一种基于体内释药行为的胸腺五肽微球体外加速释放方法（英文）

An in vitro accelerated approach based on in vivo release to assess thymopentin release from PLGA microspheres

目的建立一种与体内释药数据相关的体外加速释药评价方法，用于胸腺五肽微球的处方优化和质量控制。方法残留法测定微球在大鼠体内的释放情况，绘制体内累积释药曲线；对体外加速释放的重要条件进行筛选，包括释放介质种类、乙醇浓度、表面活性剂浓度、加热温度，进行体内外释放相关性拟合，最大程度模拟体内释放，并采用最终优化的条件验证另两种处方。结果最终优化的体外释放条件为：20%（V/V）乙醇中含0.06%（W/V）Tween 80作为释放介质，程序升温（0～1 h 40°C，1～6 h 45°C，6～30 h 50°C）的方法用于介质加热，（8、13和28）×1033种相对分子质量PLGA制备的微球体外加速曲线与体内释药曲线相关系数r2依次为0.9783、0.9886和0.9780。结论释放介质中加入乙醇并采取程序升温的办法，能最大程度模拟体内释药，可用于胸腺五肽微球的处方优化和质量控制。

Objective To establish an accelerated method that has good correlations with in vivo release data for formulation optimization and quality control purposes of thymopentin-loaded poly（DL-lactide-co-glycolide）（PLGA）microspheres. Methods In vivo thymopentin release from the microspheres was studied in Sprague-Dawley rats and relevant cumulative release curves were plotted. Key factors including release medium types,ethanol concentrations,surfactant concentrations and heating temperature were investigated for the in vitro accelerated release. The conditions for accelerated release were optimized to make the accelerated release cures fit the in vivo release well. The final optimized accelerated release method was validated in other two formulations. Results The final optimized accelerated release conditions were： 20% hydro-alcoholic solutions （V/V）and 0.06% Tween 80 （W/V）as the release media,gradient heating program （0-1 h at 40 °C,1-6 h at 45 °C and 6-30 h at 50 °C）as the media heating method. After fitted with the in vivo release curves,the correlation constant r2 of （8,13 and 28）×103 PLGA microspheres was 0.9783,0.9886 and 0.9780,respectively. Conclusion By introducing alcohol into the release media and applying gradient heating program,the reported accelerated method can be used in the formulation optimization and quality control of thymopentin-loaded PLGA microspheres.