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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
Published:15 December 2024,
Received:22 July 2024,
Revised:22 October 2024,
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李睿,路丽艳,许楚等.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 Δ[J].中国药房,2024,35(23):2889-2895.
LI Rui,LU Liyan,Chu XU,et al.Study on in vivo pharmacokinetics and in vitro anti-inflammatory effects of cannabidiol-cholesterol succinate monoester-g-carboxymethyl chitosan nano-micelles[J].ZHONGGUO YAOFANG,2024,35(23):2889-2895.
李睿,路丽艳,许楚等.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 Δ[J].中国药房,2024,35(23):2889-2895. DOI: 10.6039/j.issn.1001-0408.2024.23.09.
LI Rui,LU Liyan,Chu XU,et al.Study on in vivo pharmacokinetics and in vitro anti-inflammatory effects of cannabidiol-cholesterol succinate monoester-g-carboxymethyl chitosan nano-micelles[J].ZHONGGUO YAOFANG,2024,35(23):2889-2895. DOI: 10.6039/j.issn.1001-0408.2024.23.09.
目的
2
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
2
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、15 μg/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
2
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68.240 μg/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
、AUC
0-∞
、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,CBD-CCMC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
2
CBD-CCMC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
2
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
2
CBD-CCMC 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 nano-micelle 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 15 µg/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
2
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 68.240 μg/mL. The pharmacokinetic results showed that the AUC
0-48 h
, AUC
0-∞
, 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 compared with CBD of the same mass concentration
CBD-CCMC nano-micelles can significantly increase cell viability (
P
<0.05 or
P
<0.01), enhance TEER, and reduce the levels of IL-8, IL-1β and TNF-α in cells (
P
<0.01), and the secretion levels of inflammatory cytokines IL-8, IL-1β and TNF-α were significantly decreased (
P
<0.01).
CONCLUSIONS
2
CBD-CCMC nano-micelles can increase the plasma concentration and tissue distribution concentration of CBD, and improve anti-inflammatory activity of CBD.
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
nano-micellescholesterol succinate monoestercarboxymethyl chitosanpharmacokinetics
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