Claims for Patent: 9,617,303

Summary 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, Saito Kazuhiro, Hoshino Tetsuo, Hori Masuhisa
Assignee:	Takeda Pharmaceutical Company Limited
Application Number:	US14547467
Patent 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—CHor 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 wherein the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11 claim 2 ,600 to about 20 claim 2 ,000 claim 2 , 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 wherein the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19 claim 2 ,000 to about 27 claim 2 ,000 claim 2 , 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 wherein the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11 claim 2 ,600 to about 20 claim 2 ,000 claim 2 , 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 wherein the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19 claim 2 ,000 to about 27 claim 2 ,000 claim 2 , 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 claim 1 ,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 claim 1 ,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 claim 1 ,000 or less whose content is about 0.1% by weight or less.18. The method according to in which the weight-average molecular weight (Mw) of the lactic acid polymer is 12 claim 2 ,000 to 19 claim 2 ,000.19. The method according to in which the weight-average molecular weight (Mw) of the lactic acid polymer is 13 claim 2 ,000 to 18 claim 2 ,000.20. The method according to in which the weight-average molecular weight (Mw) of the lactic acid polymer is 19 claim 2 ,500 to 26 claim 2 ,500.21. The method according to in which the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11 claim 2 ,600 to about 20 claim 2 ,000 claim 2 , 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 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11 claim 2 ,600 to about 20 claim 2 ,000 claim 2 , 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 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (i) about 11 claim 2 ,600 to about 20 claim 2 ,000 claim 2 , 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 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19 claim 2 ,000 to about 27 claim 2 ,000 claim 2 , 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 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19 claim 2 ,000 to about 27 claim 2 ,000 claim 2 , 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 in which the weight-average molecular weight (Mw) of the lactic acid polymer is (ii) about 19 claim 2 ,000 to about 27 claim 2 ,000 claim 2 , 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 claim 2 , comprising administering to a mammal an effective amount of a sustained-release composition in which a physiologically active substance claim 2 , which is a peptide of formula: 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH—CHor an acetate thereof claim 2 , is substantially uniformly dispersed in a microcapsule comprised of a lactic acid polymer or a salt thereof claim 2 , wherein the physiologically active substance is contained in an amount of 15 to 35 (weight/weight) % to the total microcapsules claim 2 , and weight-average molecular weight (Mw) of the lactic acid polymer is about 11 claim 2 ,000 to about 27 claim 2 ,000 and the sustained-release composition further contains stearic acid.