温敏型黄体酮原位凝胶的制备及体外释药

Preparation and in vitro release of progesterone thermosensitive in situ gel

以黄体酮为模型药物,泊洛沙姆407为温敏凝胶材料,制备温敏型黄体酮原位凝胶。通过单因素实验筛选保湿材料和生物黏附材料,考察处方因素对温敏凝胶胶凝温度的影响。采用自制体外释放装置,研究甘油、油酸聚乙二醇甘油酯、液体石蜡、泊洛沙姆407用量和药物粒径等处方因素对温敏原位凝胶体外释药的影响,分别以零级、一级和Higuchi方程对药物的体外释放数据进行了模型拟合。实验表明,甘油的保湿效果最佳,聚卡波非的生物黏附能力最强。确定最优处方中各成分的质量分数分别为:黄体酮4.0%,泊洛沙姆407 20%,甘油5.0%,液体石蜡5.0%,油酸聚乙二醇甘油酯2.0%,聚卡波非0.2%,山梨酸0.08%,分散介质为0.1 mol/L枸橼酸磷酸盐缓冲液(pH 4.0),其胶凝温度为33.8℃。体外释放研究表明,药物粒径对药物释放影响较大,而油酸聚乙二醇甘油酯、液体石蜡、甘油和泊洛沙姆407用量对药物释放无明显影响。与普通黄体酮凝胶相比,温敏凝胶中药物释放更快,且黄体酮在温敏原位凝胶中的释药符合一级动力学特征。

In this paper, progesterone was selected as a model drug and poloxamer 407 was selected as thermo- sensitive agent to prepare progesterone thermosensitive in situ gel. Selection of the moistening and bioadhesive agents, and the effects of the excipients on the gelation temperature were evaluated. In addition, the impacts of content of glycerol, paraffin liquid, labrafil, poloxamer 407 and different drug particle sizes on the drug release process were determined using a custom-made in vitro release device. In vitro release vs time profile was then mathematically modeled by zero order kinetic, first order kinetic and Higuchi equation, respectively. Glycerol was found to possess the best moistening effect, and polycarbophil had the strongest bioadhension. The optimal formulation consisted of 4.0% progesterone, 20% poloxamer 407, 5.0% glycerol, 5.0% paraffin liquid, 2.0% labrafil, 0.2% polycarbophil, 0. 08% sorbic acid and 0. 1 mol/L citrate phosphate buffer（ pH 4. 0）, whose gelation temperature was 33.8 ℃. The in vitro release study indicated that the release rate was related to drug particle size, content of labrafil and paraffin liquid, and that release of progesterone was best fitted to first-order kinetics. Compared with common Carbomer gel, the thermosensitive gel obtained using this formula could promote the release of progesterone.