Details for Patent: 9,617,303

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)
Filing Date:	Nov 19, 2014
Application Number:	14/547,467
Claims:	1. A method for treating prostate cancer, prostatic hyperplasia, endometriosis, uterine fibroid, uterine fibroma, precocious puberty, dysmenorrhea, or breast cancer, or a method of contraception, comprising administering to a mammal an effective amount of a sustained-release composition in which a physiologically active substance, which is a peptide of formula: 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 method 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 method 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, and the sustained-release composition comprises maintaining an effective drug blood level over a period of about 60 days to 130 days by in vivo release of the physiologically active substance from the sustained-release composition. 4. The method 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, and the sustained-release composition comprises maintaining an effective drug blood level over a period of about 120 days to 400 days by in vivo release of the physiologically active substance from the sustained-release composition. 5. The method according to claim 1, wherein a ratio of stearic acid to the total microcapsules is about 0.01 to about 50% by weight. 6. The method according to claim 1, wherein an amount of stearic acid to be added is 0.1 to 10 moles relative to one mole of the water-soluble physiologically active peptide or the salt thereof. 7. The method according to claim 1, wherein the sustained-release composition is easily dispersible in a disperse medium. 8. The method according to claim 7, wherein the sustained-release composition is stable for 24 hours or more after dispersion in the disperse medium. 9. The method 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. 10. The method 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. 11. The method according to claim 1, wherein the lactic acid polymer is polylactic acid. 12. The method according to claim 1, wherein the lactic acid polymer is poly-DL-lactic acid. 13. The method according to claim 1, wherein the lactic acid polymer is a lactic acid-glycolic acid polymer. 14. The method according to claim 13, wherein a composition ratio of lactic acid/glycolic acid in the lactic acid-glycolic acid polymer is 60/40 to 99.9/0.1. 15. The method according to claim 1, wherein the lactic acid polymer is a polymer containing a polymer having a molecular weight of 5,000 or less whose content is about 5.0% by weight or less. 16. The method according to claim 1, wherein the lactic acid polymer is a polymer containing a polymer having a molecular weight of 3,000 or less whose content is about 1.5% by weight or less. 17. The method according to claim 1, wherein the lactic acid polymer is a polymer containing a polymer having a molecular weight of 1,000 or less whose content is about 0.1% by weight or less. 18. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is 12,000 to 19,000. 19. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is 13,000 to 18,000. 20. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is 19,500 to 26,500. 21. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11,600 to about 20,000, and the sustained-release composition is characterized in that a ratio of a maximum blood concentration of a physiologically active substance within 24 hours after the administration to an average blood concentration of the physiologically active substance for a period from 24 hours to one month after the administration is 2 to 50. 22. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11,600 to about 20,000, and the sustained-release composition is characterized in that a ratio of a maximum blood concentration of a physiologically active substance within 24 hours after the administration to an average blood concentration of the physiologically active substance for a period from one month to three months after the administration is 20 to 350. 23. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11,600 to about 20,000, and the sustained-release composition is characterized in that area under the blood concentration-time curve (AUC) of a physiologically active substance within 24 hours after the administration calculated from the blood concentration is 3% to 30% of the whole AUC. 24. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19,000 to about 27,000, and the sustained-release composition is characterized in that a ratio of a maximum blood concentration of a physiologically active substance within 24 hours after the administration to an average blood concentration of the physiologically active substance for a period from 24 hours to one month after the administration is 10 to 90. 25. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19,000 to about 27,000, and the sustained-release composition is characterized in that a ratio of a blood maximum concentration of a physiologically active substance within 24 hours after the administration to an average blood concentration of the physiologically active substance for a period from one month to six months after the administration is 20 to 500. 26. The method according to claim 2 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19,000 to about 27,000, and the sustained-release composition is characterized in that area under the blood concentration-time curve (AUC) of a physiologically active substance within 24 hours after the administration calculated from the blood concentration is 1% to 20% of the whole AUC. 27. A method for reducing premenopausal breast cancer postoperative recurrence, comprising administering to a mammal an effective amount of a sustained-release composition in which a physiologically active substance, which is a peptide of formula: 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, and 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.