Testosterone ester triglyceride preparations

Abstract

The present invention provides a photostable testosterone ester pharmaceutical formulation for parenteral administration. [Solution] A testosterone ester triglyceride formulation is provided, which further contains an adduct to testosterone ester containing an antioxidant and a triglyceride. A method for measuring the photostability of a testosterone ester pharmaceutical formulation is also provided.

Claims

1. A pharmaceutical preparation for parenteral administration, Formula 1: 【Chemistry 1】 Testosterone ester, antioxidant, and formula 2: 【Chemistry 2】 It comprises a pharmaceutically acceptable carrier comprising triglycerides, During the ceremony: R １ is an alkyl or alkenyl substituent; R ２ , R ３ , and R ４ Each of these is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The aforementioned pharmaceutical preparation.

2. R １ The pharmaceutical formulation according to claim 1, wherein the active ingredient is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentyl ethyl, and unsaturated analogs thereof.

3. The pharmaceutical formulation according to claim 1, wherein the testosterone ester is testosterone enanthate, testosterone cypionic acid, testosterone propionic acid, or testosterone undecanoate.

4. The pharmaceutical formulation according to claim 1, wherein the testosterone ester is testosterone enanthate.

5. The pharmaceutical formulation according to claim 1, wherein the triglyceride is selected from the group consisting of LLL, OLL, OOL, OOO, PLL, POL, POO, and SOL.

6. A pharmaceutical formulation according to claim 1, wherein the pharmaceutically acceptable carrier includes a vegetable oil.

7. The pharmaceutical preparation according to claim 6, wherein the vegetable oil is sesame oil.

8. The pharmaceutical formulation according to claim 1, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and monosodium glutamate.

9. The pharmaceutical formulation according to claim 1, wherein the testosterone ester is testosterone enanthate, the pharmaceutically acceptable carrier contains sesame oil, and the antioxidant is BHT.

10. The pharmaceutical formulation according to claim 9, wherein the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL.

11. A pharmaceutical preparation according to claim 10, wherein the concentration of BHT is 0.01% to 0.1%.

12. A pharmaceutical preparation according to claim 10, wherein the concentration of BHT is 0.1 mg / mL to 1 mg / mL.

13. Formula 3: 【Transformation 3】 A testosterone ester adduct, During the ceremony: R １ These are alkyl or alkenyl substituents, which may be the same or different in each independent occurrence; R ５ This is an acyl group corresponding to an unsaturated fatty acid; G is a glycerol, monoglyceride, or diglyceride residue; n is 1, 2, or 3; and Testosterone residues are R ５ Linked to the allyl carbon or double allyl carbon, The aforementioned testosterone ester adduct.

14. Formula 4: 【Chemistry 4】 A testosterone ester adduct according to claim 13, having the following characteristics.

15. R １ which, upon each independent occurrence, is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and unsaturated analogs thereof, of the testosterone ester of claim 13 Additions.

16. R １ The testosterone ester adduct of claim 13, wherein is hexyl.

17. Formulas 5, 6, 7, 8, or 9: 【Chemistry 5-1】 【Chemistry 5-2】 It has, In the formula, R ６ and R ７ Each of these is independently an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The testosterone ester adduct according to claim 13.

18. Formula 10: 【Transformation 6】 A testosterone ester adduct according to claim 13, having the following characteristics.

19. Formula 11: 【Transformation 7】 A testosterone ester adduct according to claim 13, having the following characteristics.

20. A pharmaceutical preparation for parenteral administration comprising a pharmaceutically acceptable carrier comprising a testosterone ester of formula 1, a triglyceride of formula 2, and optionally a testosterone ester adduct according to any one of claims 13 to 19 at a concentration of 0.000 mg / ml to 25 mg / ml, wherein: R １ is an alkyl or alkenyl substituent; and R ２ , R ３ , and R ４ Each of these is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The aforementioned pharmaceutical preparation.

21. R １ The pharmaceutical formulation of claim 20, wherein, at each independent appearance, is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentyl ethyl, and their unsaturated analogs.

22. The pharmaceutical formulation according to claim 20, wherein the testosterone ester is testosterone enanthate, testosterone cypionic acid, testosterone propionic acid, or testosterone undecanoate.

23. The pharmaceutical formulation according to claim 20, wherein the testosterone ester is testosterone enanthate.

24. The pharmaceutical formulation according to claim 20, wherein the triglyceride is selected from the group consisting of LLL, OLL, OOL, OOO, PLL, POL, POO, and SOL.

25. The pharmaceutical formulation according to claim 20, wherein the pharmaceutically acceptable carrier includes a vegetable oil.

26. The pharmaceutical formulation according to claim 20, further comprising an antioxidant.

27. The pharmaceutical formulation according to claim 26, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and monosodium glutamate.

28. The pharmaceutical formulation of claim 26, wherein the testosterone ester is testosterone enanthate, the pharmaceutically acceptable carrier contains sesame oil, the antioxidant is BHT, and the testosterone adduct has formula 10.

29. A pharmaceutical formulation according to claim 28, further comprising a testosterone ester adduct of formula 11.

30. The pharmaceutical formulation of claim 26, wherein the testosterone ester is testosterone enanthate, the pharmaceutically acceptable carrier contains sesame oil, the antioxidant is BHT, and the testosterone ester adduct has formula 11.

31. The pharmaceutical formulation according to claim 26, wherein the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL.

32. The pharmaceutical formulation according to claim 28, wherein the concentration of BHT is 0.01% to 0.1%, or 0.1 mg / mL to 1 mg / mL.

33. The pharmaceutical formulation according to claim 28 or 29, wherein the concentration of the testosterone ester adduct of formula 10 is less than the concentration of testosterone enanthate.

34. The pharmaceutical formulation according to claim 29 or 30, wherein the concentration of the testosterone ester adduct of formula 11 is less than the concentration of testosterone enanthate.

35. A photostable testosterone ester pharmaceutical formulation for parenteral administration, comprising a pharmaceutically acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and a triglyceride of formula 2, wherein: R １ is an alkyl or alkenyl substituent; and R ２ , R ３ , and R ４ Each of these is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The photostability of the preparation is evaluated by measuring the concentration of available testosterone esters 30 to 60 days after preparation and comparing it with the initial testosterone ester concentration of the preparation.

36. A photostable testosterone ester pharmaceutical preparation for parenteral administration, comprising testosterone of formula 1. It comprises a chlorofluoroester, an antioxidant, and a pharmaceutically acceptable carrier comprising a triglyceride of formula 2, wherein: R １ is an alkyl or alkenyl substituent; and R ２ , R ３ , and R ４ Each of these is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The photostability of the preparation is evaluated by measuring the concentration of available testosterone esters within 30 to 60 days after preparation and comparing it with the initial testosterone ester concentration of the preparation, and by detecting the presence of the testosterone ester adduct of any one of claims 13 to 19 in the preparation and measuring its concentration.

37. A photostable testosterone ester pharmaceutical formulation for parenteral administration, comprising a pharmaceutically acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and a triglyceride of formula 2, wherein: R １ is an alkyl or alkenyl substituent; and R ２ , R ３ , and R ４ Each of these is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The photostability of the formulation is 200 watt-hours / m². ２ The pharmaceutical formulation is evaluated by exposing it to UV light and visible light exposure of 1.2 million lux-hours or more, measuring the concentration of available testosterone esters, and comparing it with the initial testosterone ester concentration of the formulation.

38. A photostable testosterone ester pharmaceutical formulation for parenteral administration, comprising a pharmaceutically acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and a triglyceride of formula 2, wherein: R １ is an alkyl or alkenyl substituent; and R ２ , R ３ , and R ４ Each of these is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The photostability of the formulation is 200 watt-hours / m². ２ The pharmaceutical formulation is evaluated by exposing it to UV light and visible light exposure of 1.2 million lux-hours or more, measuring the concentration of available testosterone esters, and comparing it with the initial testosterone ester concentration of the formulation to detect the presence of the testosterone ester adduct of any one of claims 13 to 19 in the formulation and measuring its concentration.

39. A photostable testosterone ester pharmaceutical formulation according to any one of claims 35 to 38, wherein the available concentration of testosterone ester is at least 66.8% to 75.0% of the initial testosterone ester concentration.

40. The photostable testosterone ester pharmaceutical formulation according to claim 36 or 38, wherein the concentration of the testosterone ester adduct in the formulation is less than the concentration of the available testosterone ester.

41. A method for measuring the photostability of a testosterone ester pharmaceutical preparation comprising a pharmaceutically acceptable carrier comprising a testosterone ester of formula 1 and a triglyceride of formula 2: The initial testosterone ester concentration of the preparation is measured; After the period has elapsed, measure the concentration of available testosterone ester in the preparation; and Let's compare these two concentrations. This includes, Here: R １ is an alkyl or alkenyl substituent; and R ２ , R ３ , and R ４ Each of these is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. The aforementioned method.

42. The pharmaceutical preparation is administered at 200 watt-hours / m². ２ The method of claim 41, further comprising exposure to UV light and visible light exposure of 1.2 million lux hours or more.

43. The method of claim 42, wherein the pharmaceutical preparation further comprises an antioxidant selected from the group consisting of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and monosodium glutamate.

44. The method of claim 42, wherein the period is between 30 and 60 days.

45. The method of claim 42, further comprising detecting the presence of a testosterone ester adduct according to any one of claims 13 to 19 in the pharmaceutical preparation and measuring its concentration.

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