目的 基于药物-脂质共轭技术（lipid-drug conjugates，LDC）与磷脂/胆盐纳米胶束（phospholipid/bile salt mixed micelles，MMs）递送系统，采用月桂酸（lauric acid，LA）对槲皮素进行亲脂性结构修饰，合成槲皮素-月桂酸共轭物（quercetin-lauric acid conjugate，LA-Qu），显著提升槲皮素在纳米胶束体系中的载药量与包封率，口服生物利用度提高，为槲皮素的高效口服制剂开发提供了新策略。方法 采用酰化法合成LA-Qu，柱色谱及制备液相色谱进一步分离纯化；采用薄膜分散法制备LA-Qu MMs，并对其理化特征及稳定性进行评价；通过检测槲皮素的含量，对LA-Qu MMs进行了大鼠体内药物动力学和小鼠组织分布研究。结果 通过改变反应溶剂种类、催化剂种类及用量，建立了LA-Qu的4种合成路线，合成收率均在77%～80%。采用MS、¹H-NMR鉴定结构，成功合成LA-Qu。在最佳处方条件下，LA-Qu MMs平均粒径为（53.57±1.02）nm，PDI为0.274±0.020，ζ电位为（−29.93±3.12）mV，载药量为（9.09±0.12）%，包封率为（100.00±0.00）%，纳米胶束形态均呈类球形，分散性好，无聚集粘连，粒径均一，稳定性良好。LA-Qu MMs的生物利用度分别是槲皮素混悬液的19.04倍，Qu MMs的1.42倍，明显促进槲皮素的口服吸收。槲皮素主要在肝脏、肾脏、肺中分布，尤其肝脏的选择性强。结论 LA-Qu MMs有效改善了槲皮素的渗透性，明显提高槲皮素口服生物利用度。

Objective The study is based on the technologies of lipid-drug conjugates and phospholipid/bile salt mixed micelles. The lipophilicity structure of quercetin was modified with lauric acid (LA) to synthesize the quercetin-lauric acid conjugate (LA-Qu), which significantly increased the drug loading and encapsulation efficiency of quercetin in the nanomicelle system, and improved the oral bioavailability, providing a new strategy for the development of efficient oral preparations of quercetin. Methods LA-Qu was synthesized by acylation method, and further separated and purified by column chromatography and preparative liquid chromatography. LA-Qu MMs was prepared by the thin-film dispersion method, and its physicochemical characteristics and stability were evaluated. By detecting the content of quercetin, the pharmacokinetics of LA-Qu MMs in rats and the tissue distribution in mice were studied. Results Four synthetic routes of LA-Qu were established by changing the type of reaction solvent, the type and dosage of catalyst, the synthesis yield was between 77% and 80%. The structure was identified by MS and ¹H-NMR, successfully synthesized LA-Qu. Under the optimal prescription conditions, the average particle size of LA-Qu MMs was (53.57 ± 1.02) nm, PDI was 0.274 ± 0.020, ζ potential was (−29.93 ± 3.12) mV, drug loading was (9.09 ± 0.12)%, encapsulation efficiency was (100.00 ± 0.00)%, and the morphology of micelles were spherical, with good dispersion, no aggregate adhesion, uniform particle size and good stability. The bioavailability of LA-Qu MMs was 19.04 times that of the quercetin suspension and 1.42 times that of Qu MMs, which significantly promoted the oral absorption of quercetin. Quercetin was mainly distributed in the liver, kidneys and lungs, especially in the liver. Conclusion LA-Qu MMs effectively improved the permeability of quercetin, significantly enhanced the oral bioavailability of quercetin.

R283.6

青海省科技合作专项（2017-HZ-814）