LIPID COMPOSITION

• US 20110039814A1
• Filed: 04/27/2009
• Published: 02/17/2011
• Est. Priority Date: 04/28/2008
• Status: Active Grant

• Current Assignee: Diurnal Limited (Neurocrine Biosciences Inc.)
• Original Assignee: Diurnal Limited (Neurocrine Biosciences Inc.)
• Inventors: Huatan, Hiep, Ross, Richard
• Granted Patent: US 9,012,436 B2
• Time in Patent Office: Days
• US Class Current: 514/180
• 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• 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: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

We describe lipid based pharmaceutical compositions adapted for oral delivery and optionally delivery in accordance with a circadian rhythm.

Claims

1. A pharmaceutical composition adapted for oral delivery of testosterone or a functional variant of testosterone comprising:

testosterone, or a functional variant of testosterone,

a lipid based carrier wherein said carrier includes at least one triglyceride fatty acid wherein the fatty acid is at least 10 carbon atoms in length; and

at least one agent that enhances the solubility of testosterone or said functional variant in the composition.

2. The composition according to claim 1 wherein said functional variant is testosterone propionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate, testosterone buciciate, methyltestosterone, fluoxymesterone or mesterolone.

3. The composition according to claim 1 wherein said fatty acid chain length is 10-22 carbon atoms.

4. The composition according to claim 3 wherein said fatty acid chain is 14-18 carbon atoms in length.

5. The composition of claim 1 wherein the ratio of unsaturated fatty acid to saturated fatty acid is at least or greater than 3.

6. The composition of claim 1 wherein said fatty acid is monosaturated.

7. The composition according to claim 6 wherein said monosaturated fatty acid is at least 30% of the lipid content of the composition.

8. The composition of claim 1 wherein said fatty acid is polysaturated.

9. The composition according to claim 8 wherein said polysaturated fatty acid is at least 30% of the lipid content of the composition.

10. The composition of claim 1 wherein said fatty acid is an essential fatty acid.

11. The composition according to claim 10 wherein said essential fatty acid is linoleic acid, linolenic acid, oleic acid, myristoleic acid, palmitoleic acid, arachidonic acid, eicosapentaenoic acid, erucic acid or docohexaenoic acid.

15. The composition of claim 1 wherein said lipid based carrier is oil.

16. The composition according to claim 15 wherein said oil is a vegetable oil.

17. The composition according to claim 16 wherein said vegetable oil is almond oil, arachis oil, canola oil, cod liver oil, corn oil, cotton seed oil, flaxseed oil, grape seed oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower oil or walnut oil.

19. The composition according to claim 16 wherein said vegetable oil includes at least one polyalkylene polyol.

20. The composition according to claim 19 wherein said polyalkylene polyol is polyoxyethylated apricot kernel oil, polyoxyethylated corn oil or polyethylated hydrogenated coconut.

21. The composition of claim 1 wherein said lipid based carrier includes at least one or a combination of fatty acids selected from the group consisting of:

caprylic/capric triglycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/myristic/stearic fatty acid triglycerides, capylic/capric/succinic fatty acid triglycerides, caprylic/capric triglycerides with stearalkonium benonite and propylene carbonate, caprylic/capric triglycerides with stearalkonium hectorite and propylene carbonate.

22. The composition of claim 1 wherein said lipid based carrier includes at least one or a combination of coco-glycerides or coco triglycerides.

23. The composition of claim 1 wherein said lipid based carrier comprises or consists of myristic acid triglyceride, palmitic acid triglyceride or stearic acid triglyceride.

26. The composition of claim 1 wherein said lipid based carrier comprises a combination of a triglyceride and a polyalkylene polyol.

27. The composition according to claim 26 wherein said polyalkylene polyol is polyoxyethylated apricot kernel oil, polyoxyethylated corn oil or polyoxyethylated coconut oil.

28. The composition of claim 1 wherein said lipid based carrier comprises a propylene glycol fatty acid.

29. The composition according to claim 28 wherein said propylene glycol fatty acid is a monoester.

30. The composition according to claim 29 wherein said monoester is propylene glycol monolaurate or propylene glycol monomyristate.

31. The composition according to claim 30 wherein said monoester is propylene glycol monolaurate.

32. The composition according to claim 28 wherein said propylene glycol fatty acid is a diester.

33. The composition according to claim 32 wherein said diester is dicaprylate/dicaprate, prolylene glycol dicaprylate/dicaprate or propylene glycol dicaprylate/dicaprate.

34. The composition of claim 1, wherein said solubalizing agent is ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, diethylene glycol monoethyl ether, cremaphor, polysorbate (Tween 80), or combinations thereof.

36. The composition of claim 1, wherein said composition comprises:

testosterone, sesame oil, lauroglycol, ethanol and benzyl alcohol.

37. The composition according to claim 36 wherein said composition consists essentially of:

2.5-7.5% w/w testosterone;

at least 40% w/w sesame oil;

at least 30% w/w lauroglycol;

at least 5% w/w ethanol; and

at least 15% w/w benzyl alcohol.

38. The composition according to claim 37 wherein said composition consists of testosterone, sesame oil, lauroglycol, ethanol and benzyl alcohol as described in table 2.

41. A method to treat a condition that would benefit from testosterone or a functional variant of testosterone replacement therapy comprising:

administering an effective amount of the composition of claim 1 to a subject in need of testosterone replacement wherein the composition is administered in accordance with the circadian secretion of testosterone to provide physiological replacement of testosterone.

42. The method according to claim 41 wherein said functional variant is testosterone propionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate, testosterone buciciate, methyltestosterone, fluoxymesterone or mesterolone.

43. The method according to claim 41 wherein said composition is administered prior to sleep.

44. The method according to claim 43 wherein said composition is administered between 20:

00 and 24;

00.

45. The method of claim 41, wherein testosterone replacement therapy is the treatment of male hypogonadism.

12-14. -14. (canceled)

18. (canceled)

24-25. -25. (canceled)

35. (canceled)

39-40. -40. (canceled)

46. A pharmaceutical composition adapted for oral delivery of a steroid comprising:

a steroid,

a lipid based carrier wherein said carrier includes at least one triglyceride fatty acid wherein the fatty acid is at least 10 carbon atoms in length and at least one agent that enhances the solubility of the steroid in the composition

47. The composition according to claim 46 wherein said steroid hormone is an oestrogen.

48. The composition according to claim 47 wherein said oestrogen is selected from the group consisting of:

oestradiol, estriol and estrone.