定位释药胶囊型中药渗透泵控释制剂的构建及释放与吸收相关性的研究

Project Team intends to develop in the early positioning release osmotic pump capsule shell based on Paeonol , panax notoginseng saponins, Fufangdanshen were selected as a model drug, to carry out the positioning release capsule formulation osmotic pump adaptation of traditional Chinese medicine and Compound research, so as to further clarify the relationship between the structure of the capsule osmotic pump type, prescription factors, technological factors and release laws, especially the accumulation of osmotic pump capsule medicine multi-component (water-soluble components, fat-soluble group points) synchronous release and laws firsthand. And the use of advanced three-dimensional structure of quantitative research synchrotron radiation biomedical imaging and computed tomography X- ray technology, access high-resolution imaging of complex structures inside preparations reveal fractal capsule osmotic pump controlled release formulations of the internal structure of its complex dynamics release characteristics of relevance. Meanwhile experiment with different physical and chemical properties means (different particle sizes, different charge) release liquid separation systems, in vitro Caco-2 cell monolayers in vitro intestinal sac flip situ intestinal perfusion fluid, such as evaluation of the physicochemical properties of the release regulation of the absorption of the active ingredient and transportation. Implementation of this project will help to build a more rational osmotic pump traditional Chinese medicine preparations, to lay a solid theoretical foundation for the development of new formulations of traditional Chinese medicine.

课题组拟在前期研制定位释放渗透泵控释胶囊壳的基础上，分别选择丹皮酚、三七总皂苷、复方丹参为模型药物，开展定位释放胶囊型渗透泵制剂在中药及复方的适应性研究，从而为进一步明确渗透泵控释胶囊的结构类型、处方因素、工艺因素及其释放规律的关系，特别是积累在胶囊型渗透泵中中药多组分（水溶性组分，脂溶性组分）同步释放及规律的第一手资料。并采用同步辐射光源生物医学成像和计算机X-射线断层扫描技术等先进的立体结构定量研究，获得制剂内部复杂结构的高分辨成像，揭示胶囊型渗透泵控释制剂的内部复杂动态结构的分形与其释放特征的相关性。同时对具有不同理化性质（不同粒子大小、不同电荷）释放液进行系统分离，经体外Caco-2单层细胞膜、离体翻转肠囊、原位肠循环灌注等实验手段评价释放液的理化性质对活性成分吸收与转运的调节作用。本课题的实施将有助于构建更为合理的中药复方渗透泵制剂，为中药新剂型的开发奠定坚实的理论基础。

课题组采用蘸胶法制备肠溶、结肠定位渗透泵胶囊壳，以成囊性及累积释放度为评价指标，筛选胶囊壳的处方组成及制备工艺。分别选择盐酸青藤碱、去甲斑蝥素、三七总皂苷、复方丹参等为模型药物，开展定位释放胶囊型渗透泵制剂在中药及复方的适应性研究,并对释药机理进行研究。.重要结果:.（1）制备肠溶、结肠定位渗透泵胶囊壳的处方及工艺简单可行，所制备的肠溶、结肠定位渗透泵胶囊壳的外观、脆碎度、松紧度等均符合中国药典要求，并有肠溶、结肠定位效果，达到预期目的。 .（2）经单因素考察及处方工艺验证确定的结肠定位胶囊最优处方工艺如下：CA浓度为8%，PEG 6000用量为25%，尤特奇S100用量为35%，溶剂（丙酮:水）比例为95:5，NaCl用量为40%，蘸胶3次，释药孔径为0.8 mm。.（3）制得的盐酸青藤碱肠溶渗透泵胶囊、去甲斑蝥素、三七总皂苷、复方丹参结肠定位渗透泵胶囊体外释药基本不受转速和释放装置的影响，其释药机理是以胶囊内外渗透压差为释药动力，药物释放行为与零级方程相符，具有较好的定位控释效果。.（4） Beagle犬体内整合药动学研究结果显示，自制结肠定位渗透泵胶囊中三七总皂苷血药浓度相对市售普通胶囊和结肠溶胶囊较平稳，达峰时间、半衰期和体内平均滞留时间均有不同程度的延长，达到了缓释的效果，同时避免了胃酸对PNS的破坏。.关键数据及其科学意义: 本课题的实施研制的肠溶、结肠定位渗透泵胶囊壳具有可定位释放、药物选择范围大、处方制备工艺简单、成本低、效率高等优点，且可批量制备，节省并简化新型渗透泵制剂的研究过程，具有广阔的市场应用前景。将有助于构建更为合理的中药复方渗透泵制剂，为中药新剂型的开发奠定坚实的理论基础。制成的盐酸青藤碱肠溶渗透泵胶囊、去甲斑蝥素、三七总皂苷、复方丹参结肠定位渗透泵胶囊稳定性良好，生物利用度和吸收明显增大，显示了较好的优越性，有望成为一种新型给药系统。