本试验旨在开发一种新型注射用加兰他敏缓释微球制剂的体外释放试验方法。首先合成了硬脂酸加兰他敏，然后以丙交酯乙交酯共聚物为载体，采用o/w 型乳化- 溶剂挥发法制备其缓释微球。分别表征了所得微球的形貌、粒径、载药量与包封率，以SD 大鼠为动物模型考察该微球的体内药物释放行为，绘制体内累积释放曲线。为得到具有良好体内外相关性的体外释放度试验参数，本试验通过Plackett-Burman 设计筛选了流通池法中影响微球体外释放的显著因素，再用星点设计- 响应面法考察各因素及其交互作用的影响。结果显示，流通池活塞泵流速、释放介质温度、释放介质中牛血清白蛋白(BSA) 浓度是影响流通池法测得的微球体外释药数据的显著因素。基于Design-Expert 8.06 软件的拟合结果，确定体外释放试验的参数为：活塞泵流速10.55 ml/min、释放介质温度42.54 ℃、BSA 浓度为1.25％，此时测得的微球体外释放数据与其在大鼠体内的释药行为具有较好的相关性。
Abstract
The aim of this study is to establish an in vitro release test method for the novel galantamine sustained-release microspheres for injection. Galantamine stearate was synthesized, then its microspheres with poly(lactide-co-glycolide) as carriers were prepared by oil-in-water emulsion solvent evaporation method. The prepared microspheres were characterized in terms of morphology, particle size, drug loading and encapsulation efficiency. The SD rats were used as the animal models to study the in vivo drug release behaviors of the microspheres, and the cumulative release curve in vivo was drawn. In order to obtain the parameters of in vitro release test method for the microspheres with good in vivo relevance, Plackett-Burman design was used to screen out the significant factors affecting the release data of microspheres by flow-through cell method. Then, the central composite design-response surface methodology was used to investigate the influences of the selected factors and their interactions on the release behaviors. The results showed that the flow rate of piston pump, the release medium temperature, and the concentration of bovine serum albumin(BSA) in release medium were significant factors affecting the in vitro release data of the microspheres measured by flow-through cell method. Based on the fitting results by Design-Expert 8.06 software, the optimized parameters were as follows: the flow rate of piston pump, the medium temperature and BSA concentration in release medium were 10.55 ml/min, 42.54 ℃ and 1.25％, respectively. The in vitro release data of the microspheres measured under this condition had a good correlation with the in vivo release behavior in rats.
关键词
硬脂酸加兰他敏 /
缓释微球 /
Plackett-Burman 设计 /
星点设计- 响应面法 /
释放度 /
体内外相关性
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Key words
galantamine stearate /
sustained-release microsphere /
Plackett-Burman design /
central composite designresponse surface methodology /
release /
in vitro-in vivo correlation
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脚注
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基金
山东省重大科技创新工程项目(2018CXGC1409)
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