基于粒子设计原理的白头翁总皂苷结肠靶向微粒的研究

The colon-targeted drug delivery system has an advantage of site-specific drug release and precise treatment. Development of oral colon targeting preparation for traditional Chinese medicine which has definite therapeutic effect becomes one of the research hotspot in this field. However, tablets and capsules, which are the oral colon targeting preparation already on the market, often have a poor reproducibility. While colon-targeted pellets of traditional Chinese medinice have low drug loading, difficulty in drug release, and complicates process. In our previous reaearch, coationg structure of the drug and excipient can be formed based on particle design principle and superfine comminution technique. So in this project, with total saponins of Pulsatilla as a model drug, the composite particles, which have a core-shell structure, are prepared by mechanochemical process, and characterized by particle size distribution, shape/structure analysis and surface contact angle. Meanwhile, the colon targeting property of the composite particles is evaluated by its release in vitro and in vivo as well as its pharmacokinetics, and the advantages of the particle preparation are estimated combined with pharmacodynamics study. The objective of this project is to obtain a kind of oral colon-targeted particle preparation of traditional Chinese medicine, with simple preparation process, high drug loading, and good reproducibility of drug release, and to explore the practicability and feasibility of application of particle design principle on colon-targeted praparation, providing a new thought and technique for the study of colon targeting system. In addition, the technology developed in this project will have certain reference value for the study of powder modification and septation of different compatible compenents for traditional Chinese medicine.

结肠靶向给药系统具有定位释药、精准治疗的优势，开发疗效确切的传统中药结肠靶向制剂成为中医药研究热点之一。国外已上市的片剂、胶囊等结肠靶向给药系统多存在释药重现性差的弊端，而中药结肠靶向微丸载药量低、药物释放困难、工艺复杂。本课题组前期研究发现，基于粒子设计原理和超微粉碎技术可实现药物与辅料的包覆。因此，本项目以白头翁总皂苷为模型药物，采用机械化学法，将其制备形成具有“核-壳”包覆结构的复合微粒，并从粒度、形貌/结构分析、表面接触角等方面进行表征，通过体内外释药行为、药动学等评价其结肠靶向释药特性，并结合药效学综合评价复合微粒的优势。其目的是获得一种制备工艺简单、载药量高、释药重现性好的中药结肠靶向微粒制剂；同时，探索粒子设计原理运用于结肠靶向制剂的适宜性，为结肠靶向给药系统的研究拓展新的思路与方法。本课题建立的方法与技术对于中药粉体改性、不同配伍组分相互分隔等研究也将具有一定的参考价值。

中药口服结肠靶向给药系统（OCTDS）可以避免中药有效成分在胃肠道被破坏及肝脏分解的不利影响，提高药物的局部浓度，增强治疗效果或者减少毒副作用，同时为溃疡性结肠炎（UC）等需局部治疗的疾病提供有效且方便的给药方式。因此，OCTDS正成为中药新剂型与新制剂研究中的热点，受到越来越广泛的关注。.本项目完成了白头翁总皂苷提取物（PTS）的制备及相关质量标准的研究，并基于粒子设计原理和超微粉碎技术，采用机械化学法，将PTS制备成pH依赖型和酶促型两种复合微粒。采用扫描电镜、粒径分布、X-射线衍射、红外光谱、表面接触角和体外释放度等多种手段对复合微粒的形貌/结构、表面特征、释药特性等进行多维度表征。对两种不同类型的复合微粒处方工艺进行了优化，获得了具有最佳体外结肠靶向释药特性的白头翁总皂苷复合微粒；同时，以白头翁总皂苷原药为对照，对复合微粒的体内释药特性、药动学以及药效学进行了初步研究。. 通过本项目的研究掌握了PTS提取和分离纯化工艺，制备的提取物中总皂苷含量大于80%，白头翁皂苷D含量大于20%，可作为制备结肠靶向复合微粒的原料。初步掌握了基于粒子设计原理的pH依赖型和酶促型两种复合微粒的制备方法，研究结果显示复合微粒具有“核-壳”结构以及良好的体内外结肠靶向释药特性，在抗UC药效研究中也显示出了优于白头翁总皂苷原药的结果。本研究获得了两种具有良好抗溃疡性结肠炎作用的白头翁总皂苷结肠靶向制剂，初步证实了粒子设计原理可用于制备中药结肠靶向制剂，为中药结肠靶向给药系统的研究拓展了新的思路与方法。