Hu Xiaoqin, Zhang Jianwei, Tang Xuemei, Li Mingyuan, Ma Siyu, Liu Cheng, Gao Yue, Zhang Yue, Liu Yan, Yu Fanglin, Yang Yang, Guo Jia, Li Zhiping, Mei Xingguo
Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430070. China.
Curr Drug Deliv. 2018;15(1):87-96. doi: 10.2174/1567201814666170516113406.
A long release period lasting several days or several weeks is always needed and thereby it is tedious and time consuming to screen formulations of such microspheres with so long release period and evaluate their release profiles in vitro with conventional long-term or "real-time" release method. So, an accelerated release testing of such system is necessary for formulation design as well as quality control purpose. The purpose of this study is to obtain an accelerated release method of risperidone loaded poly(lactic-co-glycolic acid) (PLGA) microspheres with good in vitro/in vivo correlation (IVIVC).
Two formulations of risperidone loaded PLGA microspheres used for evaluating IVIVC were prepared by O/W method. The accelerated release condition was optimized by investigating the effect of pH, osmotic pressure, temperature and ethanol concentration on the release of risperidone from microspheres and the in vitro accelerated release profiles of risperidone from PLGA microspheres were obtained under this optimized accelerated release condition. The plasma concentration of risperidone were also detected after subcutaneous injection of risperidone loaded microspheres to rats. The in vivo cumulative absorption profiles were then calculated using Wagner-Nelson model, Loo- Riegelman model and numerical convolution model, respectively. The correlation between in vitro accelerated release and in vivo cumulative absorption were finally evaluated with Least Square Method.
It was shown that temperature and ethanol concentration significantly affected the release of risperidone from the microspheres while pH and osmotic pressure of release media slightly affected the release behavior of risperidone. The in vitro release of risperidone from microspheres were finally undergone in PBS (pH7.0, 300mosm) with 20% (V/V) ethanol at 45°C. The sustained and complete release of risperidone was observed in both formulations under the accelerated release condition although these two release profiles were dissimilar. The correlation coefficients (R2) of IVIVC were all above 0.95 and the slopes were all between 0.9564 and 1.1868 in spite of fitted model and microsphere formulation.
An in vitro accelerated release method of risperidone microspheres with good IVIVC was established in this paper and this accelerated release method was supposed to have great potential in both in vivo performance prediction and quality control for risperidone loaded PLGA microspheres.
通常需要数天或数周的长时间释放期，因此，筛选具有如此长释放期的微球制剂并使用传统的长期或“实时”释放方法在体外评估其释放曲线既繁琐又耗时。所以，对于制剂设计以及质量控制而言，对该系统进行加速释放测试是必要的。本研究的目的是获得一种具有良好体外/体内相关性（IVIVC）的利培酮聚乳酸-羟基乙酸共聚物（PLGA）微球的加速释放方法。
采用水包油法制备两种用于评估IVIVC的利培酮PLGA微球制剂。通过研究pH值、渗透压、温度和乙醇浓度对微球中利培酮释放的影响来优化加速释放条件，并在此优化的加速释放条件下获得利培酮从PLGA微球的体外加速释放曲线。给大鼠皮下注射利培酮微球后，还检测了利培酮的血浆浓度。然后分别使用Wagner-Nelson模型、Loo-Riegelman模型和数值卷积模型计算体内累积吸收曲线。最后用最小二乘法评估体外加速释放与体内累积吸收之间的相关性。
结果表明，温度和乙醇浓度对微球中利培酮的释放有显著影响，而释放介质的pH值和渗透压对利培酮的释放行为影响较小。利培酮从微球的体外释放最终在45°C、含20%（V/V）乙醇的PBS（pH7.0，300mosm）中进行。在加速释放条件下，两种制剂均观察到利培酮的持续和完全释放，尽管这两种释放曲线不同。无论拟合模型和微球制剂如何，IVIVC的相关系数（R2）均高于0.95，斜率均在0.9564至1.1868之间。
本文建立了一种具有良好IVIVC的利培酮微球体外加速释放方法，该加速释放方法在预测利培酮PLGA微球的体内性能和质量控制方面均具有巨大潜力。
