Methods for enhancing the release and absorption of water insoluble active agents
View Patent ↗Methods for enhancing the release and/or absorption of poorly water soluble active agents are described herein. The method involves dissolving, melting, or suspending a poorly water soluble active agent in one or more molten fatty acids, conjugated fatty acids, (semi-) solid surfactants of high HLB value, and/or hydrophilic polymers. The molten active agent mixture is then suspended and homogenized in a hydrophilic or lipophilic carrier to form microparticles suspended in the hydrophilic or lipophilic carrier. The particles suspended in the hydrophilic or lipophilic carrier can be encapsulated in a hard or soft gelatin or non-gelatin capsule. It is believed that the microparticles produced by the method described above will exhibit enhanced dissolution profiles. In vitro release studies of formulations containing cilostazol and fenofibrate showed 100% dissolution of cilostazol in 15 minutes and over 90% dissolution of fenofibrate in 35 minutes.
1. Microparticles comprising fenofibrate and one or more coatings materials selected from the group consisting of fatty acid, conjugated fatty acid, surfactant, and hydrophilic polymer, wherein the microparticles release at least 85% of the fenofibrate after 30 minutes using a USP dissolution apparatus II (paddles) at 75 rpm and 37.0±0.5° C. in 0.05 M sodium dodecyl sulfate, wherein the microparticles have a diameter between 100 nm and 25 microns.
2. The microparticles of claim 1 , wherein the one or more coating materials are one or more fatty acids, conjugated fatty acids, or combinations thereof.
3. The microparticles of claim 2 , wherein the one or more fatty acids are selected from the group consisting of dodecanoic (lauric) acid, tetradecanoic (myristic) acid, hexadecanoic (palmitic) acid, heptadecanoic (margaric) acid, octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic (behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotic) acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid, triacontanoic (melissic) acid, dotriacontanoic (lacceroic) acid, tritriacontanoic (ceromelissic) acid, tetratriacontanoic (geddic) acid, pentatriacontanoic (ceroplastic) acid, and combinations thereof.
4. The microparticles of claim 2 , wherein the conjugated fatty acid is selected from the group consisting of C 10 -C 18 monoglycerides, C 10 -C 18 fatty acids conjugated to a polyalkylene oxide, C 10 -C 18 fatty acids conjugated to a monosaccharide, and combinations thereof.
5. The microparticles of claim 4 , wherein the conjugated fatty acid is Polyoxyl 40 stearate or glyceryl monostearate.
6. The microparticles of claim 2 , wherein the concentration of the conjugated fatty acid is from about 1% to about 20% by weight of the composition.
7. The microparticles of claim 6 , wherein the concentration of the conjugated fatty acid is from about 5% to about 15% by weight of the composition.
8. The microparticles of claim 2 , wherein the concentration of the fatty acid is from about 1% to about 20% by weight of the composition.
9. The microparticles of claim 8 , wherein the concentration of the fatty acid is from about 5% to about 15% by weight of the composition.
10. The microparticles of claim 1 , wherein the microparticles are suspended in a hydrophilic carrier.
11. The microparticles of claim 10 , wherein the hydrophilic carrier comprises polyethylene glycol (PEG).
12. The microparticles of claim 1 , wherein the microparticles are suspended in a lipophilic carrier.
13. A pharmaceutical composition comprising the microparticles of claim 1 .
14. The composition of claim 12 , wherein the microparticles are encapsulated in a soft or hard, gelatin, or non-gelatin capsule.
15. A composition comprising:
a) microparticles comprising fenofibrate and one or more coatings materials selected from the group consisting of fatty acid, conjugated fatty acid, surfactant, and hydrophilic polymer, wherein the microparticles release at least 85% of the fenofibrate after 30 minutes using a USP dissolution apparatus II (paddles) at 75 rpm and 37.0±0.5° C. in 0.05 M sodium dodecyl sulfate, and
b) a hydrophilic carrier.
16. The particles of any of claim 15 , wherein the percent dissolution of fenofibrate is about 95% after 45 minutes.
17. The particles of any of claim 15 , wherein the percent dissolution of fenofibrate is about 100% after 60 minutes.
18. The microparticles of claim 15 , wherein the one or more coating materials are one or more fatty acids, conjugated fatty acids, or combinations thereof.
19. The microparticles of claims 15 , wherein the one or more fatty acids are selected from the group consisting of dodecanoic (lauric) acid, tetradecanoic (myristic) acid, hexadecanoic (palmitic) acid, heptadecanoic (margaric) acid, octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic (behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotic) acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid, triacontanoic (melissic) acid, dotriacontanoic (lacceroic) acid, tritriacontanoic (ceromelissic) acid, tetratriacontanoic (geddic) acid, pentatriacontanoic (ceroplastic) acid, and combinations thereof.
20. The microparticles of claim 15 , wherein the conjugated fatty acid is selected from the group consisting of C 10 -C 18 monoglycerides, C 10 -C 18 fatty acids conjugated to a polyalkylene oxide, C 10 -C 18 fatty acids conjugated to a monosaccharide, and combinations thereof.
21. The microparticles of claim 15 , wherein the conjugated fatty acid is Polyoxyl 40 stearate or gylceryl monostearate.
22. The microparticles of claim 2 , wherein the concentration of the conjugated fatty acid is from about 1% to about 20% by weight of the composition.
23. The microparticles of claim 15 , wherein the concentration of the conjugated fatty acid is from about 5% to about 15% by weight of the composition.
24. The microparticles of claim 15 , wherein the concentration of the fatty acid is from about 1% to about 20% by weight of the composition.
25. The microparticles of claim 15 , wherein the concentration of the fatty acid is from about 5% to about 15% by weight of the composition.
26. The microparticles of claim 15 , wherein the hydrophilic carrier comprises polyethylene glycol (PEG).
27. A pharmaceutical composition comprising the microparticles of claim 1 .
28. The composition of claim 15 , wherein the microparticles are encapsulated in a soft or hard, gelatin, or non-gelatin capsule.
29. Microparticles consisting essentially of fenofibrate and one or more coatings materials selected from the group consisting of fatty acid, conjugated fatty acid, and combinations thereof, wherein the microparticles release at least 85% of the fenofibrate after 30 minutes using a USP dissolution apparatus II (paddles) at 75 rpm and 37.0±0.5° C. in 0.05 M sodium dodecyl sulfate.
30. . The particles of claim 29 , wherein the percent dissolution of fenofibrate is about 95% after 45 minutes.
31. The particles of any of claim 29 , wherein the percent dissolution of fenofibrate is about 100% after 60 minutes.
32. The microparticles of claims 29 , wherein the one or more fatty acids are selected from the group consisting of dodecanoic (lauric) acid, tetradecanoic (myristic) acid, hexadecanoic (palmitic) acid, heptadecanoic (margaric) acid, octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic (behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotic) acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid, triacontanoic (melissic) acid, dotriacontanoic (lacceroic) acid, tritriacontanoic (ceromelissic) acid, tetratriacontanoic (geddic) acid, pentatriacontanoic (ceroplastic) acid, and combinations thereof.
33. The microparticles of claim 29 , wherein the conjugated fatty acid is selected from the group consisting of C 10 -C 18 monoglycerides, C 10 -C 18 fatty acids conjugated to a polyalkylene oxide, C 10 -C 18 fatty acids conjugated to a monosaccharide, and combinations thereof.
34. The microparticles of claim 29 , wherein the conjugated fatty acid is Polyoxyl 40 stearate or gylceryl monostearate.
35. The microparticles of claim 29 , wherein the concentration of the conjugated fatty acid is from about 1% to about 20% by weight of the composition.
36. The microparticles of claim 29 , wherein the concentration of the conjugated fatty acid is from about 5% to about 15% by weight of the composition.
37. The microparticles of claim 29 , wherein the concentration of the fatty acid is from about 1% to about 20% by weight of the composition.
38. The microparticles of claim 29 , wherein the concentration of the fatty acid is from about 5% to about 15% by weight of the composition.
39. The microparticles of claim 29 , wherein the microparticles are suspended in a hydrophilic carrier.
40. The microparticles of claim 39 , wherein the hydrophilic carrier comprises polyethylene glycol (PEG).
41. The microparticles of claim 29 , wherein the microparticles are suspended in a lipophilic carrier.
42. A pharmaceutical composition comprising the microparticles of claim 29 .
43. The composition of claim 42 , wherein the microparticles are encapsulated in a soft or hard, gelatin, or non-gelatin capsule.
44. The particles of claim 1 , 15 or 16 , wherein the percent dissolution of fenofibrate is about 95% after 45 minutes.
45. The particles of claim 1 , 15 or 16 , wherein the percent dissolution of fenofibrate is about 100% after 60 minutes.