Bu Pengli, Ji Yue, Narayanan Silpa, Dalrymple Damon, Cheng Xingguo, Serajuddin Abu T M
Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States; Department of Biological Sciences, College of Liberal Arts and Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.
Department of Biological Sciences, College of Liberal Arts and Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.
Eur J Pharm Sci. 2017 Mar 1;99:350-360. doi: 10.1016/j.ejps.2016.12.018. Epub 2016 Dec 24.
Lipid-based self-emulsifying drug delivery systems (SEDDS) are commonly used for solubilizing and enhancing oral bioavailability of poorly water-soluble drugs. However, their effects on viability of intestine epithelial cells and influence on membrane permeation are poorly understood. The present study was undertaken for safety assessment of lipid-based formulations containing medium-chain fatty acid esters as lipids and polysorbate 80 as the surfactant using the Caco-2 in vitro model. Any possible paracellular permeation enhancement through Caco-2 monolayers by the nontoxic formulations was also investigated.
Mixtures of monoglyceride (Capmul MCM EP or 708G) or propylene glycol monoester (Capmul PG-8 NF) of medium chain fatty acids with polysorbate 80, with and without the incorporation of a medium-chain triglyceride (Captex 355), were prepared. After suitable dilution with aqueous culture medium, the formulations were incubated with a series of Caco-2 cultures of different maturity. Cell viability and membrane integrity were assessed. Any effects of nontoxic formulations on the transport of the fluorescent dye, Lucifer yellow, through Caco-2 monolayers were also determined.
Formulations containing 1:1 ratios of monoglyceride or propylene glycol monoester to triglyceride (30% polysorbate 80, 35% monoglyceride or monoester and 35% triglyceride) were best tolerated by Caco-2 cells. Increased maturity obtained through longer culture durations rendered Caco-2 cells greater tolerance towards lipid-based formulations, and maximum tolerance to lipid-based formulations was observed with Caco-2 monolayers after being cultured for 21-23days. Furthermore, extent of cell membrane rupture caused by lipid-surfactant mixtures correlated positively with levels of cytotoxicity, suggesting a potential underlying mechanism. Permeation studies using Caco-2 monolayer model revealed that certain formulations significantly enhanced paracellular transport activities.
Lipid-based SEDDS containing mixtures of monoglyceride (or monoester) and triglyceride of medium chain fatty acids formed fine microemulsions and were significantly less toxic than other formulations. Fully differentiated Caco-2 monolayer was more resistant to lipid-surfactant mixtures than less mature cultures. Certain formulations were also capable of enhancing paracellular permeation.
基于脂质的自乳化药物递送系统（SEDDS）常用于增溶和提高难溶性药物的口服生物利用度。然而，它们对肠上皮细胞活力的影响以及对膜渗透的影响尚不清楚。本研究采用Caco-2体外模型对以中链脂肪酸酯为脂质、聚山梨酯80为表面活性剂的脂质制剂进行安全性评估。还研究了无毒制剂通过Caco-2单层细胞可能增强的细胞旁渗透作用。
制备中链脂肪酸甘油单酯（Capmul MCM EP或708G）或丙二醇单酯（Capmul PG-8 NF）与聚山梨酯80的混合物，添加或不添加中链甘油三酯（Captex 355）。用含水培养基适当稀释后，将制剂与一系列不同成熟度的Caco-2培养物孵育。评估细胞活力和膜完整性。还测定了无毒制剂对荧光染料路西法黄透过Caco-2单层细胞转运的任何影响。
甘油单酯或丙二醇单酯与甘油三酯比例为1:1的制剂（30%聚山梨酯80、35%甘油单酯或单酯和35%甘油三酯）最能被Caco-2细胞耐受。通过更长培养时间获得的更高成熟度使Caco-2细胞对脂质制剂具有更高的耐受性，在培养21 - 23天后的Caco-2单层细胞中观察到对脂质制剂的最大耐受性。此外，脂质 - 表面活性剂混合物引起的细胞膜破裂程度与细胞毒性水平呈正相关，提示了一种潜在的机制。使用Caco-2单层模型的渗透研究表明，某些制剂显著增强了细胞旁转运活性。
含有中链脂肪酸甘油单酯（或单酯）和甘油三酯混合物的基于脂质的SEDDS形成了良好的微乳液，且毒性明显低于其他制剂。完全分化的Caco-2单层细胞比不太成熟的培养物对脂质 - 表面活性剂混合物更具抗性。某些制剂也能够增强细胞旁渗透。
