效应面法优化甘草酸胆盐/磷脂混合胶束舌下速溶膜

Optimization of glycyrrhizic acid bile salt/phospholipid mixed micelles fast dissolving sublingual films by response surface method

目的制备甘草酸胆盐/磷脂混合胶束舌下速溶膜,优化其处方,并初步评价其体外黏膜吸收情况。方法采用薄膜分散法制备甘草酸胆盐/磷脂混合胶束(GL-BS/PC-MM),进一步制成舌下速溶膜(fast dissolving sublingual films,FDSFs)。以海藻酸钠用量、丙二醇用量以及甘草酸胶束加入量为考察因素,以崩解时间、5 min时累积释放度及膜复溶后的胶束粒径为指标,采用Box-Behnken设计效应面法优化甘草酸胆盐/磷脂混合胶束舌下速溶膜(GL-BS/PC-MM-FDSFs)的处方。以离体猪舌下黏膜为渗透模型,采用Franz扩散池进行体外黏膜渗透试验。结果以最优处方:23 g/L海藻酸钠、148.5 g/L丙二醇、7.58 m L甘草酸胶束制得的速溶膜崩解时间为(22.1±0.7)s,5 min时药物体外累积释放度为(85.30±2.91)%,膜复溶后粒径为(146.46±6.42)nm。理论预测值与实测值偏差接近,模型具有良好的预测性。胶束成膜前后各时间点累积渗透率差异不大。结论将GL-BS/PC-MM固化成GL-BS/PC-MM-FDSFs工艺简单可行,GL-BS/PC-MM-FDSFs可显著改善甘草酸的黏膜吸收。

Objective To prepare and optimize glycyrrhizic acid bile salt/phosphatidylcholine mixed-micelles fast dissolving sublingual films（GL-BS/PC-MM-FDSFs） and preliminarily evaluate its mucous membrane permeation in vitro. Methods The formulations of GL-BS/PC-MM-FDSFs were optimized by employing Box-Behnken design-response surface methodology with the amounts of sodium alginate, propylene glycol, and GL-BS/PC-MM as investigation factors, and the disintegration time, cumulative release of drug from the GL-BS/PC-MM-FDSFs within 5 min, and particle size of reconstituted MM from GL-BS/PC-MM-FDSFs as indexes. Mucous membrane permeation test was evaluated in vitro with porcine sublingual mucosa as a model by using Franz diffusion cell. Results The GL-BS/PC-MM-FDSFs prepared by optimized formulation（23 g/L sodium alginate, 148.5 g/L propylene glycol, and 7.58 m L GL-BS/PC-MM） could fast disintegrate in（22.1 ± 0.7） s, release in vitro at 5 min to（85.30 ± 2.91）%, and the particle size of reconstituted MM from GL-BS/PC-MM-FDSFs was obtained as（146.46 ± 6.42） nm. There was a little deviation between the theoretically predicted value and measured value. It showed that this model had a good prediction. There was no significant difference between the accumulative permeation profiles of GL-BS/PC-MM-FDSFs and GL-BS/PC-MM at each time point. Conclusion The process that GL-BS/PC-MM is solidified to GL-BS/PC-MM-FDSFs is simple and feasible, and GL-BS/PCMM-FDSFs could significantly improve the mucous membrane absorption of GL.