双氢青蒿素固体分散体的制备及其生物利用度研究  

Preparation and bioavailability of dihydroartemisinin solid dispersions

作　　者：蒋沅岐 田成旺[2,3,4] 周钰通 王旭光 夏媛媛 周福军 陈常青[2,3,4] JIANG Yuan-qi;TIAN Cheng-wang;ZHOU Yu-tong;WANG Xu-guang;XIA Yuan-yuan;ZHOU Fu-jun;CHEN Chang-qing(Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;Tianjin Institute of Pharmaceutical Research,Tianjin 300462,China;Tianjin Key Laboratory of Quality Marker of Traditional Chinese Medicine,Tianjin 300462,China;State Key Laboratory of Drug Delivery and Pharmacokinetics,Tianjin Institute of Pharmaceutical Research,Tianjin 300462,China;Research Unit for Drug Metabolism,Chinese Academy of Medical Sciences,Tianjin 301617,China)

机构地区：[1]天津中医药大学,天津301617 [2]天津药物研究院,天津300462 [3]天津市中药质量标志物重点实验室,天津300462 [4]释药技术与药代动力学国家重点实验室,天津300462 [5]中国医学科学院药物代谢新技术创新单元,天津301617

出　　处：《中草药》2022年第4期1013-1020,共8页Chinese Traditional and Herbal Drugs

基　　金：国家重大科技专项(2017ZX09101002-001-005);中国医学科学院医学与健康科技创新工程项目资助(2019-I2M-5-020)。

摘　　要：目的制备双氢青蒿素(dihydroartemisinin,DHA)固体分散体(solid dispersion,SD)(DHA-SD),对其进行处方优化和表征,以提高DHA的体外溶出度及其在大鼠体内的生物利用度。方法通过溶解度筛选出与DHA相容性较好的载体材料,以体外溶出度为评价指标,采用正交试验对DHA-SD进行处方优化,应用扫描电子显微镜(SEM)、差示扫描量热分析(DSC)、X-射线衍射分析(XRD)和红外光谱(IR)对所制备的DHA-SD进行表征。将DHA-SD进行初步压片,采用LC-MS/MS法分析DHA在大鼠体内的药动学特征,比较片剂及原料药的相对生物利用度,采用WinNonlin 8.3.1软件非房室模型统计矩法,计算DHA的主要药动学参数。结果平衡溶解度结果显示,以羟丙基-β-环糊精(H-β-CD)和大豆磷脂为主要载体的DHA-SD对DHA的增溶效果较好;优化后的DHA-SD处方为DHA 20%、H-β-CD 66.12%、大豆磷脂13.22%、柠檬酸0.66%,其在纯水中30 min的溶出度达到了94.51%。体内生物利用度结果显示,SD大鼠ig给予DHA片剂后,最大血药浓度(Cmax)和药时曲线下面积(AUC0~t)分别为原料药的4.44、2.94倍。结论DHA-SD可显著提高DHA的溶解度和口服生物利用度。Objective To prepare the solid dispersion(SD) of dihydroartemisinin(DHA)(DHA-SD), optimize and characterize its formulation to improve its dissolution rate in vitro and bioavailability in rats. Methods By solubility test, the carrier materials with better compatibility to DHA were screened out. Taking the in vitro dissolution rate as the evaluation index, the formulation of DHASD was optimized utilizing the orthogonal test. The prepared DHA-SD was characterized with the help of scanning electron microscope(SEM), differential scanning calorimetry(DSC), X-ray diffraction analysis(XRD) and infrared spectroscopy(IR). Then, the DHA-SD was compressed into tablets, the pharmacokinetic characteristics of DHA in rats were analyzed by LC-MS/MS method, and the relative bioavailability of tablets and APIs was compared. Finally, WinNonlin 8.3.1 software non-compartmental model statistical moment method was used to calculate the main pharmacokinetic parameters of DHA. Results The results of equilibrium solubility showed that the DHA-SD with H-β-CD and soybean phospholipid as the carrier had a better solubilization effect on DHA;the optimized DHASD prescription was DHA 20%, H-β-CD 66.12%, soybean phospholipid 13.22%, citric acid 0.66%, whose dissolution rate in pure water could reach 94.51% within 30 min. The results of in vivo bioavailability showed that, after intragastric administration of DHA tablets to SD rats, Cmax and AUC0-t were 4.44 times and 2.94 times that of the crude drug, respectively. Conclusion DHA-SD can significantly improve the in vitro dissolution and oral bioavailability of the drug.

关 键 词：双氢青蒿素 固体分散体 溶解度 体外溶出度 生物利用度 LC-MS/MS 药动学 

分 类 号：R283.6[医药卫生—中药学]