A novel mifepristone-loaded implant for long-term treatment of endometriosis: In vitro and in vivo studies

Abstract The objective of this study was to prepare a novel mifepristone-loaded PCL/Pluronic F68 implant to achieve long-term treatment of endometriosis. PCL/Pluronic F68 compound (90/10, w/w) with viscosity average molecular weight of 65,000 was successfully synthesized. The end-capped Pluronic F68 was incorporated in PCL matrixes as molecular dispersion without forming a copolymer. The mifepristone-loaded implant made of PCL/Pluronic F68 compound was a cylindrical capsule with an outer diameter of 2.5 mm and an inner diameter of 2.2 mm. The surface of PCL/Pluronic F68 compound appears porous because Pluronic F68 which is water soluble could leach out due to the water phase. Drug loading of 0.75-, 1.5- and 3.0-cm length implants was 3.05 ± 0.18, 6.06 ± 0.41 and 11.87 ± 0.39 mg, respectively. A sustained mifepristone release rate without obvious initial burst and later decline over a period of 180 d was observed. The cumulative drug release showed a linear relationship with time, indicating that mifepristone release from the implants followed zero-order kinetics ( R 2  > 0.99). The data showed that the C max and AUC 0–inf were proportional to imlant length and dose, and all groups reached plasma C max at about the same time (approximately 7 d) and had similar T 1/2 (approximately 150 d) and MRT (approximately 220 d). There were obvious inhibitory effects on the growth of endometrial explants in Wister rats in a dose-dependent manner after administration of mifepristone-loaded implants with implant length from 1.5 to 9.0 cm for 1–3 months. However, mifepristone-loaded implants with implant length of 12.0 cm had no better inhibitory effects on the growth of endometrium when compared with the implants with implant length of 9.0 cm ( P  > 0.05). In conclusion, subcutaneous implantation of mifepristone-loaded PCL/Pluronic F68 capsules was proven an effective means for long-term treatment of chronic endometriosis.