米非司酮阴道环的处方前研究

Pre-formulation study on mifepristone-loaded vaginal ring

目的:对米非司酮进行处方前研究,为设计优良的缓释米非司酮阴道环的处方提供依据。方法:采用紫外-可见分光光度法测定米非司酮在水和磷酸盐缓冲液(pH4.0和pH6.8)介质中的溶解度;以差式扫描量热法(DSC)对米非司酮在硅橡胶中的溶解度进行测定;以PVPK30为载体,制备米非司酮固体分散体,并测定其在pH4.0磷酸盐缓冲液中的溶解度;分别考察了含有米非司酮、米非司酮与辅料PVPK30物理混合物及固体分散体的阴道环的体外释放度,以及米非司酮与辅料PVPK30和载体硅橡胶之间的相容性。结果:米非司酮在水和磷酸盐缓冲液介质中于24 h内稳定性良好,在pH4.0磷酸盐缓冲液中的溶解度最大,而米非司酮固体分散体在pH4.0磷酸盐缓冲液中的溶解度则显著增加;米非司酮在硅橡胶中的溶解度为16.80 mg·g-1;载有米非司酮原料药和物理混合物的阴道环无法释放出药物,而含有米非司酮固体分散体的阴道环则能很好地释放药物;米非司酮与辅料PVPK30和硅橡胶的混合物在光照、高温及高湿条件下有关物质未见显著增加。结论:处方前研究表明米非司酮适合制备成阴道黏膜给药系统,固体分散技术是制备米非司酮阴道环的关键技术,它能够使难溶性药物从载体硅橡胶中释放出来。米非司酮与辅料PVPK30和载体硅橡胶之间的相容性良好。

OBJECTIVE To study the properties of mifepristone for designing the optimal vaginal ring containing mifepris- tone. METHODS The saturation concentrations of mifepristone in water and phosphate buffer （pH 4. 0 and pH 6. 8） were in- vestigated by UV visible spectrophotometric method. The solubility of mifepristone in silicone elastomer was determined by dif- ferential scanning calorimeter. The solid dispersion （SD） was prepared with PVPK30 as the carrier,and the solubility of SD of mifepristone in pH 4. 0 phosphate buffer was determined. The drug release in vitro characteristics of vaginal rings containing free mifepristone, physical mixture and solid dispersion of mifepristone with PVPK30 were compared. The eompatibilities of mifepristone with PVPK30 or silicon elastomer were evaluated. RESULTS Mifepristone had a good solubility in pH 4. 0 phos- phate buffer and stability in water and phosphate buffer within 24 h, and the solubility of solid dispersion of mifepristone was found to be significantly increased than that of mifepristone in pH 4. 0 phosphate buffer. The solubility of mifepristone in sili- cone elastomer was 16. 80 mg.g 1. Mifepristone could only be released from the vaginal rings loading solid dispersion of mile pristone with PVPK30. There was no significant change on the related substance of mifepristone with PVPK30 or silicon elas tomer under light radiation, high temperature and high humidity. CONCLUSION The vaginal drug delivery system is suitable for the delivery of mifeprisotne. The solid dispersion technology is an important factor to ensure mifepristone release from drug- loaded vaginal ring. Finally mifepristone has a good capacitability with PVPK30 and silicon elastomer, there are no obvious in-teractions between them.