Gao Hang, Wang Miao, Sun Dandan, Sun Shilin, Sun Cheng, Liu Jianguo, Guan Qingxiang
The First Hosptial of Jilin University, No. 71, Xinmin Street, Changchun 130021, PR China.
School of Pharmacy, Jilin University, No. 1266, Fujin Road, Changchun 130021, PR China.
Eur J Pharm Sci. 2017 Aug 30;106:212-219. doi: 10.1016/j.ejps.2017.06.005. Epub 2017 Jun 4.
Currently, many surfactants used in self-emulsifying drug delivery systems (SMEDDS) can cause gastrointestinal mucosal irritation and systemic toxicity. In the present study, SMEDDS were loaded with pueraria flavones, using sodium taurocholate to replace polyoxyl 40 dydrogenated castor oil (Cremophor® RH 40) as the surfactant (PF-SMEDDS) to reduce the toxicity of SMEDDS using Cremophor® RH 40 as the surfactant (PF-SMEDDS). The absorption rate constants (K) and intestinal permeability coefficients (P) were measured. The effects of P-glycoprotein inhibitor (verapamil), adenosine triphosphate (ATP) inhibitor (2,4-dinitrophenol), and carrier inhibitor on K and P values in the ileum were determined. Biological safety was also evaluated. The K and P values increased for PF-solution concentrations of 200μg/ml>100μg/ml>400μg/ml in individual segments of the intestines. The results indicated that P values of PF-SMEDDS were distinctly higher than those of SMEDDS loaded with pueraria flavones using Cremophor®RH 40 as the surfactant (PF-SMEDDS) and PF-solution in four intestinal segments. However, the K values of PF-SMEDDS were higher only in the jejunum and ileum segments compared with those of PF-SMEDDS and PF-solution. The K and P values without verapamil were significantly lower than those with verapamil. 2,4-Dinitrophenol had no effect on K and P values. The K and P values of PF-SMEDDS significantly decreased after perfusing B-SMEDDS for 1h prior to the study. The cell viabilities after exposure to SMEDDS were higher than those of SMEDDS in the range of 81-324μg/ml. Lactate dehydrogenase release from cells treated with PF-SMEDDS or B-SMEDDS was significantly lower than that from cells treated with PF-SMEDDS or B-SMEDDS at surfactant concentrations of 243 and 324μg/ml. However, there were no differences with SMEDDS treatment at surfactant concentrations of 0-162μg/ml. Hence, we conclude that SMEDDS using sodium taurocholate as the surfactant can reduce the toxicity of SMEDDS, meanwhile, maintain the characteristics of SMEDDS, and enhance intestinal absorption.
目前，许多用于自乳化药物递送系统（SMEDDS）的表面活性剂可引起胃肠道黏膜刺激和全身毒性。在本研究中，用牛磺胆酸钠替代聚氧乙烯40氢化蓖麻油（克列莫佛®RH 40）作为表面活性剂，将葛根黄酮载入SMEDDS中（PF-SMEDDS），以降低以克列莫佛®RH 40为表面活性剂的SMEDDS（PF-SMEDDS）的毒性。测定了吸收速率常数（K）和肠道渗透系数（P）。确定了P-糖蛋白抑制剂（维拉帕米）、三磷酸腺苷（ATP）抑制剂（2,4-二硝基苯酚）和载体抑制剂对回肠中K和P值的影响。还评估了生物安全性。在肠道各段中，PF-溶液浓度为200μg/ml＞100μg/ml＞400μg/ml时，K和P值升高。结果表明，在四个肠段中，PF-SMEDDS的P值明显高于以克列莫佛®RH 40为表面活性剂载入葛根黄酮的SMEDDS（PF-SMEDDS）和PF-溶液。然而，与PF-SMEDDS和PF-溶液相比，PF-SMEDDS的K值仅在空肠和回肠段较高。未加维拉帕米时的K和P值明显低于加维拉帕米时。2,4-二硝基苯酚对K和P值无影响。在研究前用B-SMEDDS灌注1小时后，PF-SMEDDS的K和P值显著降低。在81-324μg/ml范围内，暴露于SMEDDS后的细胞活力高于SMEDDS。在表面活性剂浓度为243和324μg/ml时，用PF-SMEDDS或B-SMEDDS处理的细胞中乳酸脱氢酶的释放明显低于用PF-SMEDDS或B-SMEDDS处理的细胞。然而，在表面活性剂浓度为0-162μg/ml时，与SMEDDS处理无差异。因此，我们得出结论，以牛磺胆酸钠为表面活性剂的SMEDDS可降低SMEDDS的毒性，同时保持SMEDDS的特性，并增强肠道吸收。
