中药汤剂微粒体系对有效成分吸收的影响及机制研究

Decoction of traditional Chinese medicine is one of the main formulations in traditional Chinese medicine treatments. Although many kinds of active ingredients of Chinese medicine can theoretically not be absorbed by the means of oral administration, the bioavailability are often very good through the decoction form. It is well documented that the drug absorption, especially the macromolecular drug absorption, can be significantly enhanced by oral particles drug delivery system. The effect and mechanism of particle systems in decoction of traditional Chinese medicine on active ingredients absorption are still not clear. This project will respectively decoct the traditional Chinese medicine of Astragulus, Coptis chinensis, and Honeysuckle, which contained active ingredients with characteristics of water-insolubility or bad biological stability, in a conventional manner, filter the leaves, systematically separate the particles by a series of technological means, according to the physicochemical properties of particle size, surface charge, surface wettability, etc., evaluate the regulating action of particle physicochemical properties on active ingredients absorption by Caco-2 monolayer cell membrane and everted gut sac in vitro, in situ intestinal perfusion and loops, and analysis the regulating mechanism. This project will contribute to clarify the characteristics of particles in decoction of traditional Chinese medicine, and its effect and mechanism on active ingredients absorption, and will provide theoretic and applied bases to explain the scientific implications of decoction and to develop the new dosage-form.

汤剂是中医治疗疾病的主要药物剂型之一，很多理论上口服难以吸收的中药活性成分以汤剂形式给药往往生物利用度较好。口服微粒给药系统可以显著提高药物的吸收已经得到了广泛的证实，然而汤剂在煎煮过程中形成的固体微粒体系对中药有效成分在胃肠道的吸收与转运是否存在作用以及作用机制均不明确。本课题分别选择以水溶性差或生物稳定性差的黄芪甲苷、小檗碱与绿原酸为主要药物活性成分的药材黄芪、黄连与金银花为研究对象，经常规手段水煎煮后除净药渣，对水煎液中具有不同理化性质（粒径、表面电荷、亲疏水性等）的微粒进行系统分离，经体外Caco-2单层细胞膜、离体翻转肠囊、原位肠循环灌注、原位肠袢等实验手段评价水煎液中微粒体系理化性质对活性成分吸收与转运的调节作用，并分析其机制。本课题的实施将有助于阐明中药煎煮过程中微粒形成特点及其对中药有效成分吸收的影响与机制，为诠释中药汤剂的科学内涵与开发中药新剂型提供有益的理论及应用基础。

本课题首先以梯度离心﹑离子交换层析﹑微孔滤膜过滤等方法对黄芪／黄连经水煎煮过程中形成的固体微粒进行分离，并对其进行形貌﹑粒径﹑表面电位﹑化学组成等理化性质进行分析。经大鼠在体肠循环实验发现，黄芪／黄连水煎液中固体微粒可显著提高活性成分黄芪甲苷／小檗碱的单位肠面积吸收量﹑单位肠面积吸收率与肠壁通透性。为研究中药汤剂微粒体系对活性成分肠吸收的影响机制，本课题组分别以壳聚糖﹑聚乙烯亚胺接枝壳聚糖﹑乙基纤维素、聚乳酸-羟基乙酸共聚物、黄芪多糖、黄连多糖为基材，制备具有不同粒径与电位特征的固体微粒。单向肠灌注实验显示，固体微粒对活性成分的肠吸收促进作用存在一个最佳的粒径范围，在该粒径范围内肠吸收促进作用最为显著；固体微粒主要富集于肠道淋巴组织；携带正电荷微粒有利于活性成分吸收，但汤剂分离微粒与汤剂提取多糖制备微粒虽携带负电荷，其促活性成分肠吸收作用显著高于正电荷高分子微粒。经进一步的肠组织切片观察与液质联用检测微粒与药物组织分布后推测：固体微粒可能通过M细胞的吞噬后影响了药物经肠上皮细胞间紧密连接的细胞旁路途径吸收，但具体过程需要进一步的研究。本课题的实施将有助于阐明中药煎煮过程中微粒形成特点及其对中药有效成分吸收的影响与机制，为诠释中药汤剂的科学内涵与开发中药新剂型提供有益的理论及应用基础。