Progesterone Solutions for Increased Bioavailability

• US 20100255085A1
• Filed: 04/01/2010
• Published: 10/07/2010
• Est. Priority Date: 04/06/2009
• Status: Active Grant

• Current Assignee: Patheon Softgels, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: Banner Pharmacaps Incorporated (Thermo Fisher Scientific Incorporated)
• Inventors: Gosangari, Saujanya L., Liu, Zhi, Fatmi, Aqeel, Toops, Dana S.
• Granted Patent: US 9,011,908 B2
• Time in Patent Office: Days
• US Class Current: 424/456
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 5/34 Gestagens

Abstract

Fill materials for hydrophobic drugs, such as progesterone, and methods of making and using thereof are described herein. The fill material contains the hydrophobic drug dissolved in one or more fatty acids. The concentration of the hydrophobic drug is typically from about 7% to about 50% by weight of the fill material. The concentration of the one or more fatty acids is from about 60% to about 95% by weight of the carrier. The formulation also contains an organic acid and one or both of one or more pharmaceutically acceptable alcohols and one or more pharmaceutically acceptable mono-, di-, or triesters of medium or long chain fatty acids. The fill material can be encapsulated in a hard or soft capsule. The formulations described herein have a higher dissolution rate and faster onset of dissolution compared to micronized progesterone suspended in an oil and thus should have increased bioavailability in vivo.

Claims

1. A hard or soft capsule comprising a shell and a fill material, the fill material comprising from about 7% to about 50% by weight of the fill of progesterone, wherein the progesterone is dissolved in a carrier comprising:

(a) from about 60% to about 95% by weight of one or more pharmaceutically acceptable fatty acids;

(b) from about 1% to about 20% by weight of one or more pharmaceutically acceptable organic acids selected from C₁ to C₁₂ acids; and

(c) one or both of from about 1% to about 20% by weight of one or more pharmaceutically acceptable alcohols selected from C₁ to C₆ alcohols; and

from about 1% to about 40% by weight of one or more pharmaceutically acceptable mono, di- or tri-ester of medium or long chain fatty acids.

2. The capsule of claim 1, wherein the concentration of progesterone is from about 7% to about 15% by weight of the fill material.

3. The capsule of claim 1, wherein the concentration of progesterone is from about 8% to about 12% by weight of the fill material.

4. The capsule of claim 1, wherein the concentration of progesterone is from about 9% to about 11% by weight of the fill material.

5. The capsule of claim 4, wherein the concentration of the one or more fatty acids is from about 65% to about 80% by weight of the carrier.

6. The capsule of claim 5, wherein the concentration of the one or more fatty acids is from about 65% to about 75% by weight of the carrier.

7. The capsule of claim 6, wherein the one or more fatty acids are selected from the group consisting of oleic acid, linoleic acid, myristoleic acid, palmitoleic acid, arachidonic acid and combinations thereof.

8. The capsule of claim 7, wherein the concentration of the one or more organic acids is from about 2% to about 18% by weight of the carrier.

9. The capsule of claim 8, wherein the concentration of the one or more organic acids is from about 3% to about 15%.

10. The capsule of claim 9, wherein the one or more organic acids is selected from the group consisting of lactic acid, acetic acid, glycolic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, caproic acid, succinic acid, and combinations thereof.

11. The capsule of claim 10, wherein the concentration of the one or more alcohols is from about 2% to about 18% by weight of the carrier.

12. The capsule of claim 11, wherein the concentration of the one or more alcohols is from about 5% to about 15%.

13. The capsule of claim 12, wherein the one or more alcohols is selected from the group consisting of ethanol, isopropanol, isobutanol, butanol, t-butanol, glycerol, propylene glycol, and combinations thereof.

14. The capsule of claim 13, wherein the concentration of the one or more mono, di or tri ester of medium or long chain fatty acids is from about 5% to about 35% by weight of the carrier.

15. The capsule of claim 14, wherein the concentration of the one or more mono, di or tri ester of medium or long chain fatty acids is from about 10% to about 30% by weight of the carrier.

16. The capsule of claim 15, wherein the one or more mono, di or tri ester of medium or long chain fatty acids is selected from the group consisting of mono and diglycerides of capric and caprylic acids, mono, di and tri glycerides of coconut oil, glyceryl monooleate, glyceryl monolinoleate, propylene glycol monocaprylate, propylene glycol caprylate, propylene glycol dicaprylocaprate, propylene glycol monolaurate, propylene glycol laurate, polyethoxylated fatty acid esters, polyethylene glycol monostearate, polyoxy stearate, polyethylene glycol hydroxystearate, macrogol hydroxystearate, and combinations thereof.

17. The capsule of claim 1, wherein the concentration of progesterone is from about 9% to about 11% by weight of the fill material, the fatty acid is oleic acid present from about 65% to about 75% by weight of the carrier, the organic acid is lactic acid present at about 3% to about 15% by weight of the carrier, and the alcohol is ethanol present at about 5% to about 15% by weight of the carrier.

18. The capsule of claim 1, wherein the concentration of progesterone is from about 9% to about 11% by weight of the fill material, the fatty acid is oleic acid present from about 65% to about 75% by weight of the carrier, the organic acid is lactic acid present at about 3% to about 15% by weight of the carrier, and the mono, di or tri ester of a fatty acid is propylene glycol monocaprylate present at about 10 to about 30% by weight of the carrier.

19. The capsule of claim 1, wherein the capsule shell is a hard capsule shell.

20. The capsule of claim 1, wherein the capsule shell is a soft capsule shell.

21. The capsule of claim 20, wherein the capsule shell is a gelatin shell.

22. The capsule of claim 20, wherein the capsule shell is a non-gelatin shell.

23. The capsule of 22, wherein the capsule is an enteric capsule.

24. The capsule of claim 23, wherein the capsule is coated with an enteric coating.

25. The capsule of claim 24, wherein an enteric polymer is a component of the capsule shell.

26. A method of making a hard or soft capsule of claim 25, comprising fully dissolving the progesterone in a carrier comprising one or more fatty acids and, optionally, one or more co-solvents to form a fill material, and encapsulating the fill material in a hard or soft capsule.

27. A method of administering progesterone to a patient in need thereof, the method comprising administering the hard or soft capsule of claim 26.

28. The method of claim 27, wherein the capsule exhibit increased bioavailability in vivo compared to a softgel capsule encapsulating micronized progesterone suspended in peanut oil.

29. The method of claim 27, wherein the capsule exhibit less interpatient and intrapatient variability compared to a softgel capsule encapsulating micronized progesterone suspended in peanut oil.