以白及多糖为骨架材料构建阴道给药新剂型：柔性脂质体后膨胀型水凝胶泡沫气雾剂

Vaginal drug delivery (VDD) is a effective drug delivery route for treatment of gynecological disease. However,the major technical difficulties for VDD are how to prompt the medication spread in vagina fully and have a long retention time to maximize drug release. Our initial research have shown that the foams have a laggingly swelling process namely post-expansile behavior after the viscosity of foam liquid membrane increased by water-soluble polymer, and the flexible liposomes could effectivly enhance permeation of drug through the mucosa and caused a long retention time at the site of administration. Accordingly, we speculate that when the drug loaded flexible liposomes were made into hydrogel foam aerosol, the laggingly swelling process of hydrogel foams would promote drug loaded flexible liposomes spread uniformly in vaginal canal and contact the vaginal mucous membrane tightly, as a result, the permeability of drug through vaginal mucosa and the quantity of drug remaining in the vagina tissue would be obviously improved by flexible liposomes. Bletilla striata polysaccharide（BSP）is a natural degradable biological adhesion material, possess a variety of effects, could be used as pharmaceutical raw materials, biological material, etc. Therefore, this work would to construct post-expansile hydrogel foam aerosol of flexible liposomes（PEHFL）with the bletilla striata polysaccharide for the first time. Then investigate the pharmaceutical characteristics of PEHFL, clarify the behavior characteristics, influencing factors and interrelated mechanisms for PEHFL how to prompt the medication spread in vagina fully and enhance the permeability of drug through vaginal mucosa. The effects of PEHFL on the vaginal physiological function would be investigated too.This work would to provide a highly efficient new dosage form for gynecological vaginal drug delivery applications,and provide reference and ideas for the subsequent similar research.

阴道给药是治疗妇科疾病的有效手段，但是，目前国内外面临的重大技术难点是如何使药物在阴道腔体内铺展分布均匀，且吸收效率高。我们前期研究发现，用高分子增加泡沫的液膜粘稠度，可赋予泡沫缓慢膨胀与生物粘附的特性；柔性脂质体可显著促进药物的透黏膜吸收。白及多糖是天然可降解的高分子，具有生物粘附性与多种功效，可作为药用辅料与生物材料。据此，我们首次提出"将载药柔性脂质体分散于白及多糖凝胶液中构建柔性脂质体后膨胀型水凝胶泡沫气雾剂（PEHFL）"，药物在阴道内将随泡沫的缓慢膨胀而铺展分布，在白及多糖的粘附作用下与阴道壁紧密接触，通过柔性脂质体促进药物透黏膜吸收。为此，本课题以苦参碱为模型药物，考察PEHFL的药剂学性质，阐明PEHFL促进药物铺展分布与透黏膜吸收的行为特点、影响因素及其机理，并通过药代动力学与毒理学阐明PEHFL用于阴道给药的优势。本课题将为阴道给药提供一种新剂型，为同类研究提供借鉴。

阴道给药(Vaginal drug delivery，VDD)是治疗妇科疾病的有效给药途径，具有可避免口服给药的肝首过效应与不良反应；局部靶向作用强、生物利用度高；存在良好的“第一子宫传递效应”与使用方便等优点而成为研究重点，近年来发展较快。目前，VDD领域常见的给药剂型有片剂、栓剂、胶囊剂、洗剂、凝胶剂等，这些传统剂型的共性技术难点/瓶颈是药物在阴道腔体内难于铺展分布均匀与水溶性药物难以透过黏膜脂溶性屏障而进入黏膜深层。本项目基于纳米柔性脂质体构建了一种新型给药系统-后膨胀型纳米柔性脂质体凝胶泡沫剂，利用天然高分子形成的凝胶泡沫而提高制剂的生物黏附性与柔软舒适性，进而提高患者的依从性；利用凝胶泡沫的后膨胀特点，使载药泡沫进入阴道后发生缓慢膨胀与变形作用，从而促进了药物在阴道腔体内铺展、分布均匀；利用纳米柔性脂质体技术提高了药物进入阴道黏膜组织的渗透性，并提高药物在组织中的“储库效应”，也提高了药物的生物利用度。项目的主要研究结果：泡沫具有缓慢的膨胀过程(约15s)，且泡沫持续时间/寿命为80min；泡沫的生物黏附性良好约1500mN/cm2；模型药物纳米柔性脂质体粒径约185±19nm、表面电位-53±2.7mV，对药物的包封率为78±2.14%；模型药物纳米柔性脂质体透黏膜的累积透过量显著高于其他给药形式，也具有明显的“药物储库效应”；药物在阴道与子宫等生殖系统的分布剂量分别是血液、脾、肝、肾、血液与肺的2.64、7.83、8.09、11.87、12.49 和 34.98倍(t-test, P＜0.05)而具有较好的局部靶向性；本品对阴道黏膜安全无刺激。. 综上，本项目成果解决了国际上阴道给药系统面临的药物进入阴道后在腔体内难于铺展分布均匀与吸收效率低的重大技术难点，填补了领域的空白！本项目截止目前已经发表核心论文7篇，其中1篇1区的SCI(TOP期刊，IF=7.441)，获授权发明专利1项，申请1项。

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