基于静电自组装的微针-立方液晶复合系统的构建及其促盐酸青藤碱透皮性能评价

Combined application of physical enhancement methods and pharmaceutical enhancing permeation techniques in research on improvement of transdermal permeation of ionic drug have promising prospects. The aim of this program is to improve the permeation rate of model drugs (sinomenine hydrochloride) by a combination stratege of polymer microneedles and lyolropic liquid crystalline cubic phases. Sinomenine hydrochloride-loaded microneedles based on MEMS technology will be fabricated using a negatively charged biological polymer, chondroitin sulfate, which can help the repair and maintenance of cartilage joint. The positively charged lyolropic liquid crystalline cubic phases encapsulating sinomenine hydrochloride will be prepared using high pressure homogenization technology. The liquid crystalline cubic phases and drug-loaded microneedles can form a compound penetration transdermal delivery system using electrostatic self-assembly technique by virtue of adhesion function and surface electricity. The combined body may give full play to the advantages, such as physical enhancing function and deposit effects. The penetration of sinomenine hydrochloride and level of PGE2 will be real-time monitored by a multiple site microdialysis technique in carotid artery, skin and articular cavity of rats. The effects of the transdermal delivery system on swelling and pain degree of joint in adjuvant arthritis rats will be predicted. This study is expected to build preparation technology platform and in vivo evaluation system of microneedle - cubic liquid crystal compound transdermal system, and to provide new ideas for research on transdermal permeation of ionic drug.

物理促渗手段与药剂学促渗技术的联合应用在提高离子型药物透皮性能方面极具前景。本项目以治疗风湿痹症的盐酸青藤碱为模型药物，以具有促进关节软骨修复功能的负电性物质硫酸软骨素为基材，采用基于MEMS技术的复合工艺制备载盐酸青藤碱微针；同时利用高压均质技术制备载盐酸青藤碱的电正性脂质立方液晶，借助立方液晶自身的强黏附特性及荷电性，通过静电作用与载药微针实现自组装并固定，构建载药微针-立方液晶复合透皮系统，以实现微针的物理促渗性能和立方液晶药物贮库功能的联用。并建立大鼠颈总动脉、皮肤与关节腔多位点微透析取样方法，实时监测大鼠血液、皮肤、关节腔中的药物浓度及关节滑膜透析液中前列腺素E2的含量，预测该经皮制剂对佐剂性关节炎大鼠关节局部肿胀与疼痛的经时影响。构建治疗风湿痹症载药微针-立方液晶复合透皮系统的制备技术平台及体内外评价体系，为离子型药物经皮吸收系统研究及临床抗风湿药物的新剂型研究提供新思路。

物理促渗手段与药剂学促渗技术的联合应用在提高离子型药物透皮性能方面极具前景。本课题以治疗风湿痹症的盐酸青藤碱为模型药物，采用自制的微针模具，以硫酸软骨素与聚维酮PVP为复合基材，浇注法制备载盐酸青藤碱的自溶性聚合物微针；以植烷三醇为两亲性物质，构建载盐酸青藤碱的六角相液晶，通过直接融合浇注方式构建新型载药微针-六角相液晶复合透皮系统，相比于课题申报书中静电自组装制备载药微针-立方液晶复合透皮系统，直接融合制备方法更简单，且六角相液晶载药量大，缓释效果更理想。建立了大鼠皮肤、关节腔及颈总动脉多位点微透析方法；考察了复合透皮给药系统的大鼠经皮药动学，复合载药系统相对于载药微针和载药液晶，大鼠血液中AUC分别提高了2.01倍和1.46倍；皮肤中AUC分别提高了2.12倍和1.94倍,且血药浓度更加平缓，显示出良好的缓释效应，且安全性良好。分别采用LC-MS/MS法和酶联免疫吸附测定法（ELISA）法检测急性炎症大鼠关节滑膜液中青藤碱和炎性介质PGE2的经时变化。考察了复合透皮给药系统对AA大鼠的初步药效学，结果显示载药微针-六角相液晶复合透皮系统可有效改善AA大鼠的足肿胀和关节炎指数。总之，本研究成功构建了载盐酸青藤碱微针-六角相液晶复合透皮系统，并开展了载药体表征及体内外评价研究，为透皮吸收差的离子型药物经皮给药系统构建提供了有益的思路和策略。