以纳米晶体为载药形态的难溶性中药成分肺吸入复合粒子的构建、稳定化及其肺部给药研究

Pulmonary drug delivery of poorly soluble drug is the difficulty of TCM pharmaceutics. How to design the new inhalable delivery system with the excellent aerodynamic particle size and good stability for the poor soluble ingredients of Chinese medicine, and to improve the pulmonary bioavailability of poorly soluble ingredients of Chinese medicine, become a difficult problem of pulmonary drug delivery. Therefore, we are trying to design the novel inhalable composite microparticle. The inhalable composite microparticles composed of "one-stage particles" and "two-stage particles", "one-stage particles" used as porous carrier particles for nanocrystals (two-stage particles) particles, and easily redispersed into the two-stage particles after inhalation and facilitate lung deposition. And “two-stage particles” as PEGylated nanocrystals of drug and used to improve the dissolution of poorly soluble drug”. Therefore, our group will prepare the inhaled composite particles loading drug nanocrystals by means of nanocrystal technology and spray-freeze-drying technology, and to explore the internal mechanism of the surface properties of nanocrystals related with its mucus penetration by multiparticle tracking technology, and elucidate the stabilization mechanism on dispersion of composite particles using glass transition theory and water activity theory, and obtain the forming technique and control strategy for pulmonary inhaled composite microparticles. This study can provide the novel technology and method for inhalation administration of poorly soluble drug.

难溶性中药成分的肺吸入给药是中药药剂学研究的难点。如何构筑具备良好的空气动力学粒径且稳定性能好的肺吸入粒子，实现难溶性药物肺部高效给药，是难溶性药物肺吸入给药研究的关键。本课题提出“构建以纳米晶体为载药形态的肺吸入复合粒子，其由一、二级粒子组成。一级粒子为承载纳米晶体粒子的多孔微粒，易于肺部沉积，给药后可水化再分散出二级粒子；二级粒子为PEG化修饰的纳米晶体粒子，可快速穿越肺粘液层屏障，改善难溶性药物溶出与吸收”。为此，本项目创新性地运用纳米晶体技术与喷雾冷冻干燥造粒技术制备以纳米晶体为载药形态的肺吸入复合粒子，运用多粒子追踪等技术探讨纳米晶体表面性质与其肺黏液穿透性能的内在机制，运用玻璃化转变理论与水分活度理论系统阐明影响复合粒子再分散性能的内在规律与稳定化机制，建立以纳米晶体为载药形态的肺吸入复合微粒的粒子化技术方法与稳定化调控策略。本项目将为难溶性中药成分的肺吸入给药提供新的方法。

肺吸入给药是可实现肺靶向或全身给药的理想给药途径。难溶性中药成分溶解性差与生物利用度低，成药性差，为肺吸入给药系统的设计提出了巨大挑战。设计新型肺吸入高端制剂技术，改善难溶性药物的疗效，具有重大的临床价值与意义。然而，然而如何改善难溶性中药成分的溶出，如何逃逸肺粘液与肺巨噬细胞的生理屏障作用，是难溶性中药成分肺吸入给药系统设计的关键。本项目以难溶性中药有效成分（灯盏花素、冬凌草甲素、去氢骆驼篷碱素等）作为模型药物，运用纳米晶体技术与雾化造粒技术，旨在构建以纳米晶体为载药形态的肺吸入复合粒子，一级粒子为承载纳米晶体粒子的多孔微粒，易于肺部沉积，给药后可水化再分散出二级粒子，二级粒子为TPGS修饰的纳米晶体粒子，可快速穿透肺粘液层屏障，改善难溶性药物溶出与吸收。创新制备了具有可穿透粘液屏障、高载药能力的纳米晶体复合粒子，运用粘液穿透表征技术探讨纳米晶体表面性质等对纳米晶体粘液透过性能的相关规律及其机制；阐释了雾化造粒技术对不同模型药物肺吸入纳米晶体复合粒子的空气动力学特性的影响规律，发现了3种可制备稳定药物纳米晶体固体粒子的支架保护剂；阐明了纳米晶体复合粒子体系支架剂或保护剂类型、含水量或湿度、储存时间、储存温度等因素对纳米晶体肺吸入复合微粒分散稳定性能的影响规律与稳定化机制，建立了基于玻璃化转变温度调控的纳米晶体肺吸入复合粒子的稳定化控制方法；以纳米晶体复合粒子为中间体，构建了以纳米晶体为载药形态的纳米晶体肺吸入给药系统，显著改善了灯盏花素、冬凌草甲素等难溶性中药成分的肺部给药的体内生物利用度。本项目相关研究结果发表高水平论文8篇，其中SCI论文5篇，获得江西省自然科学奖二等奖1项，授权发明专利1项，培养研究生4名。本项目的完成为难溶性中药成分纳米晶体的肺吸入高效给药提供了理论支持与参考依据，为解决难溶性中药成分的给药问题提供新的方法。