Claims for Patent: 8,241,664

Summary for Patent: 8,241,664

Title:	Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
Abstract:	A drug delivery system for oral administration of hydrophobic drugs with enhanced and extended absorption and improved pharmacokinetics is provided. In one embodiment, formulations comprising testosterone and testosterone esters, e.g., testosterone palmitate, are disclosed. Methods of treating a hormone deficiency or effecting male contraception with the inventive formulations are also provided.
Inventor(s):	Dudley; Robert E. (Rosemary Beach, IL), Constantinides; Panayiotis P. (Gurnee, IL)
Assignee:	Clarus Therapeutics, Inc (Northbrook, IL)
Application Number:	11/911,446
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,241,664
Patent Claims:	1. A pharmaceutical composition suitable for oral administration to a mammalian subject, comprising: (a) 10-20 percent by weight of solubilized testosterone ester; (b) 5-20 percent by weight of hydrophilic surfactant; (c) 50-70 percent by weight of lipophilic surfactant; and (d) 10-15 percent by weight of digestible oil, which composition is free of ethanol and exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, which indicates release from the composition of substantially all of the solubilized testosterone ester within about 2 hours. 2. The pharmaceutical composition of claim 1, in which the testosterone ester is a short-chain (C.sub.2-C.sub.6) or a medium-chain (C.sub.7-C.sub.13) fatty acid ester. 3. The pharmaceutical composition of claim 2, in which the testosterone ester is a medium-chain fatty acid ester selected from the group consisting of testosterone cypionate, testosterone octanoate, testosterone enanthate, testosterone decanoate, and testosterone undecanoate. 4. The pharmaceutical composition of claim 3, in which the testosterone ester is testosterone undecanoate. 5. The pharmaceutical composition of claim 1, in which the hydrophilic surfactant exhibits an HLB of 10 to 45. 6. The pharmaceutical composition of claim 5, in which the hydrophilic surfactant is selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, hydrogenated castor oil ethoxylates, PEG mono- and di-esters of palmitic and stearic acids, fatty acid ethoxylates, and combinations thereof. 7. The pharmaceutical composition of claim 6, in which the hydrophilic surfactant is a hydrogenated castor oil ethoxylate. 8. The pharmaceutical composition of claim 1, in which the lipophilic surfactant exhibits an HLB of less than 10. 9. The pharmaceutical composition of claim 8, in which the lipophilic surfactant exhibits an HLB of less than 5. 10. The pharmaceutical composition of claim 9, in which the lipophilic surfactant exhibits an HLB of 1 to 2. 11. The pharmaceutical composition of claim 8, in which the lipophilic surfactant exhibits an HLB of less than 5. 12. The pharmaceutical composition of claim 9, in which the lipophilic surfactant exhibits an HLB of 1 to 2. 13. The pharmaceutical composition of claim 12, in which the lipophilic surfactant is a fatty acid selected from the group consisting of octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. 14. The pharmaceutical composition of claim 8, in which the lipophilic surfactant is a fatty acid selected from the group consisting of octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. 15. The pharmaceutical composition of claim 1, in which the digestible oil is a vegetable oil selected from the group consisting of soybean oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil, arachis oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage oil, peppermint oil and apricot kernel oil. 16. The pharmaceutical composition of claim 1, which comprises one or more additional lipid-soluble therapeutic agents. 17. The pharmaceutical composition of claim 16, in which the one or more additional lipid-soluble therapeutic agents are selected from the group consisting of a synthetic progestin, an inhibitor of type-I and/or type II 5.alpha.-reductase, finasteride, dutasteride and combinations thereof. 18. The pharmaceutical composition of claim 16, in which the one or more additional lipid-soluble therapeutic agents comprises a second testosterone ester. 19. The pharmaceutical composition of claim 1 filled into a hard or soft gelatin capsule. 20. The pharmaceutical composition of claim 1, which exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, indicating release from the composition of substantially all of the solubilized testosterone ester within about 1 hour. 21. A pharmaceutical composition suitable for oral administration to a mammalian subject, comprising: (a) 10-20 percent by weight of solubilized testosterone undecanoate; (b) 5-20 percent by weight of a hydrogenated castor oil ethoxylate; (c) 50-70 percent by weight of oleic acid; and (d) 10-15 percent by weight of digestible oil, which composition is free of ethanol and exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, which indicates release from the composition of substantially all of the solubilized testosterone ester within about 2 hours. 22. A pharmaceutical composition suitable for oral administration to a mammalian subject, comprising: (a) 15-20 percent by weight of solubilized testosterone ester; (b) 5-20 percent by weight of hydrophilic surfactant; (c) 50-70 percent by weight of lipophilic surfactant; and (d) 10-15 percent by weight of digestible oil, which composition is free of ethanol and exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, which indicates release from the composition of substantially all of the solubilized testosterone ester within about 2 hours. 23. The pharmaceutical composition of claim 22, in which the testosterone ester is a short-chain (C.sub.2-C.sub.6) or a medium-chain (C.sub.7-C.sub.13) fatty acid ester. 24. The pharmaceutical composition of claim 23, in which the testosterone ester is a medium-chain fatty acid ester selected from the group consisting of testosterone cypionate, testosterone octanoate, testosterone enanthate, testosterone decanoate, and testosterone undecanoate. 25. The pharmaceutical composition of claim 24, in which the testosterone ester is testosterone undecanoate. 26. The pharmaceutical composition of claim 22, in which the hydrophilic surfactant exhibits an HLB of 10 to 45. 27. The pharmaceutical composition of claim 26, in which the hydrophilic surfactant is selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, hydrogenated castor oil ethoxylates, PEG mono- and di-esters of palmitic and stearic acids, fatty acid ethoxylates, and combinations thereof. 28. The pharmaceutical composition of claim 27, in which the hydrophilic surfactant is a hydrogenated castor oil ethoxylate. 29. The pharmaceutical composition of claim 22, in which the lipophilic surfactant exhibits an HLB of less than 10. 30. The pharmaceutical composition of claim 22, in which the digestible oil is a vegetable oil selected from the group consisting of soybean oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil, arachis oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage oil, peppermint oil and apricot kernel oil. 31. The pharmaceutical composition of claim 22, which comprises one or more additional lipid-soluble therapeutic agents. 32. The pharmaceutical composition of claim 31, in which the one or more additional lipid-soluble therapeutic agents are selected from the group consisting of a synthetic progestin, an inhibitor of type-I and/or type II 5.alpha.-reductase, finasteride, dutasteride and combinations thereof. 33. The pharmaceutical composition of claim 32, in which the one or more additional lipid-soluble therapeutic agents comprises a second testosterone ester. 34. The pharmaceutical composition of claim 22 filled into a hard or soft gelatin capsule. 35. The pharmaceutical composition of claim 22, which exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, indicating release from the composition of substantially all of the solubilized testosterone ester within about 1 hour. 36. A pharmaceutical composition suitable for oral administration to a mammalian subject, comprising: (a) 15-20 percent by weight of solubilized testosterone undecanoate; (b) 5-20 percent by weight of a hydrogenated castor oil ethoxylate; (c) 50-70 percent by weight of oleic acid; and (d) 10-15 percent by weight of digestible oil, which composition is free of ethanol and exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, which indicates release from the composition of substantially all of the solubilized testosterone ester within about 2 hours. 37. A pharmaceutical composition suitable for oral administration to a mammalian subject, comprising: (a) 15-20 percent by weight of solubilized testosterone ester; (b) 5-20 percent by weight of hydrophilic surfactant; (c) 50-70 percent by weight of a lipophilic surfactant which is a C.sub.14-C.sub.24 fatty acid; and (d) 10-15 percent by weight of digestible oil, which composition exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, which indicates release from the composition of substantially all of the solubilized testosterone ester within about 2 hours. 38. The pharmaceutical composition of claim 37, in which the testosterone ester is a short-chain (C.sub.2-C.sub.6) or a medium-chain (C.sub.7-C.sub.13) fatty acid ester. 39. The pharmaceutical composition of claim 38, in which the testosterone ester is a medium-chain fatty acid ester selected from the group consisting of testosterone cypionate, testosterone octanoate, testosterone enanthate, testosterone decanoate, and testosterone undecanoate. 40. The pharmaceutical composition of claim 39, in which the testosterone ester is testosterone undecanoate. 41. The pharmaceutical composition of claim 37, in which the hydrophilic surfactant exhibits an HLB of 10 to 45. 42. The pharmaceutical composition of claim 41, in which the hydrophilic surfactant is selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, hydrogenated castor oil ethoxylates, PEG mono- and di-esters of palmitic and stearic acids, fatty acid ethoxylates, and combinations thereof. 43. The pharmaceutical composition of claim 42, in which the hydrophilic surfactant is a hydrogenated castor oil ethoxylate. 44. The pharmaceutical composition of claim 37, in which the lipophilic surfactant exhibits an HLB of less than 10. 45. The pharmaceutical composition of claim 44, in which the lipophilic surfactant exhibits an HLB of less than 5. 46. The pharmaceutical composition of claim 45, in which the lipophilic surfactant exhibits an HLB of 1 to 2. 47. The pharmaceutical composition of claim 44, in which the lipophilic surfactant is selected from the group consisting of myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. 48. The pharmaceutical composition of claim 37, in which the digestible oil is a vegetable oil selected from the group consisting of soybean oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil, arachis oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage oil, peppermint oil and apricot kernel oil. 49. The pharmaceutical composition of claim 37, which comprises one or more additional lipid-soluble therapeutic agents. 50. The pharmaceutical composition of claim 49, in which the one or more additional lipid-soluble therapeutic agents are selected from the group consisting of a synthetic progestin, an inhibitor of type-I and/or type II 5.alpha.-reductase, finasteride, dutasteride and combinations thereof. 51. The pharmaceutical composition of claim 50, in which the one or more additional lipid-soluble therapeutic agents comprises a second testosterone ester. 52. The pharmaceutical composition of claim 37 filled into a hard or soft gelatin capsule. 53. The pharmaceutical composition of claim 37, which exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, indicating release from the composition of substantially all of the solubilized testosterone ester within about 1 hour. 54. A pharmaceutical composition suitable for oral administration to a mammalian subject, comprising: (a) 15-20 percent by weight of solubilized testosterone undecanoate; (b) 5-20 percent by weight of a hydrogenated castor oil ethoxylate; (c) 50-70 percent by weight of oleic acid; and (d) 10-15 percent by weight of digestible oil, which composition exhibits a percent (%) in vitro dissolution profile in phosphate buffered saline, which indicates release from the composition of substantially all of the solubilized testosterone ester within about 2 hours. 55. A method of alleviating symptoms of testosterone deficiency in a mammalian subject, comprising orally administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 1, 2, 3, 16, 17, 9, 10, 32, 33, or 48. 56. The method of claim 55, in which the mammalian subject is a human male. 57. The method of claim 55, in which the mammalian subject is a human female. 58. The method of claim 55, in which an effective amount of the pharmaceutical composition is administered only once or twice daily. 59. The method of claim 55, which further comprises administering an amount of a synthetic progestin sufficient to substantially inhibit gonadotropin release in said mammalian subject.