可实现中药多成分同步包载和释放的脂质纳米递药系统的研究

As is known that multicomponents of TCM are useful in the treatment of human serious disease,such as tumor,cardiovascular disease and hepatitis.However,many fatal weaknesses reduce their curative effect.For example,the toxic properties of the total alkaloids of Semen Strychni limit its application,oleanolic acid has low bioavailability due to its lower solubility. It is a key issue of the low bioactivity and safety of TCM composite. Nanoparticles delivery system are one of the best drug loaded cartiers for controlling drug release and targeting treatment of carcinoma and hepatitis..This research is based on the synergistic effect of TCM composite by using new biological material to design and evaluate New nano lipid deliverydrug system,which has special properties coupling with weak electricity and offered good hydrophilic and oleophilic properties. We preparea new nanolipids carrier delivery drug system by choosing representative multicompents of TCM, in order to improve curative effect and to solve existing problems of multicomponents of TCM.. Solid lipid homogeneous encapsulation will be used for enveloping multicomponents, which has a few difference of their physicochemical properties. Nanostructured lipid carriers be used for encapsulating multicomponents which has more differences of their hydrophilic lipophilic properties. For multicomponents which has more differences of their physicochemical properties,we enloaded it by using a Novel Nanoparticles Modificated Phospholipid layer. All of them will be prepared by the reverse micelle double emulsify method. Emulsifier and stabilizer will be chosed and its amounts should be optimized ,so as to build up a safety, high efficiency novel nano lipid delivery system. We also design the targeted type and longterm nano-structured lipid delivery system, and evaluate them by the balance envelopement and equilibrium release principle. We hope that the research of single component nanoparticles turn into multicomponents．We try to create the TCM mode, with its characteristics of modern nanometer pass medicine multicomponents so as to improve the level of the treatment of cancer and liver disease. It will be supposed that our reserch can provide a theoretical foundation and design basis for other multicomponents of TCM.

本课题基于中药多成分协同作用，利用生物医药新材料的特殊性能, 通过固态脂质均相包封、液态脂质与固态脂质混合包封、磷脂修饰的脂质载体等三种形式，进行中药多成分新型纳米递药系统的设计、组装与评价,以分子量差异小、理化性质差异较大和油水分配系数差异大的三组代表性中药多成分为切入点,在优选载体材料、添加致孔剂等基础上，优化工艺参数，通过包合/吸附、改变储药空间和调控释药速度等手段，建立中药多成分纳米递药体系，阐明中药多成分平衡包封和均衡释药的规律。从而实现由中药单一成分向多成分新型递药系统的转变，力图创建具有中药特色的现代中药纳米递药模式，研究成果不仅可为现代给药技术应用于传统中药体系提供科学依据，而且可为构建体内外均衡释放、持久起效、靶向定位的中药多成分纳米化技术平台提供科学参考，为以有效部位为治疗药物的现代剂型设计提供借鉴。更为重要的是还可丰富中医药理论的现代化内涵，促进中医药理论不断创新。

本课题基于中药多成分协同作用，利用生物医药新材料的特殊性能，进行中药多成分新型纳米递药系统的设计、组装与评价，阐明中药多成分平衡包封和均衡释药的规律，实现中药单一成分向多成分新型递药系统的转变，力图创建具有中药特色的现代中药纳米递药模式。主要研究内容及结果如下：（1）固体均相分散型中药多成分纳米递药系统的研究。以分子量差异小的中药多成分——马钱子总生物碱中的马钱子碱和士的宁作为模型药物，设计长效和靶向融为一体的固体脂质纳米粒递药系统。结果构建了适合分子量差异小的药物的递药系统，包封规律为竞争关系，其包封率的高低与载体材料的亲和有关，药物可实现均衡释放。构建的SLN具缓释性且生物利用度、 靶向性、药效明显提高。（2）固液非均相分散型中药多成分纳米递药系统的研究。以油水分配系数差异较大的中药多成分——龙胆中五环三萜类（齐墩果酸）、环烯醚萜苷类（龙胆苦苷）为模型药物，设计长效和靶向融为一体的纳米结构脂质载体。结果构建了适合油水分配系数差异较大药物的高包封率、高载药量递药系统，包封规律为竞争关系，即此消彼长，药物可实现均衡释放。构建的NLC具缓释性且生物利用度、靶向性、药效明显提高。进一步深入探讨了透明质酸修饰载中药多成分的纳米脂质载体系统（齐墩果酸、熊果酸、人参皂苷Rg3）。（3）PEG修饰型的PLGA嵌段共聚物中药多成分纳米递药系统的研究。以分子量、体积等存在较大差异的中药多成分——丁香叶中对于乙型肝炎具有确切疗效的中药多成分——丁香苦苷（环烯醚萜类化合物）与羟基酪醇（多酚类化合物）为模型药物设计长效和靶向融为一体的PEG修饰型的PLGA嵌段共聚物纳米递药系统。结果构建了适合于多成分水溶性药物的高包封率、高载药量纳米递药系统。包封与释放规律表明分子量小、体积小的药物比分子量大、体积大的药物包封率和释放速率高。构建的递药系统具缓释性且生物利用度、靶向性明显提高。该研究成果不仅可为现代给药技术应用于传统中药体系提供科学依据，而且可为构建体内外均衡释放、持久起效、靶向定位的中药多成分纳米化技术平台提供科学参考，为以有效部位为治疗药物的现代剂型设计提供借鉴。更为重要的是还可丰富中医药理论的现代化内涵，促进中医药理论不断创新。