基于球晶技术固体自微乳的构建及淋巴转运特性研究

Solid self-microemulsifying drug delivery system could increase the solubility of insoluble drugs, also increased stability; storage time; gastrointestinal irritation reducing;to meet sustained and controlled release, enteric, and other needs and advantages,in addition to a dispersion of self- microemulsion. Based on the spherical crystallization technique, solid self-microemulsifying microspheres of baicalein have been successfully prepared , and the proof of the release of microspheres according to self-microemulsion way. To build solid self- micro emulsifying drug delivery system ,the 2-3 model drug would be selected to further explore the method and conditions of curing from microemulsion-new ways, and further build a stable, controllable solid self-microemulsifying drug delivery system, by selecting the appropriate solvent systems.The literature are not involved in the spherical crystallization technique preparation of solid self- microemulsifying drug delivery system or solidify of self-microemulsifying drug delivery system . Using the fluorescent tracer technique, intend to study cell uptake, lymphatic transshipment situation. To clarify the solid self-microemulsifying drug delivery system of a major transit way,rats as animal models, eyes take blood collected, to intubation drainage of thoracic duct lymph,compare the pharmacokinetic parameters.Investigated solid self-microemulsion particle size and distribution on the translocation efficiency of the lymphatic pathway. Intends to reveal solid self-microemulsifying drug delivery system lymphatic transport mechanism and influencing factors, the theoretical basis for its clinical application.

固体自微乳释药系统除具有自微乳的分散性好，可提高难溶性药物的溶解度等优点外，还具有稳定性增加、贮存时间延长、胃肠道刺激性减少、可满足缓控释、肠溶等多种需求等优点。本课题组在研究球晶技术的基础上，通过选择合适的溶剂系统，已成功制备了黄芩素固体自微乳微球，且证明该固体微球能以自微乳方式释药，后期拟在此基础上，选择2-3种模型药物进一步探索自微乳固化的方法与条件- - 固体自微乳构建的新途径，进一步构建稳定、可控的固体自微乳。目前文献中均未见有涉及球晶技术制备固体自微乳或自微乳固化的报道。本课题拟采用荧光示踪技术研究固体自微乳经细胞摄取、淋巴转运情况；以大鼠为模型动物，胸导管插管引流淋巴液，同时眼眶取血收集血液，比较药动学参数，阐明固体自微乳的主要转运途径；同时考察固体自微乳粒径大小与分布对淋巴途径转运效率的影响，意在揭示固体自微乳淋巴转运转运机制及影响因素，为其临床应用奠定理论基础。

本课题采用球晶技术（乳化溶剂扩散法）进行环孢素A、 葛根素、石杉碱甲以及蛇床子素自微乳的固化研究。通过单因素试验（高分子阻滞剂、良溶剂、不良溶剂系统、搅拌速度、分散介质等）考察了制剂制备过程中的处方及工艺因素对制剂的影响，在单因素考察的过程中以能否成球、收率、休止角、卡氏指数、释放度等为考察指标，来筛选最优量。并且以收率、载药量和包封率为指标来评价制剂的优劣。经正交试验设计筛选出最佳处方工艺，并对优化条件下制备得到的产品进行质量评价和工艺的验证。对环孢素A、 葛根素、石杉碱甲以及蛇床子素自微乳制剂进行大鼠体内生物利用度和不同肠段吸收的研究。.重要结果：.（1）制备的环孢素A、 葛根素、石杉碱甲以及蛇床子素固体自微乳为圆整的球形颗粒、大小均匀、在不同介质自乳化后和固体自微乳的粒径基本保持一致，说明自微乳在固化的过程中，没有被破坏。该制剂30min释放约10%，20h释放90%以上。初步稳定性实验证实，自微乳进行固化后可有效提高在制剂中的稳定性，所得的固体制剂低温密封保存6个月，性质无明显变化。.（2） 在体内药动学研究中，缓释固体自微乳与原料药相比，其Tmax 、t1/2与MRT显著延长，达到了缓释效果，能够持久的发挥疗效；相对生物利用度显著提高，固体自微乳显著提高了生物利用度。.（3）生物利用度研究中，自微乳制剂组的血药浓度要远高于原料药组的药物浓度，且体内的t1/2和MRT均显著延长，表明固体自微乳制剂在体内消除较慢，达到缓释的效果且生物利用度明显提高。.（4）大鼠的在体肠吸收实验表明，固体自微乳的肠吸收参数不受药物浓度的影响，而与灌流速度和不同肠部位有关；胆汁的分泌与排泄不影响药物的肠吸收；药物在肠吸收主要是通过被动扩散。.科学意义：通过对环孢素A、葛根素、石杉碱甲以及蛇床子素的固体自微乳研究表明：采用球晶技术制备固体自微乳的处方和制备工艺可行，制成的固体自微乳稳定性良好，生物利用度和吸收明显增大，显示了较好的优越性，有望成为一种新型给药系统。