计算机分子模型（MOE）设计酶促释放（ETR）纳米乳（SNEDDS）及口服吸收机理研究

The nanoemulsion can significantly improve the oral absorption of poorly soluble drugs, but its absorption mechanism is so far unclear. The studies of our and other researcher have shown that BCSII drug solubility can be increased significantly using the nanoemulsions, but the absorption of drug decreased significantly conversely by the Fick's simply diffusion and absorption in vitro model. How doed the improvement of drug oral absorption should be interpreted by the nanoemulsion? The enzyme triggered release (ETR) hypothesis is proposed in the project to carry on new exploration for absorption mechanism of the nanoemulsions. The active sites of porcine pancreatic lipase (PPL) will be selected as target and the computer molecules model MOE will be applied to design scientifically nanoemulsions (SNEDDS) formulation. On the basis, in vitro lipolysis model will be used for clarifies the relationship between ETR hypothesis with SNEDDS drug dissolution, Physiological-physical Chemistry diffusion in vitro absorption model will used to reveal the drug absorption mechanism based on the ETR hypothesis. Finally, in vitro and in vivo correlation (IVIVC) will be established in multiple angles to prove correctness of ETR hypothesis. The project will promote the development of the emulsion delivery system from the theory and methods and has important significance and application prospects.

纳米乳能显著提高难溶性药物的口服吸收，但吸收机理至今不清。我们及其他学者的研究结果表明纳米乳显著增加BCSII药物溶解度，但基于Fick's第一定律的扩散吸收体外模型表明吸收反而显著下降。纳米乳增加药物口服吸收应如何解释？本项目提出酶触释放（enzyme trigger release, ETR）假说对纳米乳吸收机理进行新的探索。在以猪胰脂肪酶（porcine pancreatic lipase, PPL）活性位点为靶标、应用计算机分子模型MOE科学、准确、合理设计纳米乳（SNEDDS）基础上，采用体外脂解模型阐明ETR假说与SNEDDS药物溶出的相关性，采用基于ETR 的生理－物理化学扩散吸收体外模型，揭示基于ETD假说的SNEDDS药物吸收机理，从多角度的体内外吸收相关性（IVIVC）进一步论证ETR假说正确性。本项目从理论与方法上推动乳剂给药系统发展，具有重要研究意义及良好应用前景

1. 纳米乳处方设计。MOE应用于SNEDDS处方设计，柔性较大的油及表面活性剂选择性较差。.2. ETR与SNEDDS药物溶出度。脂解比非脂解药物释放明显提高，说明ETR 学术解释纳米乳中药物的释放确与PPL对油的降解相关。.3. 体外吸收机理。体外动态脂解后药物绝大部分分布在水相，沉淀相（包括药物及脂解产物）及脂质均很少，因此体外采用脂解液进行了人工膜及猪小肠渗透及吸收实验。与ETR释放相比，CIN在体外人工膜及离体小肠的渗透与吸收要低得多，其原因是人工膜、离体小肠与整体动物实际胃肠道的实际生理环境差异较大造成。.4. 体内吸收机理。药物的性质不同，SNEDDS吸收机理不同。GRI-SNEDDS的GRI血药浓度达峰时为Tm2~4h，提示门肝系统吸收为主; 含LCT的CIN-SNEDDS，特别是高含量LCT，血药浓度最高峰明显滞后（Tm8~12h），提示淋巴系统对CIN的吸收有重要影响。.5. 影响吸收的因素。（1）药物性质：CIN（Cs 0.39e-04mg/mL, lgP5.77)，采用SNEDDS，生物利用度最高提高12倍，而GRI（Cs 5.04e-02 mg/mL, lgP2)生物利用度仅提高2倍；（2）SNEDDS中油的组成及含量：对CIN而言：相同浓度下，LCT生物利用度是MCT的1.81倍；相同LCT，浓度增加1倍，CIN吸收增加1倍；相同油浓度，含有LCT（能脂解）是仅含油酸（不脂解）的1.44倍。油对GRI吸收的影响不显著。(3) SNEDDS中的乳化剂浓度显著增加CIN的吸收。.6.体内外相关性。药物的ETR溶出与体内AUC正相关；乳化剂的含量与CIN的体内AUC正相关； CIN-LCT-SNEDDS, 脂解后水性分散相CIN的浓度与体内AUC正相关；体外脂解后沉淀相CIN含量与体内AUC负相关。