a Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences , University of Shizuoka , 52-1 Yada , Suruga-ku , Shizuoka , Japan.
Drug Dev Ind Pharm. 2018 Nov;44(11):1838-1844. doi: 10.1080/03639045.2018.1503294. Epub 2018 Aug 31.
The main objective of this study was to develop a self-emulsifying drug delivery system (SEDDS) of carvedilol (CAR) with improved oral absorption and hepatoprotective properties. SEDDS-CAR was prepared based on d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and physicochemically characterized. Pharmacokinetic behaviors after the oral administration of CAR samples in rats were evaluated to clarify the possible enhancement of the oral absorption of CAR. The hepatoprotective effects of orally dosed CAR samples were assessed in a rat model of acute hepatic injury induced by carbon tetrachloride (CCl). SEDDS-CAR showed the immediate formation of fine micelles with a mean droplet size of 84 nm when introduced in aqueous media. SEDDS-CAR improved the dissolution behavior of CAR in distilled water as evidenced by at least five-fold higher solubility than the equilibrium solubility of CAR. After the single oral administration of SEDDS-CAR (10 mg-CAR/kg) in rats, enhanced CAR exposure was observed with an increase of AUC showing a 2.5-fold increase compared with crystalline CAR. In CCl-treated rats, orally dosed SEDDS-CAR (10 mg-CAR/kg, p.o.) led to 91.8 and 91.2% reductions of ALT and AST, respectively; however, crystalline CAR was found to be less effective. From these findings, SEDDS-CAR might be an efficacious oral dosage option for enhancing the hepatoprotective potential of CAR.
本研究的主要目的是开发一种具有改善口服吸收和保肝作用的卡维地洛（CAR）自乳化药物传递系统（SEDDS）。SEDDS-CAR 是基于生育酚聚乙二醇 1000 琥珀酸酯（TPGS）制备的，并对其理化性质进行了表征。通过评估大鼠口服 CAR 样品后的药代动力学行为，阐明了 CAR 口服吸收增强的可能性。通过四氯化碳（CCl）诱导的急性肝损伤大鼠模型评估了口服给予 CAR 样品的保肝作用。SEDDS-CAR 在引入水介质时立即形成平均粒径为 84nm 的细小胶束。SEDDS-CAR 改善了 CAR 在蒸馏水中的溶解行为，其溶解度至少比 CAR 的平衡溶解度高五倍。在大鼠单次口服 SEDDS-CAR（10mg-CAR/kg）后，观察到 CAR 暴露增加，AUC 增加，与结晶 CAR 相比增加了 2.5 倍。在 CCl 处理的大鼠中，口服给予 SEDDS-CAR（10mg-CAR/kg，po）分别使 ALT 和 AST 降低 91.8%和 91.2%；然而，结晶 CAR 的效果较差。从这些发现中可以看出，SEDDS-CAR 可能是增强 CAR 保肝作用的有效口服剂型选择。
