence of the mixture to produce fenofibrate microparticles having a volume-weighted mean particle size that is about 50% smaller than particles produced without the presence of the surfactant using the same energy input procedure. 5. The method according to any one of claims 1, 2, 3, or 4, wherein step (1) further comprises: mixing the fenofibrate particles with (a) at least two phospholipids and at least one surfactant, (b) a phospholipid and at least two surfactants, or (c) at least two phospholipids and at least two surfactants. 6. The method according to any one of claims 1, 2, 3, or 4, wherein the method comprises preparing a pharmaceutically acceptable composition from the composition of fenofibrate microparticles. 7. The method according to claim 6, wherein the method comprises preparing a suspension of the fenofibrate microparticles. 8. The method according to claim 6, wherein the method comprises preparing a powder from the composition by lyophilization, fluid drying, or spray drying. 9. The method according to claim 8, wherein the method comprises preparing an orally administrable gel capsule comprising the powder. 10. The method according to claim 8, wherein the method comprises preparing an orally administrable granule from the powder. 11. The method according to claim 8, wherein the method comprises preparing an orally administrable tablet comprising the powder. 12. The method according to claim 6, wherein the composition is spray dried and the surfactant consists of polyvinylpyrrolidone, or a combination of polyvinylpyrrolidone and one or more additional surfactants. 13. The method according to claim 12, wherein the composition is further converted into granules. 14. A composition comprising fenofibrate microparticles produced by the method according to any one of claims 1, 2, 3, or 4. 15. A pharmaceutically acceptable composition comprising granules produced by the method according to claim 13. 16. The method according to any one of claims 1, 2, 3, or 4, wherein the surfactant is selected from the group consisting of casein, tragacanth, enteric resins, cholesterol esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines, polyvinyl alcohol, polyvinylpyrrolidone, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, negatively-charged glycerol esters, quatemary ammonium compounds, chitosans, colloidal clays, sodium dodecylsulfate, sodium deoxycholate, and combinations thereof. 17. A method of preparing fenofibrate microparticles comprising the steps of: (1) mixing the fenofibrate particles with (a) a natural or synthetic phospholipid and (b) at least one non-ionic, anionic or cationic surfactant to form a mixture, prior to or during a reduction of particle size, said surfactant being selected from one or more of casein, tragacanth, enteric resins, cholesterol esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines, polyvinyl alcohol, polyvinylpyrrolidone, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, negatively-charged glycerol esters, quaternary ammonium compounds, chitosans, colloidal clays, sodium dodecylsulfate, sodium deoxycholate, and combinations thereof, and (2) subjecting the mixture of step (1) to size reduction by an energy input procedure selected from one or more of sonication, milling, homogenization, microfluidization, or precipitation from solution using antisolvent and solvent precipitation in the presence of the mixture to produce fenofibrate microparticles having a volume-weighted mean particle size that is about 50% smaller than particles produced without the presence of the surfactant using the same energy input procedure. 18. The method according to claim 17, wherein step (1) further comprises: mixing the fenofibrate particles with (a) at least two phospholipids and at least one surfactant, (b) a phospholipid and at least two surfactants, or (c) at least two phospholipids and at least two surfactants. 19. The method according to claim 17, wherein the mixture comprises an alkyl aryl polyether sulfonate, a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene stearate, a polyethylene glycol, benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, or a combination of any thereof. 20. The method according to claim 17, wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, sphingomyelin, dimyristoyl phosphatidylglycerol sodium salt, phosphatidic acid, lysophospholipids and combinations thereof. 21. The method according to claim 17, wherein the fenofibrate microparticles are 5-100 μm in size, said fenofibrate microparticles having a volume-weighted mean particle size value that is about 80% smaller than particles produced without the presence of the surfactant using the same energy input. 22. The method according to claim 17, wherein the mixture comprises a surfactant in a concentration above its critical micelle concentration. 23. The method according to claim 17, wherein the method comprises preparing a pharmaceutically acceptable composition from the composition of fenofibrate microparticles. 24. The method according to claim 23, wherein the method comprises preparing a suspension of the fenofibrate microparticles. 25. The method according to claim 23, wherein the method comprises preparing a powder from the composition by lyophilization, fluid drying, or spray drying. 26. The method according to claim 25, wherein the method comprises preparing an orally administrable tablet comprising the powder. 27. The method according to claim 23, wherein the composition is spray dried and the surfactant consists of polyvinylpyrrolidone, or a combination of polyvinylpyrrolidone and one or more additional surfactants. 28. The method according to claim 27, wherein the composition is further converted into granules. 29. A pharmaceutically acceptable composition comprising granules produced by the method according to claim 28.