目的 制备不同稳定剂修饰的槲皮素纳米晶（quercetin nanocrystals，QT-NCs），探讨稳定剂种类对QT-NCs体外溶出和口服药动学的影响。方法 分别以羟丙甲纤维素E15（HPMC-E15）、普朗尼克F127（F127）和甘草酸（glycyrrhizinic acid，GL）为稳定剂，采用介质研磨法分别制备3种QT-NCs，即QT-NCs/F127、QT-NCs/HPMC E15、QT-NCs/GL，并进行形态、晶型表征，考察其体外溶出及口服药动学。结果 3种稳定剂修饰的QT-NCs的粒径均约为200 nm，PDI约为0.20，扫描电子显微镜显示QT-NCs均呈短棒状及不规则的颗粒状；X射线衍射结果显示QT-NCs均以结晶态存在；体外溶出结果显示，与槲皮素原料药相比，3种稳定剂修饰的QT-NCs的累积溶出度均明显提高，且30 min内累积溶出率QT-NCs/F127 （74.90%）>QT-NCs/GL（59.30%）>QT-NCs/HPMC E15（53.65%）；药动学结果显示，与槲皮素原料药相比，3种稳定剂修饰的QT-NCs口服生物利用度均显著提高，且AUC_0～t呈如下顺序：QT-NCs/E15（78.09±6.05）mg·h/L>QT-NCs/GL （61.72±7.59）mg·h/L>QT-NCs/F127（49.94±9.30）mg·h/L。结论 纳米晶能够显著改善槲皮素的体外溶出及口服生物利用度，稳定剂种类对QT-NCs的体外溶出和口服药动学有显著影响。

Objective To prepare quercetin nanocrystals (QT-NCs) modified by different stabilizers and explore the effects of different stabilizers on in vitro dissolution and oral pharmacokinetics of QT-NCs. Methods QT-NCs stabilized by three types of stabilizers including hydroxypropyl methyl cellulose E15 (HPMC E15), pluronic F127 (F127), and glycyrrhizin acid (GL) were respectively prepared by wet media milling method, namely QT-NCs/HPMC E15, QT-NCs/F127, and QT-NCs/GL, and then characterized by morphology and crystal state. Their dissolution in vitro and oral pharmacokinetics were also investigated. Results The particle size of QT-NCs modified by three types of stabilizers were about 200 nm with PDI was about 0.20. Scanning electron microscopy showed that QT-NCs were all short rods and irregular particles, while X-ray diffraction results showed that QT-NCs existed in crystalline state. The in vitro dissolution results showed that the cumulative dissolution of QT-NCs modified by three types of stabilizers were significantly improved as compared to QT, and the cumulative dissolution rate within 30 min was in an order of QT-NCs/F127 (74.90%) > QT-NCs/GL (59.30%) > QT-NCs/HPMC E15 (53.65%). The pharmacokinetic results showed that, compared with quercetin, the oral bioavailability of QT-NCs modified with three types of stabilizers were significantly enhanced, and their AUC_0-t was in the following order:QT-NCs/E15 (78.09 ±6.05) mg·h/L > QT-NCs/GL (61.72 ±7.59) mg·h/L > QT-NCs/F127 (49.94 ±9.30) mg·h/L. Conclusion NCs can significantly improve the in vitro dissolution and oral bioavailability of poorly soluble drugs, and the stabilizer's types significantly affect the in vitro dissolution and oral pharmacokinetics of NCs.

R283.6

国家自然科学基金资助项目（81803741）；国家自然科学基金资助项目（81873092）