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Claims for Patent: 8,921,326

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Claims for Patent: 8,921,326

Title:Sustained-release composition and method for producing the same
Abstract: Sustained-release compositions wherein a water-soluble physiologically active peptide is substantially uniformly dispersed in a microcapsule comprised of a lactic acid polymer or a salt thereof, and the physiologically active substance is contained in an amount of 15 to 35 wt/wt % to the total microcapsules and weight-average molecular weight (Mw) of the lactic acid polymer is about 11,000 to about 27,000, which is characterized by having a high content of the physiologically active substance, and suppression of the initial excessive release within one day after the administration and a stable drug sustained-release over a long period of time, and method for producing the same.
Inventor(s): Futo; Tomomichi (Osaka, JP), Saito; Kazuhiro (Osaka, JP), Hoshino; Tetsuo (Osaka, JP), Hori; Masuhisa (Osaka, JP)
Assignee: Takeda Pharmaceutical Company Limited (Osaka, JP)
Application Number:12/312,751
Patent Claims: 1. A sustained-release composition in which a physiologically active substance, which is a peptide of formula: TABLE-US-00010 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C.sub.2H.sub.5

or an acetate thereof, is substantially uniformly dispersed in a microcapsule comprised of a lactic acid polymer or a salt thereof, wherein the physiologically active substance is contained in an amount of 15 to 35 (weight/weight) % to the total microcapsules, weight-average molecular weight (Mw) of the lactic acid polymer is about 11,000 to about 27,000, and the sustained-release composition further contains stearic acid.

2. The sustained-release composition according to claim 1, wherein the weight-average molecular weight (Mw) of the lactic acid polymer is any one selected from: (i) about 11,600 to about 20,000 and (ii) about 19,000 to about 27,000.

3. The sustained-release composition according to claim 1, wherein a content of the contained physiologically active substance is 17 to 26 (weight/weight) % to the total microcapsules.

4. The sustained-release composition according to claim 1 which is obtained by dissolving the lactic acid polymer or the salt thereof in a volatile water-immiscible first solvent to prepare a first solution, dissolving the physiologically active substance in a water-miscible second solvent to prepare a second solution, mixing the resultant first solution and the resultant second solution to prepare a third solution in which the lactic acid polymer or the salt thereof and the physiologically active substance are uniformly dissolved, dispersing the resultant third solution in a fourth solution comprised of an aqueous solution of an emulsifier to prepare an O/W emulsion, and removing the first solvent and the second solvent from the generated microcapsule.

5. The sustained-release composition according claim 4, wherein a mixed solvent in which a water-miscible third solvent is further added to the first solvent is used as a solvent for dissolving the lactic acid polymer or the salt thereof in the preparation of the first solution.

6. The sustained-release composition according to claim 4, wherein a controlled temperature of the emulsifying step is adjusted to about 15 to about 35.degree. C. in the step of removing the first solvent and the second solvent from the microcapsule.

7. The sustained-release composition according claim 6, wherein the temperature control of the emulsifying step is performed by adjusting the temperature of the O/W emulsion to about 15 to 35.degree. C.

8. The sustained-release composition according to claim 4, wherein the respective temperatures of the third solution and the fourth solution in the preparation of the O/W emulsion are about 15 to about 35.degree. C.

9. The sustained-release composition according to claim 4, wherein the step of removing the first solvent and the second solvent from the microcapsule is performed by an in-water drying method.

10. The sustained-release composition according to claim 4, wherein the first solvent is dichloromethane.

11. The sustained-release composition according to claim 4, wherein the second solvent and/or the third solvent is a lower alcohol.

12. The sustained-release composition according to claim 11, wherein the lower alcohol is methanol, ethanol, or propanol.

13. The sustained-release composition according to claim 4, wherein a volume ratio of the water-immiscible solvent and the water-miscible solvent in the third solution is 35:65 to 55:45.

14. The sustained-release composition according to claim 4, wherein a polymer concentration in the first solution is about 33 to 45% by weight.

15. The sustained-release composition according to claim 4, wherein a loading amount of the physiologically active substance in the preparation of the third solution is 17 to 50% by weight.

16. The sustained-release composition according to claim 4, wherein a content of the contained physiologically active substance is 17 to 26 (weight/weight) % to the total microcapsules.

17. The sustained-release composition according to claim 16, wherein a loading amount of the physiologically active substance in the preparation of the third solution is 19 to 38% by weight.

18. The sustained-release composition according to claim 16, wherein a loading amount of the physiologically active substance in the preparation of the third solution is 20 to 23% by weight.

19. The sustained-release composition according to claim 1, wherein a ratio of said stearic acid to the total microcapsules is about 0.01 to about 50% by weight.

20. The sustained-release composition according to claim 1, wherein an amount of said stearic acid to be added is 0.1 to 10 moles relative to one mole of the peptide or an acetate thereof.

21. The sustained-release composition according to claim 2 wherein the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11,600 to about 20,000, which is characterized in that a ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) is more than 1.9.

22. The sustained-release composition according to claim 2 wherein the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19,000 to about 27,000, which is characterized in that a ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) is more than 1.5.

23. The sustained-release composition according to claim 1, wherein the lactic acid polymer is polylactic acid.

24. The sustained-release composition according to claim 1, wherein the lactic acid polymer is poly-DL-lactic acid.

25. The sustained-release composition according to claim 1, wherein the lactic acid polymer is a lactic acid-glycolic acid polymer.

26. The sustained-release composition according to claim 25, wherein a composition ratio of lactic acid/glycolic acid in the lactic acid-glycolic acid polymer is 60/40 to 99.9/0.1.

27. The sustained-release composition according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is 12,000 to 19,000.

28. The sustained-release composition according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is 13,000 to 18,000.

29. The sustained-release composition according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is 19,500 to 26,500.

30. A pharmaceutical composition comprising the sustained-release composition according to claim 1.

31. A prophylactic or therapeutic agent for prostate cancer, prostatic hyperplasia, endometriosis, uterine fibroid, uterine fibroma, precocious puberty, dysmenorrhea, or breast cancer, or a contraceptive agent, comprising the sustained-release composition according to claim 1.

32. A prophylactic agent for premenopausal breast cancer postoperative recurrence, comprising the sustained-release composition according to claim 1.

33. The sustained-release composition according to claim 1, wherein the amount of said stearic acid to be added is 0.25 to 2 moles relative to one mole of the peptide or an acetate thereof.

34. The sustained-release composition according to claim 1, which does not contain hydroxynaphthoic acid.
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