Details for Patent: 9,713,595

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 Pharmaceuticals Company Limited (Osaka, JP)
Filing Date:	Feb 28, 2017
Application Number:	15/444,712
Claims:	1. A process for preparation of a sustained-release composition of a microcapsule containing 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, at 15 to 35% by weight to the whole microcapsules, comprising steps of: (i) dissolving a lactic acid polymer or a salt thereof having a weight-average molecular weight (Mw) of about 11,000 to about 27,000 in a volatile water-immiscible first solvent to prepare a first solution, (ii) dissolving the physiologically active substance comprised of a water-soluble physiologically active peptide in a water-miscible second solvent to prepare a second solution, (iii) 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, (iv) dispersing the resultant third solution in a fourth solution comprised of an aqueous solution of a surfactant to prepare an O/W emulsion, and (v) removing the first solvent and the second solvent from the microcapsule by an in-water drying method at a controlled temperature of about 15 to about 35.degree. C., which is characterized in that stearic acid is further added to the first solution and/or the second solution or the third solution. 2. The process according to claim 1, wherein the weight-average molecular weight (Mw) of the lactic acid polymer is about 11,600 to about 20,000. 3. The process according to claim 1, wherein the weight-average molecular weight (Mw) of the lactic acid polymer is about 19,000 to about 27,000. 4. The process according to claim 1, characterized in that 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 step (i). 5. The process according to claim 1, characterized in that the respective temperatures of the third solution and the fourth solution in the preparation of the O/W emulsion are adjusted to about 15 to about 35.degree. C. 6. The process for the preparation of a sustained-release composition according to claim 1, which is characterized in that thereof stearic acid is dissolved in the second solution. 7. The process for the preparation of a sustained-release composition according to claim 1, which is characterized in that a loading amount of the physiologically active substance in the preparation of the third solution is 17 to 50% by weight. 8. The process for the preparation of a sustained-release composition according to claim 1, which is characterized in that a content of the contained physiologically active substance is 17 to 26 (weight/weight) % to the total microcapsules. 9. The process for the preparation of a sustained-release composition according to claim 8, which is characterized in that a loading amount of the physiologically active substance in the preparation of the third solution is 19 to 38% by weight. 10. The process for the preparation of a sustained-release composition according to claim 8, which is characterized in that a loading amount of the physiologically active substance in the preparation of the third solution is 20 to 23% by weight. 11. The process for the preparation of a sustained-release composition according to claim 1, which is characterized by 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. 12. The process for the preparation of a sustained-release composition according to claim 1, which is characterized by 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.