PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS FOR ADMINISTRATION OF HYDROPHOBIC DRUGS

• US 20100137271A1
• Filed: 11/24/2009
• Published: 06/03/2010
• Est. Priority Date: 06/30/1999
• Status: Abandoned Application

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: CHEN, FENG-JING, FIKSTAD, DAVID T., GILIYAR, CHANDRASHEKAR, ZHANG, HUIPING, PATEL, MAHESH V.
• Application Number:
  US12/625,284
• Publication Number:
  US 20100137271A1
• Time in Patent Office: Days
• US Class Current: 514/181
• CPC Class Codes: A61B 17/0467 Instruments for cutting sutures surgical cutting instruments A61B17/32
• CPC Class Codes: A61B 17/0483 Hand-held instruments for holding sutures A61B17/0469 takes precedence; other holders for needles or sutures A61B17/06061; surgical forceps A61B17/28; surgical pincettes A61B17/30
• CPC Class Codes: A61B 17/0485 Devices or means, e.g. loops, for capturing the suture thread and threading it through an opening of a suturing instrument or needle eyelet
• CPC Class Codes: A61B 2017/0474 Knot pushers
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• 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 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 : Organic macromolecular compounds
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs are provided. The pharmaceutical compositions include a therapeutically effective amount of a hydrophobic drug, preferably a steroid; a solubilizer, and a surfactant. The synergistic effect between the hydrophobic drug and the solubilizer results in a pharmaceutical formulation with improved dispersion of both the active agent and the solubilizer. As a result of the improved dispersion, the pharmaceutical composition has improved bioavailability upon administration. Methods of improving the bioavailability of hydrophobic drugs administered to a patient are also provided.

Claims

1. A pharmaceutical composition comprising:

a) a therapeutically effective amount of a sex hormone; and

b) an effective solubilizing amount of a solubilizer, the solubilizer comprising a vitamin E substance, a glycerol fatty acid ester, a propylene glycol fatty acid ester, an ethylene glycol fatty acid ester, a trialkyl citrate, a lower alcohol fatty acid ester, a phospholipid, ethanol, PEG, or a combination thereof,

wherein the bioavailability of the sex hormone is improved when the pharmaceutical composition is administered compared to the biovailability of the sex hormone administered without an effective solubilizing amount of the solubilizer.

2. The pharmaceutical composition of claim 1, wherein the solubilizer is a glycerol fatty acid ester.

3. The pharmaceutical composition of claim 2, wherein the glycerol fatty acid ester is a monoglyceride.

4. The pharmaceutical composition of claim 2, wherein the glycerol fatty acid ester is a diglyceride.

5. The pharmaceutical composition of claim 2, wherein the glycerol fatty acid ester is a triglyceride.

6. The pharmaceutical composition of claim 1, wherein the solubilizer is present in the composition in an amount of from about 5 wt % to about 95 wt %.

7. The pharmaceutical composition of claim 6, wherein the solubilizer is present in the composition in an amount of from about 20 wt % to about 70 wt %.

8. The pharmaceutical composition of claim 1, further comprising a surfactant.

9. The pharmaceutical composition of claim 8, wherein the surfactant comprises a polyethoxylated fatty acid, an alcohol-oil transesterification product, a transesterification product of a oil and alcohol, or a combination thereof.

10. The pharmaceutical composition of claim 9, wherein the surfactant is a polyethoxylated castor oil or polyethoxylated hydrogenated castor oil.

11. The pharmaceutical composition of claim 10, wherein the surfactant comprises polyoxyl 35 castor oil, PEG-40 hydrogenated castor oil, or a combination thereof.

12. The pharmaceutical composition of claim 8, wherein the surfactant is present in the composition in an amount of up to about 80 wt %.

13. The pharmaceutical composition of claim 12, wherein the surfactant is present in the composition in an amount of from about 10 wt % to about 50 wt %.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a liquid, semi-solid, or solid.

15. The pharmaceutical composition of claim 14, wherein the composition is formulated into a capsule.

16. The pharmaceutical composition of claim 1, wherein the solubilizer enhances the bioabsorption of the sex hormone.

17. The pharmaceutical composition of claim 1, wherein the solubilizer increases the rate and extent of absorption of the sex hormone.

18. The pharmaceutical composition of claim 1, wherein the solubilizer provides for a more rapid onset of therapeutic action, better bioperformance characteristics, or a combination thereof of the sex hormone.

19. The pharmaceutical composition of claim 1, wherein the sex hormone is progesterone, testosterone, or an ester thereof.

20. The pharmaceutical composition of claim 19, wherein the sex hormone is testosterone enanthate, testosterone propionate, testosterone undecanoate, testosterone palmitate, or a combination thereof.

21. The pharmaceutical composition of claim 19, wherein the testosterone ester is testosterone enanthate.

22. The pharmaceutical composition of claim 19, wherein the testosterone ester is testosterone proprionate.

23. The pharmaceutical composition of claim 19, wherein the testosterone ester is testosterone undecanoate.

24. The pharmaceutical composition of claim 19, wherein the testosterone ester is testosterone palmitate.

25. The pharmaceutical composition of claim 1, wherein upon dilution of the composition, the active agent increases the extent of dispersion of the vitamin E substance by at least 20% relative to the dispersion of the composition without the active agent.

26. A method of providing hormone therapy in a patient comprising orally administering to a patient in need thereof a pharmaceutical composition comprising:

a) a therapeutically effective amount of sex hormone; and

b) an effective solubilizing amount of a solubilizer selected from the group consisting of a vitamin E substance, a glycerol fatty acid ester, a propylene glycol fatty acid ester, an ethylene glycol fatty acid ester, a trialkyl citrate, a lower alcohol fatty acid ester, a phospholipid, ethanol, PEG, or a combination thereof.

27. The method of claim 26, wherein the solubilizer is a glycerol fatty acid ester.

28. The method of claim 27, wherein the glycerol fatty acid ester is a monoglyceride.

29. The method of claim 27, wherein the glycerol fatty acid ester is a diglyceride.

30. The method of claim 27, wherein the glycerol fatty acid ester is a triglyceride.

31. The method of claim 26, wherein the solubilizer is present in the composition in an amount of from about 5 wt % to about 95 wt %.

32. The method of claim 31, wherein the solubilizer is present in the composition in an amount of from about 20 wt % to about 70 wt %.

33. The method of claim 26, further comprising a surfactant.

34. The method of claim 33, wherein the surfactant comprises a polyethoxylated fatty acid, an alcohol-oil transesterification product, a transesterification product of a oil and alcohol, or a combination thereof.

35. The method of claim 34, wherein the surfactant is a polyethoxylated castor oil or polyethoxylated hydrogenated castor oil.

36. The method of claim 35, wherein the surfactant comprises polyoxyl 35 castor oil, PEG-40 hydrogenated castor oil, or a combination thereof.

37. The method of claim 33, wherein the surfactant is present in the composition in an amount of up to about 80 wt %.

38. The method of claim 37, wherein the surfactant is present in the composition in an amount of from about 10 wt % to about 50 wt %.

39. The method of claim 26, wherein the pharmaceutical composition is a liquid, semi-solid, or solid.

40. The method of claim 39, wherein the composition is formulated into a capsule.

41. The method claim 26, wherein bioabsorption of the sex hormone is enhanced compared to a method of administering the sex hormone without the solubilizer.

42. The method claim 26, wherein onset and duration of absorption of the sex hormone is increased compared to a method of administering the sex hormone without the solubilizer.

43. The method claim 26, wherein onset of therapeutic action is more rapid, bioperformance characteristics of the sex hormone are better, or a combination thereof compared to a method of administering the sex hormone without the solubilizer.

44. The method claim 26, wherein the sex hormone is progesterone, testosterone or an ester thereof.

45. The method of claim 44, wherein the sex hormone is testosterone enanthate, testosterone propionate, testosterone undecanoate, testosterone palmitate, or a combination thereof.

46. The method claim 44, wherein the testosterone ester is testosterone enanthate.

47. The method claim 44, wherein the testosterone ester is testosterone proprionate.

48. The method claim 44, wherein the testosterone ester is testosterone undecanoate.

49. The method of claim 44, wherein the testosterone ester is testosterone palmitate.