云南特色中药关键成分的控制释放

The Traditional Chinese Medicine (TCM) resources in yunnan are very rich and the species of medicinal plants are the most in China. Some key compontents of Chinese Patent Medicine have been listed as new drugs. However, few studies were performed to control the release of the key compontents and to prepare the long-term effective formulations of Traditional Chinese Medicine. This project is disigned to study the controlled release of the key compontents from some feature TCM, such as Scutellarin with cardivascular protective potentcy and Bergenin with anti-tumor potentcy. The drug-polylactide nanoconjugates (drug-PLA NCs) are prepared by drug-initiated ring-opening polymerization of lactide O?carboxyanhydride or lactide O?carboxyanhydrides with different functional groups. The sustained release microspheres are prepared with these drug-PLA NCs to achieve the purpose of long-acting release. In the project, the structures and properties of drug-PLA NCs and microspheres, drug release mechanism, pharmacological activities and the relationship between the degree of polymerization and drug release properties are studied. By these studies, a novel controlled release formulation that the scutellarin and bergenin have optimum release time and reasonable efficacy can be screened. Meanwhile, the correlation with preparation conditions, structure of drug-PLA NCs and controlled release properties is established. In particular, the project will offer theory support for the preparation of sustained and controlled release formulation of scutellarin and bergenin, and provide a novel idea for the research of sustained-release formulations of Traditional Chinese Medicine.

云南中药资源丰富，药用植物种数居全国第一，一些中成药关键组分已经作为新药上市,但开展中药关键成分的控制释放,制备长效中成药剂型研究较少。项目以对心脑血管疾病具有良好疗效的灯盏花乙素和具有抗癌作用的岩白菜素为示范研究对象，并以这两种药物作为引发剂，引发乳酸氧酸酐类单体聚合，制备出药物-聚乳酸纳米结合物，利用该结合物制备成微球缓释剂型，来达到长效缓释的目的。研究药物-聚乳酸纳米结合物及药物-聚乳酸纳米结合物微球的结构与性能，药物释放机理，药理活性及聚合度与药物释放性能的关系，并通过研究筛选出能够使灯盏花乙素和岩白菜素达到最佳释放时间和合理药效的控制释放新剂型，建立制备条件-药物-聚乳酸纳米结合物结构-控制释放性能的相关性，为灯盏花乙素和岩白菜素缓控释剂型的可控制备提供理论依据，为云南特色中药关键组分新剂型研发提供一种新的研究思路。

项目以一种新颖的方式来研究云南特色中药关键成分—岩白菜素、灯盏花乙素的控释释放，根据药物的结构特点来针对性地设计载体材料进行化学负载，通过合成手段制备药物-聚乳酸结合物控释材料。.依据以乳酸氧酸酐合成聚乳酸的原理，以岩白菜素作为引发剂，分别以乳酸氧酸酐或L-4-氨基-2-羟基丁酸氧酸酐为单体，制备出岩白菜素-聚乳酸基功能材料结合物，以期达到长效缓释的目的。通过研究岩白菜素-聚乳酸基功能材料结合物的结构与性能，药物释放时间及生物相容性，筛选出满足岩白菜素、灯盏花乙素控制释放的复合材料，为研发新剂型奠定基础，并得出以下结论：.（1）岩白菜素-PLA有晶态和非晶态两种形式，DSC和TG显示其具有良好的热稳定性，生物相容性试验和体外抗肿瘤试验表明，比例为1:30的岩白菜素-PLA在0.4μg/mL、4μg/mL和40 μg/mL时均具有良好的生物学性能和较低的细胞毒性，而且与对照组相比其存在抗肿瘤活性，为其开发为新型长效释放药物奠定了一定的理论基础。.（2）岩白菜素-amino PLA在不同比例下均呈现出非晶态，DSC和TG显示聚合物具有比较好的热稳定性，生物相容性试验和体外抗肿瘤试验表明，与对照组相比，比例为1:100的岩白菜素-amino PLA在浓度为0.4 μg/mL时具备良好的生物相容性和较低的细胞毒性，为岩白菜素-amino PLA聚合物进行临床动物实验提供基础。.（3）以PELA（9:1）Mw为9.559KDa为材料，在不同条件下制备了载灯盏花乙素微球，得到了外观圆整的光滑微球，平均粒径为1.5μm的微球。对微球进行了体外释放和降解实验，释放过程稳定，可连续释放20天。.（4）以重均分子量为14492Da，PDI为1.32的4-arm-PLGA为高分子微球材料制备了载灯盏花素的4-arm-PLGA微球，得到了外观圆整的光滑微球，平均粒径为828nm，粒径分布为0.421的微球。对微球进行了体外释放和降解实验，释放过程稳定，可连续释放15天。.项目的实施为中药关键组分的控制释放提供一种新的思路，同时可拓宽控制释放体系的研究领域，为进一步开发中药关键成分控制释放研究奠定理论基础。