新型肠道Ⅱ相代谢调控自微乳制剂及其机理研究

The extremely low oral bioavailability is an important factor in hindering resveratrol, quercetin or curcumin from broad clinical application. This project would select self-microemulsion as dosage form to perform in-depth study based on our previous research results which demonstrated that the phase II metabolism inhibitor containing nanoemulsion could efficiently enhance the oral bioavailability of resveratrol. Here we propose our hypothesis that the self-microemulsion developed from phase II metabolism inhibitors can significantly inhibit the intestinal phase II metabolism and effectively improve the oral bioavailability of phenolic compounds. The preliminary study showed that the oral bioavailability of phase II inhibitors containing self-microemulsion of resveratrol were 76.1%, compared with 6.5% for free resveratrol. The above result proved that our hypothesis was feasible. Therefore, the aim of the study was to explore the optimal formulation for self-microemulsion and to clarify the mechanisms of inhibting effects of phase II metabolism of the Pharmaceutical excipients and the enhancement for bioavailability. The main contents of the project would include: the preparation and characterization of phase II metabolic inhibitor containing self-microemulsion; elucidating the inhibitory mechanism of the self-microemulsion.

白藜芦醇、槲皮素及姜黄素等天然酚类成分临床应用受限制的重要因素是肠道Ⅱ相代谢引起的口服生物利用度极低。基于课题组前期研究结果：应用能够抑制Ⅱ相代谢的药用辅料制备的纳米乳，能够提高酚类成分的生物利用度。本项目选择更加适合口服的自微乳为递送载体，对自微乳提高酚类成分生物利用度及其机理进行深入研究。课题提出的假说为：应用Ⅱ相代谢抑制活性的药用辅料制备的自微乳能够显著抑制肠道Ⅱ相代谢，有效提高酚类药物口服生物利用度。初步研究结果表明：含Ⅱ相代谢抑制活性辅料的自微乳能够通过抑制Ⅱ相代谢，降低代谢产物的量，将白藜芦醇的口服生物利用度从6.5%提高到76.1%，证明了假说的可行性。课题旨在明确最佳自微乳处方，并且阐明药用辅料抑制Ⅱ相代谢，提高生物利用度的机制。主要研究内容包括：制备含Ⅱ相代谢抑制活性辅料的自微乳并全面对其进行评价；阐明药用辅料抑制Ⅱ相代谢的机制。

白藜芦醇、槲皮素及姜黄素等天然酚类成分临床应用受限制的重要因素是肠道Ⅱ相代谢引起的口服生物利用度极低。本项目选择自微乳为递送载体，应用具有Ⅱ相代谢抑制活性的药用辅料制备自微乳，该自微乳能够显著抑制肠道Ⅱ相代谢，有效提高酚类药物口服生物利用度。研究结果表明：含Ⅱ相代谢抑制活性辅料的自微乳能够将白藜芦醇的口服生物利用度从6.5%提高到76.1%。课题还对自微乳提高口服生物利用度的机制进行了研究，结果表明：自微乳是通过抑制Ⅱ相代谢，降低代谢产物生成的量，提高生物利用度。而自微乳制剂增加细胞摄取、转运、提高肠道淋巴结的药物分布等因素对提高口服生物利用度的作用是有限的。