Controlled release compositions of estradiol metabolites

• US 20060083778A1
• Filed: 04/25/2003
• Published: 04/20/2006
• Est. Priority Date: 05/03/2002
• Status: Abandoned Application

• Current Assignee: PR Pharmaceuticals Incorporated
• Original Assignee: PR Pharmaceuticals Incorporated
• Inventors: Schmidt, Paul, Hudnut, Paul, Allison, Dean
• Application Number:
  US10/513,542
• Publication Number:
  US 20060083778A1
• Time in Patent Office: Days
• US Class Current: 424/448
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/7038 Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The present invention provides improved sustained release formulations of estradiol metabolites, including 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestradiol and 4-methoxyestradiol, useful for therapeutic treatments. The invention also provides methods of producing sustained release forms of estradiol metabolites. The compositions of the present invention include microparticles, nanoparticles, patches, crystals, gels, rods, stints, pallets, discs, lozenges, wafers, capsules, films, microcapsules nanocapsules, hydrogels, liposomes, implants and vaginal rings. Compositions also include formulations for transdermal and intravenous delivery of estradiol metabolites. The present invention provides numerous improvements over previous forms of estradiol metabolites, such advantages including the sustained release of normally short half-life compounds to maintain therapeutic blood levels.

Claims

1. A composition of matter comprising:

(a) an estradiol metabolite; and

(b) a material providing for sustained release.

2. The composition of claim 1, wherein said material providing for sustained release is selected from the group consisting of microparticles, nanoparticles, patches, crystals, gels, rods, stints, pellets, discs, lozenges, wafers, capsules, films, microcapsules, nanocapsules, hydrogels, liposomes, implants and vaginal rings.

3. The composition of claim 2, wherein said microparticles or nanoparticles are comprised of a biodegradable polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends and copolymers thereof.

4. The composition of claim 3, wherein said microparticles or nanoparticles are comprised of poly(d,l-lactide-co-glycolide).

5. The composition of claim 2, wherein said microparticles have a diameter between 1 and 200 micrometers.

6. The composition of claim 2, wherein said nanoparticles have a diameter between 20 and 2000 nanometers.

7. The composition of claim 2, wherein said microparticles or nanoparticles further comprise an additive.

8. The composition of claim 7, wherein said additive is selected from the group consisting of butylated hydroxytoluene, propyl gallate, a α

-tocopherol, ascorbyl palmitate, an antioxidant, a release modifier and a buffer.

9. The composition of claim 1, wherein said estradiol metabolite is selected from the group consisting of 2-methoxy estradiol, 2-hydroxy estradiol, 4-methoxy estradiol and 4-hydroxy estradiol.

10. The composition of claim 1, wherein said estradiol metabolite is delivered transmucosally.

11. The composition of claim 10, wherein said transdermal transmucosal delivery is selected from the group consisting of buccal, oral, ocular, nasal, rectal and vaginal.

12. The composition of claim 1, wherein said estradiol metabolite is a prodrug.

13. The composition of claim 12, wherein said prodrug is an ester.

14. The composition of claim 13, wherein said ester is selected from the group consisting of 3-benzoyl-2-methoxy estradiol;

17-benzoyl-2-methoxy estradiol;

17-acetyl-2-methoxy estradiol;

3-acetyl-2-methoxy estradiol;

3,17-dibenzoyl-2-methoxy estradiol;

3,17-diacetyl-2-methoxy estradiol;

3-benzoyl-4-methoxy estradiol;

17-benzoyl-4-methoxy estradiol;

17-acetyl-4-methoxy estradiol;

3-acetyl-4-methoxy estradiol;

3,17-dibenzoyl-4-methoxy estradiol;

3,17-diacetyl-4-methoxy estradiol;

3-benzoyl -2-hydroxy estradiol;

17-benzoyl-2-hydroxy estradiol;

17-acetyl-2-hydroxy estradiol;

3-acetyl-2-hydroxy estradiol;

3,17-dibenzoyl-2-hydroxy estradiol;

3,17-diacetyl-2-hydroxy estradiol;

2,3-dibenzoyl-2-hydroxy estradiol;

2,17-dibenzoyl-2-hydroxy estradiol;

2,17-diacetyl-2-hydroxy estradiol;

2,3-diacetyl-2-hydroxy estradiol;

2,3,17-tribenzoyl-2-hydroxy estradiol;

2,3,17-triacetyl-2-hydroxy estradiol;

3-benzoyl-4-hydroxy estradiol;

17-benzoyl-4-hydroxy estradiol;

17-acetyl-4-hydroxy estradiol;

3-acetyl-4-hydroxy estradiol;

3,17-dibenzoyl-4-hydroxy estradiol;

3,17-diacetyl-4-hydroxy estradiol;

3,4-dibenzoyl-4-hydroxy estradiol;

4,17-dibenzoyl-4-hydroxy estradiol;

4,17-diacetyl-4-hydroxy estradiol;

3,4-diacetyl-4-hydroxy estradiol;

3,4,17-tribenzoyl-4-hydroxy estradiol;

3,4,17-triacetyl-4-hydroxy estradiol.

15. The composition of claim 1, wherein said estradiol metabolite is in a eutectic mixture.

16. The composition of claim 1, further comprising a hydrophilic polymer.

17. The composition of claim 16, wherein said hydrophilic polymer is selected from the group consisting of poly(ethylene glycol), poly(propylene glycol) and copolymers of poly(ethylene glycol) and poly(propylene glycol).

18. The composition of claim 1, wherein said estradiol metabolite is derivatized.

19. The composition of claim 18, wherein said derivative is selected from the group consisting of dicarboxylic acid compounds, diacids, polar compounds and ionic compounds.

20. The composition of claim 19, wherein such dicarboxylic acid compound is selected from the group consisting of oxalic, malonic, maleic, succinic, glutaric, adipic, pimelic and pamoic acid.

21. The composition of claim 19, wherein such diacids are selected from the group consisting of succinic, glutaric, maleic, malonic and oxalic acid.

34. The composition of claim 1, wherein the composition is useful to treat an individual.

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

35. A treatment method comprising:

(a) administering to an individual a sustained release formulation containing an estradiol metabolite.

36. The method of claim 35, wherein said sustained release formulation containing an estradiol metabolite is selected from the group consisting of microparticles, nanoparticles, patches, crystals, gels, rods, stints, pellets, discs, lozenges, wafers, capsules, films, microcapsules, nanocapsules, hydrogels, liposomes, implants and vaginal rings.

37. The method of claim 36, wherein said microparticles or nanoparticles are comprised of a biodegradable polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, biodegradable polyurethanes, blends and copolymers thereof.

38. The method of claim 37, wherein said microparticles or nanoparticles are comprised of poly(d,l-lactide-co-glycolide).

39. The method of claim 37, wherein said microparticles have a diameter between 1 and 200 micrometers.

40. The method of claim 37, wherein said nanoparticles have a diameter between 20 and 2000 nanometers.

41. The method of claim 37, wherein said microparticles or nanoparticles further comprise an additive.

42. The method of claim 41, wherein said additive is selected from the group consisting of butylated hydroxytoluene, propyl gallate, α

-tocopherol, ascorbyl palmitate, an antioxidant, a release modifier and a buffer.

43. The method of claim 35, wherein said estradiol metabolite is selected from the group consisting of 2-methoxy estradiol, 2-hydroxy estradiol, 4-methoxy estradiol and 4-hydroxy estradiol.

44. The method of claim 35, wherein said estradiol metabolite is delivered transmucosally.

45. The method of claim 44, wherein said transmucosal delivery is selected from the group consisting of buccal, oral, ocular, nasal, rectal and vaginal.

46. The method of claim 35, wherein said estradiol metabolite is a prodrug.

47. The method of claim 46, wherein said prodrug is an ester.

48. The method of claim 47, wherein said ester is selected from the group consisting of 3-benzoyl-2-methoxy estradiol;

17-benzoyl-2-methoxy estradiol;

17-acetyl-2-methoxy estradiol;

3-acetyl-2-methoxy estradiol;

3,17-dibenzoyl-2-methoxy estradiol;

3,17-diacetyl-2-methoxy estradiol;

3-benzoyl-4-methoxy estradiol;

17-benzoyl-4-methoxy estradiol;

17-acetyl-4-methoxy estradiol;

3-acetyl-4-methoxy estradiol;

3,17-dibenzoyl-4-methoxy estradiol;

3,17-diacetyl-4-methoxy estradiol;

3-benzoyl -2-hydroxy estradiol;

17-benzoyl-2-hydroxy estradiol;

17-acetyl-2-hydroxy estradiol;

3-acetyl-2-hydroxy estradiol;

3,17-dibenzoyl-2-hydroxy estradiol;

3,17-diacetyl-2-hydroxy estradiol;

2,3-dibenzoyl-2-hydroxy estradiol;

2,17-dibenzoyl-2-hydroxy estradiol;

2,17-diacetyl-2-hydroxy estradiol;

2,3-diacetyl-2-hydroxy estradiol;

2,3,17-tribenzoyl-2-hydroxy estradiol;

2,3,17-triacetyl-2-hydroxy estradiol;

3-benzoyl-4-hydroxy estradiol;

17-benzoyl-4-hydroxy estradiol;

17-acetyl-4-hydroxy estradiol;

3-acetyl-4-hydroxy estradiol;

3,17-dibenzoyl-4-hydroxy estradiol;

3,17-diacetyl-4-hydroxy estradiol;

3,4-dibenzoyl-4-hydroxy estradiol;

4,17-dibenzoyl-4-hydroxy estradiol;

4,17-diacetyl-4-hydroxy estradiol;

3,4-diacetyl-4-hydroxy estradiol;

3,4,17-tribenzoyl-4-hydroxy estradiol;

3,4,17-triacetyl-4-hydroxy estradiol.

49. The method of claim 35, wherein said sustained release formulation containing an estradiol metabolite is in a eutectic mixture.

50. The method of claim 35, further comprising a hydrophilic polymer.

51. The method of claim 50, wherein said hydrophilic polymer is selected from the group consisting of poly(ethylene glycol), poly(propylene glycol) and copolymers of poly(ethylene glycol) and poly(propylene glycol).

52. The method of claim 35, wherein said estradiol metabolite is derivatized.

53. The method of claim 52, wherein said derivative is selected from the group consisting of dicarboxylic acid compounds, diacids, polar compounds and ionic compounds.

54. The method of claim 53, wherein such dicarboxylic acid compound is selected from the group consisting of oxalic, malonic, maleic, succinic, glutaric, adipic, pimelic and pamoic acid.

55. The method of claim 53, wherein such diacids is selected from the group consisting of succinic, glutaric, maleic, malonic and oxalic acid.

56. The method of claim 35, wherein said sustained release formulation containing an estradiol metabolite is produced by spray drying a solution of polymer and estradiol metabolite dissolved in an organic solvent.

57. The method of claim 35, wherein said sustained release formulation containing an estradiol metabolite is produced by wet emulsification including a continuous and discontinuous phase followed by solvent removal.

58. The method of claim 57, wherein said discontinuous phase contains estradiol metabolites and polymer.

59. The method of claim 58, further comprising an additive.

60. The method of claim 59, wherein said additive is selected from the group consisting of an antioxidant, a buffer, and a release modifier.

61. The method of claim 57, wherein said discontinuous phase contains an organic solvent.

62. The method of claim 61, wherein said organic solvent is selected from the group consisting of one solvent, two solvents and a mixture of solvents.

63. The method of claim 57, wherein said continuous phase further comprises an emulsifier.

64. The method of claim 63, wherein said emulsifier is selected from the group consisting of phospholipids, lecithin, ionic surfactants, nonionic surfactants, poloxamers, polymers, polyvinyl pyrrolidone and polyvinyl alcohol.

65. The method of claim 64, wherein said emulsifier is polyvinyl alcohol.

66. The method of claim 35, wherein said sustained release formulation containing an estradiol metabolite was produced by the selective extraction of an oil phase solvent.

67. (canceled)

68. A composition of matter comprising;

(a) an estradiol metabolite selected from the group consisting of catecholestrogens and methoxyestradiols; and

(b) a material providing for sustained release.

69. The composition of claim 68, wherein said material providing for sustained release is a microparticle or nanoparticle comprised of a biodegradable polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, biodegradable polyurethanes, blends and copolymers thereof.

70. The composition of claim 68, wherein said estradiol metabolite is selected from the group consisting of 2-methoxy estradiol, 2-hydroxy estradiol, 4-methoxy estradiol and 4-hydroxy estradiol.