目的 采用亲油性离子液体1-丁基-3-甲基咪唑六氟磷酸盐(1-butyl-3-methylimidazolium hexafluorophosphate，BMIMPF₆)取代传统微乳油相制备甘草酸(glycyrrhizic acid，GA)离子液体微乳(ionic liquid microemulsion，IL-ME)(GA-IL-ME)，以改善甘草酸的透皮吸收。方法 通过溶解度实验、配伍实验和绘制伪三元相图筛选微乳处方；利用D-最优混料设计法以粒径为考察指标进行处方优化，并对最优处方制备的微乳进行理化性质、稳定性、体外透皮吸收以及细胞毒性评价。结果 GA-IL-ME的最佳处方为BMIMPF₆-聚山梨酯80-PEG400-蒸馏水(5.8∶32.4∶10.8∶51.0)；所得微乳为黄色澄清透明状液体，透射电子显微镜(transmission electron microscope，TEM)显示GA-IL-ME呈均匀的球形或类球形，平均粒径为(10.61±0.63)nm，多分散系数(polydispersity index，PDI)为0.130±0.022，ζ电位为(—10.29±0.22)mV；GA-IL-ME在高速离心、储存稳定性、高温以及冷热和冻融循环实验中均表现出良好的稳定性；体外透皮结果显示，GA-IL-ME在24 h内单位面积累积渗透量为(310.37±33.65)μg/cm²，为甘草酸传统水包油(O/W)型微乳的1.34倍，甘草酸水溶液的6.76倍；细胞毒性实验表明GA-IL-ME毒性低，生物相容性良好。结论 BMIMPF₆能显著增加甘草酸的溶解度，将其引入微乳体系制备新型水包离子液体型微乳，明显增加了甘草酸的经皮累积渗透量，可为中药透皮给药系统新剂型的开发提供参考，同时为甘草酸的进一步研究应用奠定基础。

Objective Glycyrrhizic acid ionic liquid microemulsion (GA-IL-ME) was prepared by replacing the traditional microemulsion oil phase with the lipophilic ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF₆) to improve the transdermal absorption of glycyrrhizic acid (GA). Methods The formulation of the microemulsion were screened by solubility investigation, compatibility test and pseudo-ternary phase diagrams, and the formulation were further optimized by D-optimal mixture design with the particle size as the evaluation index. Then the physicochemical properties, stability, in vitro transdermal absorption and cytotoxicity of the optimized microemulsion were evaluated. Results The optimized formulation was composed of 5.8% BMIMPF₆, 32.4% Tween-80, 10.8% PEG400 and 51.0% water. The prepared microemulsion was a yellow clear transparent liquid. GA-IL-ME was observed to be spherical or nearly spherical by transmission electron microscopy (TEM) and distributed evenly, with an average particle size of (10.61 ± 0.63) nm, a polydispersity index (PDI) of 0.130 ± 0.022 and an average ζ potential of (—10.29 ± 0.22) mV. GA-IL-ME showed good stability in high-speed centrifugation, high-temperature, heating-cooling and freeze-thaw cycles, and storage stability experiments. Results of in vitro transdermal experiments showed that the cumulative permeation per unit area in 24 h of GA-IL-ME was (310.37 ± 33.65) μg/cm², which was 1.34 times that of glycyrrhizic acid traditional oil in water (O/W) microemulsion and 6.76 times that of glycyrrhizic acid aqueous solution. Cytotoxicity experiments showed that GA-IL-ME had low toxicity and good biocompatibility. Conclusion BMIMPF₆ can significantly increase the solubility of GA. Introducing it into microemulsion system to prepare a new ionic liquid in water microemulsion significantly increased the transdermal permeability of GA, which could provide a reference for the development of new dosage forms of traditional Chinese medicine transdermal delivery system and lay a foundation for further research and application of GA.

国家自然科学基金项目(81873092)