甘草次酸修饰大黄素纳米结构脂质载体制备及药动学和肝靶向评价

Preparation of glycyrrhetinic acid modified emodin nanostructured lipid carrier and it’s pharmacokinetic and liver targeting evaluation

目的:制备甘草次酸修饰大黄素纳米结构脂质载体,并考察其在大鼠体内的药动学过程和肝靶向。方法:采用乳化-超声分散法制备甘草次酸修饰的大黄素纳米结构脂质载体(甘草次酸-大黄素-NLC)。UPLC-Q-Orbitrap HRMS法测定大鼠血浆及各组织中大黄素浓度,DAS 2.0软件计算药动学参数,以总靶向效率、相对摄取率来评价剂型改变后药物在体内分布的靶向性特征。结果:制备的甘草次酸-大黄素-NLC呈类球形,分布均匀,粒径为109.2 nm,聚合物分散性指数为0.22,Zeta电位为-39.5 mV,包封率为85.0%,载药量为1.04%。与大黄素溶液相比,甘草次酸-大黄素-NLC的主要药动学参数C_(max)、AUC_(0-t)、t_(1/2)、MRT_(0-t)均有显著性差异(P<0.05),相对生物利用提高到188.47%。甘草次酸-大黄素-NLC在脾中有所增加,肝中明显升高,在肝中的总靶向效率、相对摄取率分别为63.27%、3.34%,均为最高值。结论:将大黄素制成纳米结构脂质载体,在体内的药动学参数和组织分布行为发生改变,对肝具有特异的靶向性,有利于提高药物的治疗效果。

OBJECTIVE To prepare Glycyrrhetinic acid modified emodin nanostructure lipid carriers(glycyrrhetinic acid-emodin-NLC),and investigate its pharmacokinetic process and liver targeting in rats.METHODS Glycyrrhetinic acid-emodin-NLC was prepared by emulsification-ultrasonic dispersion method.The concentrations of emodin in plasma and tissues of rats were determined by UPLC-Q-Orbitrap HRMS,and pharmacokinetic parameters were calculated by software DAS 2.0.Total targeting efficiency and relative uptake rate were used to evaluate the targeting characteristics of drug distribution in vivo after dosage form change.RESULTS The prepared glycyrrhetinic acid-emodin-NLC was spherical and uniformly distributed with a particle size of 109.2 nm,polymer dispersity index of 0.22,a Zeta potential of-39.5 mV,an encapsulation efficiency of 85.0%and a drug loading of 1.04%.Compared with emodin solution,the main pharmacokinetic parameters of glycyrrhetinic acid-emodin-NLC,such as C_(max)、AUC_(0-t)、t_(1/2)、MRT_(0-t),were significantly different(P<0.05),relative bioavailability increased to 188.47%.Glycyrrhetinic acid-emodin-NLC increased in the spleen and significantly increased in the liver.Total targeting efficiency and relative uptake rate of nanoparticles in liver were 63.27%and 3.34,respectively,which were the highest values.CONCLUSION The pharmacokinetic parameters and tissue distribution behavior of emodin nanostructured lipid carrier were changed in vivo,and emodin had specific targeting to the liver,which was conducive to enhancing the therapeutic effect of drugs.