Assessment of cell viability and permeation enhancement in presence of lipid-based self-emulsifying drug delivery systems using Caco-2 cell model: Polysorbate 80 as the surfactant

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• 作者：Pengli Bu^a ; ^b ; Yue Ji^b ; Silpa Narayanan^a ; Damon Dalrymple^c ; Xingguo Cheng^a ; Abu T.M. Serajuddin^a ; ^{serajuda@stjohns.edu}
• 关键词：LBDDS ; lipid-based drug delivery system ; LBSEDDS ; lipid-based self-emulsifying drug delivery system ; SEDDS ; self-emulsifying drug delivery system ; SMEDDS ; self-microemulsifying drug delivery system ; MTT ; 3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-diphenyltetrazolium bromide ; PG ; propylene glycol ; HBSS ; Hank's Balanced Salt Solution ; DMEM ; Dulbecco's Modification of Eagle's Medium ; FBS ; fetal bovine serum ; DMSO ; dimethyl sulfoxide ; TEER ; transepithelial electrical resistance
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 March 2017
• 年：2017
• 卷：99
• 期：Complete
• 页码：350-360
• 全文大小：1561 K
• 卷排序：99

文摘

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.MethodsMixtures 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.ResultsFormulations 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 21–23 days. 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.ConclusionsLipid-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.