反酶触释放（AETR）自纳米乳（AETR-SNEDDS）避免药物胃肠首过代谢促进其口服吸收的研究

The oral administration is the most important route, but it is still face the challenge of oral absorption. The solubility, permeability biofilm and stability of drug in gastrointestinal tract are important factors for oral bioavailability. The AETR (anti enzyme trigger release) hypothesis is further proposed based on innovation ETR Hypothesis, which was used in researching absorption mechanism of SNEDDS. The PPL characteristic of active pocket will be as target，a four-dimensional joint model will be constructed to design the AETR-SNEDDS. They will be expounded systematically if the first-pass metabolism (CYP450 and UGT) in gastrointestinal of is avoided and oral absorption is promoted of the model drugs (BBR and RAL) by AETR-SNEDDS. The absorption mechanism of AETR-SNEDDS will be carried out with multi-level research mode including in vitro cell, in situ and in vivo animal. The project will focus on drug gastrointestinal first-pass metabolism, AETR-SNEDDS improves not only solubility but also biofilms permeability and stability in GI of drugs to promote their oral absorption. AETR and AETR-SNEDDS hypothesis are important complements to BCD and BDDCS, expand the applications range of SNEDDS and promote the development of emulsion delivery system and academic progress of pharmaceutics from the theory and method, so the project has very important significance.

口服是最重要给药途径，但药物口服吸收依然面对挑战。药物胃肠道溶解度、生物膜渗透性及稳定性是影响其口服生物利用度的重要因素。本项目在创新ETR假说研究SNEDDS吸收机理基础上、进一步提出AETR假说，以PPL活性部位口袋特征为靶标、并创建四维联合模型科学设计AETR–SNEDDS；系统证明AETR–SNEDDS避免模型药物（BBR与 RAL）胃肠道首过代谢（CYP450与UGT）并促进他们的口服吸收；多水平（细胞、在体及整体动物）研究AETR–SNEDDS吸收机理；建立体内外相关性预测口服吸收。本项目聚焦药物胃肠道首过代谢，AETR–SNEDDS同步提高药物溶解度、生物膜渗透性及稳定性，弥补目前SNEDDS仅提高药物溶解度现状。AETR假说及其AETR–SNEDDS是BCD及BDDCS重要补充，拓展SNEDDS应用，从理论与方法上推动乳剂给药系统发展及药剂学科进步，具有重要的研究意义。

系统地设计了反酶触释放纳米乳(anti-enzyme trigger release nanoemulsion,AETR-NE)（或非脂解纳米乳，NNE），以提高肠道内UDP葡萄糖醛酸转移酶（UGTS）和细胞色素P450酶（CYPS）首过代谢的雷洛昔芬（RAR）和小檗碱（BBR）的口服生物利用度。体外脂解法筛选RAL/BBR-NNE辅料，测定RAL/BBR溶解度、乳化效率和伪三元相图，确定NNE处方，并进行粒径、形态等表征。体外胃肠缓冲液稀释、脂解和UGT/CYPs代谢研究，研究RAL/BBR-NNE的稳定性。NNE对RAL/BBR代谢的保护作用通过其在大鼠和猪体内的生物利用度进行证实，并通过体外细胞、大鼠原位单向肠道灌注和体内淋巴转运探讨其吸收机制。NNE中含棕榈酸异丙酯、亚油酸、RH40和乙醇（3.33:1.67:3:2），RAL/BBR-NNE为球形乳滴，粒径40-80nm。RAL/BBR-NNE在胃肠道pH稀释时稳定，RAL-NNE脂解后可溶性RAL含量维持在77.18%，但BBR较低，制备成 PC得到改善，RAL-NNE 体外UGT1A10和UGT1A8代谢被显著抑制，代谢率低于11%；CYP3A4和CYP2B6对BBR的代谢也显著被抑制（代谢率低于5%）。大鼠口服给药，与混悬液相比， 传统的脂解纳米乳（RAL-LNE）与RAL-NNE均显著提高了的RAL生物利用度，但两者之间没有显著差异，而猪的相对生物利用度为541.28%，比LNE的相对生物利用度高2倍（p<0.05）。BBR-PC-NNE的相对生物利用度为1687.91%。NNE在细胞、在体肠灌流的胞饮机制研究表明，NNE通过多种内吞被吸收但主要是经小窝蛋白及网格蛋白介导的内吞机制。淋巴转运确实受到NE中油的种类和药物性质的影响。LO淋巴转运最强，其次为IPP、SO。桂利嗪（CIN，lg P 5.77，作为对照组）的淋巴转运率高于RAL（lg P 1.4）。