目的 基于藥物-脂質(zhì)共軛技術(shù)（lipid-drug conjugates，LDC）與磷脂/膽鹽納米膠束（phospholipid/bile salt mixed micelles，MMs）遞送系統(tǒng)，采用月桂酸（lauric acid，LA）對(duì)槲皮素進(jìn)行親脂性結(jié)構(gòu)修飾，合成槲皮素-月桂酸共軛物（quercetin-lauric acid conjugate，LA-Qu），顯著提升槲皮素在納米膠束體系中的載藥量與包封率，口服生物利用度提高，為槲皮素的高效口服制劑開發(fā)提供了新策略。方法 采用?；ê铣蒐A-Qu，柱色譜及制備液相色譜進(jìn)一步分離純化；采用薄膜分散法制備LA-Qu MMs，并對(duì)其理化特征及穩(wěn)定性進(jìn)行評(píng)價(jià)；通過檢測(cè)槲皮素的含量，對(duì)LA-Qu MMs進(jìn)行了大鼠體內(nèi)藥物動(dòng)力學(xué)和小鼠組織分布研究。結(jié)果 通過改變反應(yīng)溶劑種類、催化劑種類及用量，建立了LA-Qu的4種合成路線，合成收率均在77%～80%。采用MS、¹H-NMR鑒定結(jié)構(gòu)，成功合成LA-Qu。在最佳處方條件下，LA-Qu MMs平均粒徑為（53.57±1.02）nm，PDI為0.274±0.020，ζ電位為（−29.93±3.12）mV，載藥量為（9.09±0.12）%，包封率為（100.00±0.00）%，納米膠束形態(tài)均呈類球形，分散性好，無(wú)聚集粘連，粒徑均一，穩(wěn)定性良好。LA-Qu MMs的生物利用度分別是槲皮素混懸液的19.04倍，Qu MMs的1.42倍，明顯促進(jìn)槲皮素的口服吸收。槲皮素主要在肝臟、腎臟、肺中分布，尤其肝臟的選擇性強(qiáng)。結(jié)論 LA-Qu MMs有效改善了槲皮素的滲透性，明顯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

青海省科技合作專項(xiàng)（2017-HZ-814）