Evaluation of the cytotoxicity and intestinal absorption of a self-emulsifying drug delivery system containing sodium taurocholate

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Abstract

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-SMEDDSNR) to reduce the toxicity of SMEDDS using Cremophor® RH 40 as the surfactant (PF-SMEDDSR). The absorption rate constants (Ka) and intestinal permeability coefficients (Peff) were measured. The effects of P-glycoprotein inhibitor (verapamil), adenosine triphosphate (ATP) inhibitor (2,4-dinitrophenol), and carrier inhibitor on Ka and Peff values in the ileum were determined. Biological safety was also evaluated. The Ka and Peff values increased for PF-solution concentrations of 200 μg/ml > 100 μg/ml > 400 μg/ml in individual segments of the intestines. The results indicated that Peff values of PF-SMEDDSNR were distinctly higher than those of SMEDDS loaded with pueraria flavones using Cremophor®RH 40 as the surfactant (PF-SMEDDSR) and PF-solution in four intestinal segments. However, the Ka values of PF-SMEDDSNR were higher only in the jejunum and ileum segments compared with those of PF-SMEDDSR and PF-solution. The Ka and Peff values without verapamil were significantly lower than those with verapamil. 2,4-Dinitrophenol had no effect on Ka and Peff values. The Ka and Peff values of PF-SMEDDSNR significantly decreased after perfusing B-SMEDDSNR for 1 h prior to the study. The cell viabilities after exposure to SMEDDSNR were higher than those of SMEDDSR in the range of 81–324 μg/ml. Lactate dehydrogenase release from cells treated with PF-SMEDDSNR or B-SMEDDSNR was significantly lower than that from cells treated with PF-SMEDDSR or B-SMEDDSR at surfactant concentrations of 243 and 324 μg/ml. However, there were no differences with SMEDDS treatment at surfactant concentrations of 0–162 μg/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.

Graphical abstract

Fig. 10. Cell viability-concentration profiles with the MTT test. Human umbilical vein endothelial cells (HUVECs) were exposed to B-SMEDDSNR, PF-SMEDDSNR, B-SMEDDSR, or PF-SMEDDSR prior to viability testing. Data are presented as mean ± S.D. (n = 5). *P < 0.05 shows significant differences of B-SMEDDSNR and PF-SMEDDSNRversus B-SMEDDSR and PF-SMEDDSR. #P < 0.05 shows a significant difference between untreated cells and those treated with 324 μg/ml surfactant.

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