大麻二酚-胆甾醇琥珀酸单酯-g-羧甲基壳聚糖纳米胶束体内药动学及体外抗炎作用研究  

Study on in vivo pharmacokinetics and in vitro anti-inflammatory effects of cannabidiol-cholesterol succinate monoester-g-carboxymethyl chitosan nano-micelles

作　　者：李睿 路丽艳 许楚 郝瑞 田湘涵 阮文辉 王颖莉 LI Rui;LU Liyan;XU Chu;HAO Rui;TIAN Xianghan;RUAN Wenhui;WANG Yingli(College of Traditional Chinese Medicine and Food Engineering,Shanxi University of Chinese Medicine,Shanxi Jinzhong 030619,China;Shanxi Center of Drug Evaluation(Shanxi Institute of Medicine and Life Science),Taiyuan 030006,China;Experimental Management Center,Shanxi University of Chinese Medicine,Shanxi Jinzhong 030619,China)

机构地区：[1]山西中医药大学中药与食品工程学院,山西晋中030619 [2]山西省药品审评中心(山西省医药与生命科学研究院),太原030006 [3]山西中医药大学实验管理中心,山西晋中030619

出　　处：《中国药房》2024年第23期2889-2895,共7页China Pharmacy

基　　金：山西省科技创新人才团队专项计划(No.202204051002028);山西中医药大学-企业技术合作研发项目(No.2022-05);吕梁市引进高层次科技人才重点研发(社会发展)项目(No.2022RC06)。

摘　　要：目的研究大麻二酚(CBD)-胆甾醇琥珀酸单酯-g-羧甲基壳聚糖(CCMC)纳米胶束在大鼠体内的药动学及组织分布特性,并初步评价其体外抗炎作用。方法采用透析法制备CBD-CCMC纳米胶束,并对其性能进行表征。将SD大鼠分为CBD组和CBD-CCMC纳米胶束组,每组6只,分别灌胃100 mg/kg CBD和CBD-CCMC纳米胶束(以负载的CBD计);于给药后0.5、1、1.33、1.5、1.75、2、4、8、24、48 h眼眶采血,计算药动学参数。另取大鼠同法分组、给药,每组24只;分别于给药后0.25、1.5、10、24 h,每组取6只大鼠分离其心、肝、脾、肺、肾、肌肉组织,分析药物的组织分布情况。采用脂多糖诱导来建立Caco-2细胞炎症模型,分别以终质量浓度为5、10、15μg/mL的CBD和CBD-CCMC纳米胶束(以负载的CBD计)作用24 h后,检测细胞活力、跨膜电阻(TEER)和炎症刺激下细胞产生的炎症因子[白细胞介素1β(IL-1β)、IL-8、肿瘤坏死因子α(TNF-α)]水平。结果所制CBD-CCMC纳米胶束的平均粒径为(230.6±1.8)nm,多分散性指数为0.170±0.053,Zeta电位为(-13.5±1.2)mV,包封率及载药量分别为(86.35±0.56)%、(9.18±0.32)%;溶解度为68.240μg/mL。药动学结果显示,与CBD组比较,CBD-CCMC纳米胶束组大鼠的药时曲线下面积(AUC)0-48 h、AUC0-∞、半衰期、峰浓度均显著增加/延长(P<0.05或P<0.01)。组织分布研究结果表明,在同一时间点,CBDCCMC纳米胶束组大鼠组织中药物的分布浓度均高于CBD组。抗炎作用研究结果显示,与同质量浓度的CBD相比,CBD-CCMC纳米胶束可显著提高细胞活力(P<0.05或P<0.01),升高TEER,降低细胞中IL-8、IL-1β、TNF-α水平(P<0.01)。结论CBDCCMC纳米胶束能够增加CBD血药浓度和组织分布浓度,提高CBD的抗炎活性。OBJECTIVE To study the pharmacokinetics and tissue distribution of cannabidiol(CBD)-cholesterol succinate monoester-g-carboxymethyl chitosan(CCMC)nano-micelles in rats,and to evaluate its anti-inflammatory effect.METHODS CBDCCMC nano-micelles were prepared by dialysis method and the properties were characterized.SD rats were divided into CBD group and CBD-CCMC nano-micelles group with 6 rats in each group.The rats were given 100 mg/kg CBD and CBD-CCMC nanomicelle by intragastric administration,respectively(based on the CBD load).Blood was collected from the posterior ophthalmic venous plexus at 0.5,1,1.33,1.5,1.75,2,4,8,24,48 h after administration.The heart,liver,spleen,lung,kidney and muscle tissues of rats were separated at 0.25,1.5,10 and 24 h after administration of CBD and CBD-CCMC nano-micelle with the same dose.The drug content in plasma and tissues was determined,the pharmacokinetic parameters were calculated,and the tissue distribution was analyzed.The inflammatory model of Caco-2 cells was induced by lipopolysaccharide,after 24 h of treatment with 5,10,and 15μg/mL CBD and CBD-CCMC nanomicelles(based on loaded CBD),its anti-inflammatory activity was investigated by measuring cell viability,transepithelial electrical resistance(TEER)and inflammatory cytokines IL-1β,IL-8 and TNF-α.RESULTS The prepared CBD-CCMC nano-micelles had a particle size of(230.6±1.8)nm,a polydispersity index of 0.170±0.053,a Zeta potential of(-13.5±1.2)mV,an encapsulation rate of(86.35±0.56)%and a drug loading of(9.18±0.32)%,respectively;the solubility was 68.240μg/mL.The pharmacokinetic results showed that the AUC0-48 h,AUC0-∞,half-life time and peak concentration of CBD-CCMC nano-micelle group were significantly increased/extended compared with CBD group(P<0.05 or P<0.01).The results of the tissue distribution study showed that at the same time point,the drug distribution concentration of CBD-CCMC nanomicelles in the rat tissue was higher than that in the CBD group.Research on anti-inflammatory effects shows that compa

关 键 词：大麻二酚 纳米胶束 胆甾醇琥珀酸单酯 羧甲基壳聚糖 药动学 

分 类 号：R969.1[医药卫生—药理学]