促透膜靶向纳米晶给药体系的构建及其克服药物外排的研究

It is a tough problem to improve the druggability of poorly water-soluble drugs in the pharmaceutical field.Nanocrystal drug delivery system can ameliorate the druggabilty of poorly water-soluble drugs by improving the dispersibility in water, reducing the chemical variation and additives usage.Our previous researches showed that Hydroxycamptothecin nanocrystal delivery system could really increase drug loading, improve chemical stability of the formulation compared with commercial injection. But its physical stability is poor, especially is worse in liquid. At the base of literatures and researches, we think that the physical stability of nanocrystal drug delivery system may be affected by chemical composition and structure of stabilizers, and the molecular properties of drugs. This project aims to study new stabilizers and its stability mechanism to enhance the physical stability of nanocrystal drug delivery system, and to manufacture nanocrystal drug delivery system with enhancing permeation and targeting by combining with receptor targeting and drug efflux inhibitors. In this project, we will manufacture the poly(amino acid) amphipathic block copolymers with the different chemical composition and structure, and prepare nanocrystal delivery system of drug with different molecular properties using those copolymers as stabilizers. The influence of the chemical composition and structure of copolymer, pH value and drugs’ molecular properties on physical stability of nanocrystal drug delivery system will be studied by some the modern analysis technology, such as NMR, SEM, SPSS and so on. And its stable mechanism will be revealed on the molecular level. In this projet,the targeting and overcoming drug efflux of nanocrystal drug delivery system were also studied by in vivo and in vitro biological technology.The project has the advanced theoretical significance and practical value for the application of nanocrystal drug delivery system.

改善难溶性药物的成药性是制剂学领域的一大难题。纳米晶给药体系可以通过提高水分散性、减少药物化学变化和附加剂使用量等来提高药物的成药性。我们之前的研究表明：与市售注射液相比，羟基喜树碱纳米晶给药体系确实能增加制剂载药量，改善化学稳定性。但是其物理稳定性较差，尤其是液体形式更差。基于文献和前期研究，我们认为：纳米晶给药体系物理稳定性可能受稳定剂与药物的性质影响。本项目旨在研究新型稳定剂及其稳定机制以提高纳米晶给药体系的物理稳定性，并联合受体靶向和药物外排抑制剂，制备促透膜靶向纳米晶给药体系。通过合成不同化学组成、结构的聚氨基酸类两亲性共聚物，应用NMR、SEM、SPSS等现代分析技术，研究共聚物化学组成、结构和药物分子性质对纳米晶给药体系物理稳定性的影响，从分子水平上揭示其稳定机制，利用体内外生物学技术研究其靶向性和克服外排作用。本项目对纳米混悬剂的应用具有先进的理论指导意义和实际应用价值。

目前，经高通量筛选获得的药物中约40％因水溶性问题而使用受限，常使潜在的重要药品出现生物利用度差，造成患者花费大、疗效小等问题。剂型的合理设计可以克服这一难题、确保静脉给药的可行性、提高口服生物利用度，改善难溶性药物的成药性和有效性。纳米混悬剂作为一种新型载药系统，它可以通过提高溶解度、化学稳定性和减少附加剂使用量等来提高药物的成药性。但是纳米混悬剂的物理稳定性制约其大量推广的关键因素。基于文献和研究工作，我们认为：纳米混悬剂物理稳定性很可能受稳定剂的化学组成和结构及药物性质的影响。本项目研究了新型稳定剂及其稳定机制，以提高纳米混悬液的物理稳定性。在本课题研究中，（1）我们设计、合成出不同化学组成、结构的PAA-ABC，分别为聚苯丙氨酸-聚天冬氨酸（PPA-PAA）和聚乙二醇-聚天冬氨酸苄（PEG-PBLA），并采用红外光谱、核磁、GPC等手段成功对其进行了系统表征。（2）以伊曲康唑和紫杉醇为模型药物，成功制备出了纳米混悬剂，并考察其稳定性、体外溶出、体内药动学以及体外活性等性质。（3）通过考察不同聚合物对纳米混悬剂物理稳定性的影响，分析聚合物的化学组成和结构、药物的性质与纳米混悬剂的稳定性之间的定性关系，揭示聚氨基酸类两亲性共聚物对纳米粒的稳定作用机制。（4）并将叶酸共价结合聚苯丙氨酸-聚天冬氨酸（PPA-PAA）共聚物，同时混合TPGS制备紫杉醇纳米混悬剂，实现纳米混悬剂的促透性和靶向性。采用体外细胞培养技术和体内药动学及组织分布试验，研究其靶向性和抑制细胞外排作用（即促透性）。实验结果表明，紫杉醇纳米混悬剂的抗肿瘤效应良好，在肝、脾、肺中有一定的靶向性，且因为TPGS的存在，具有一定的促药物渗透性。本项目的研究成果不仅为纳米混悬剂的稳定剂种类提供了新的研究方向，同时为增加难容性药物的溶解度方面做出了一定贡献，也为将来更深入地研究难溶性药物应用于临床方面奠定了基础，制备出的口服制剂也为提高口服生物利用度方面提供了可参考性依据。