A novel mifepristone-loaded implant for long-term treatment of endometriosis: in vitro and in vivo studies.
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 2.5mm and an inner diameter of 2.2mm. 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+/-0.39mg, respectively. A sustained mifepristone release rate without obvious initial burst and later decline over a period of 180d 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 7d) and had similar T(1/2) (approximately 150d) and MRT (approximately 220d). 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 9.0cm for 1-3 months. However, mifepristone-loaded implants with implant length of 12.0cm had no better inhibitory effects on the growth of endometrium when compared with the implants with implant length of 9.0cm (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.
Mei
Lin
L
Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, The Tianjin Key Laboratory of Biomaterial Research, 236 Baidi Road, Nankai District, Tianjin 300192, China.
Bao
Junbo
J
Tang
Lina
L
Zhang
Chao
C
Wang
Hai
H
Sun
Leilei
L
Ma
Guilei
G
Huang
Laiqiang
L
Yang
Jing
J
Zhang
Linhua
L
Liu
Kexin
K
Song
Cunxian
C
Sun
Hongfan
H
D000818:Animals; D004195:Disease Models, Animal; D004343:Drug Implants; D004715:Endometriosis / Q000188:drug therapy*; D005260:Female; D006727:Hormone Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D015735:Mifepristone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008970:Molecular Weight; D051381:Rats; D017208:Rats, Wistar; D017550:Spectroscopy, Fourier Transform Infrared
D004343:Drug Implants; D006727:Hormone Antagonists; D015735:Mifepristone