阿苯达唑-盐酸盐的制备、表征及口服生物利用度的评价  

Preparation,characterization and evaluation of oral bioavailability of albendazole hydrochloride

作　　者：钟雪萍 章勇 郭宇斐 胡春晖 严海英 ZHONG Xueping;ZHANG Yong;GUO Yufei;HU Chunhui;YAN Haiying(Medical College of Qinghai University,Xining 810001,China;State Key Laboratory of Plateau Ecology and Agriculture,Xining 810016,China)

机构地区：[1]青海大学医学部,青海西宁810001 [2]三江源生态与高原农牧业国家重点实验室,青海西宁810016

出　　处：《药物评价研究》2024年第3期557-565,共9页Drug Evaluation Research

基　　金：青海省基础研究计划项目(2022-ZJ-748)。

摘　　要：目的制备阿苯达唑(ABZ)-盐酸(HCl)盐(ABZ-HCl),并对盐的固态性质、体外溶出行为、稳定性和生物利用度进行评价。方法溶剂蒸发法制备结晶的ABZ-HCl,使用核磁共振氢谱(^(1)H-NMR)对制备的ABZ-HCl进行验证,通过粉末X射线衍射(PXRD)、动态水吸附(DVS)、热重分析(TGA)和差示扫描量热法(DSC)进行固态性质的表征;对药物盐进行表观溶解度和固有溶出速率(IDR)的测定以观察其在不同pH条件下溶解度和溶出速率;进行了ABZ-HCl在强光照射(4500±500 lx)、高湿(92.5%±5%RH)和高温条件(50±2)℃,以及加速试验条件(40℃、75%±5%RH)的稳定性研究;评价ABZ、ABZ-HCl(25 mg·kg^(-1))在大鼠体内的药动学行为差异。结果通过^(1)H-NMR证实了ABZ-HCl的形成;ABZ和ABZ-HCl的PXRD图谱出现显著差异;DVS实验结果表明,ABZ原药的吸水性差,在90%相对湿度(RH)时吸水量仅为3.86%,且吸附与解吸附曲线基本重合,而ABZ-HCl在开始的0~20%RH范围内迅速吸收水分,随后质量缓慢增加,在RH达到90%时吸水量为37.65%,在解吸过程中,ABZ-HCl的吸附曲线和解吸曲线不一致,存在滞后现象;TGA和DSC实验结果表明,2种物质均无吸附水,ABZ-HCl较ABZ熔点降低;体外溶出实验结果显示ABZ-HCl的表观溶解度和IDR分别为ABZ的11.8、10.3倍;ABZ-HCl表现出良好的物理稳定性。体内药动学结果显示,与ig ABZ原料相比,ABZ-HCl的AUC_(0~24h)和C_(max)均显著提高,分别提高了8.8和6.9倍。结论所制备的ABZ-HCl可改善ABZ的溶解性能和口服生物利用度,且具有良好的物理稳定性。Objective Albendazole(ABZ)hydrochloric acid(HCl)salt(ABZ-HCl)was prepared,and the solid state properties,dissolution behavior in vitro,stability and oral bioavailability of the salt were evaluated.Method Crystallized ABZ-HCl was prepared by solvent evaporation method,and the prepared ABZ-HCl was validated by ^(1)H-NMR.Solid state properties were characterized by powder X-ray diffraction(PXRD),dynamic water adsorption(DVS),thermogravimetric analysis(TGA),and differential scanning calorimetry(DSC).Measured the apparent solubility and intrinsic dissolution rate(IDR)of drug salts to observe their solubility and dissolution rate under different pH conditions.We conducted stability studies on ABZ-HCl under strong light irradiation(4500±500 lx),high humidity(92.5%±5%RH),high temperature conditions(50±2)℃,and accelerated test conditions(40℃,75%±5%RH).Evaluated the pharmacokinetic behavior differences of ABZ and ABZ-HCl(25 mg·kg^(-1))in rats..Results The formation of ABZ-HCl was confirmed by ^(1)H-NMR.There was a significant difference in the PXRD spectra between ABZ and ABZ-HCl.The DVS experimental results showed that the water absorption of ABZ raw material was poor,with a water absorption rate of only 3.86% at 90% relative humidity(RH),and the adsorption and desorption curves basically overlapped.However,ABZ-HCl quickly absorbed water in the initial 0-20%RH range,and then slowly increased in mass.When RH reached 90%,the water absorption rate was 37.65%.During the desorption process,the adsorption and desorption curves of ABZ-HCl were inconsistent,and there was a lag phenomenon.The results of TGA and DSC experiments showed that both substances had no adsorbed water,and the melting point of ABZ-HCl was lower than that of ABZ.The results of in vitro dissolution experiments showed that the apparent solubility and IDR of ABZ-HCl were 11.8 and 10.3 times higher than those of ABZ,respectively.ABZ-HCl exhibited good physical stability.The in vivo pharmacokinetic results showed that compared with the ig ABZ raw materia

关 键 词：阿苯达唑 盐酸盐 固体性质 溶解度 稳定性 生物利用度 

分 类 号：R943[医药卫生—药剂学]