title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Pengli
authors.initials: P
authors.lastname: Bu
authors.affiliation: Department of Biological Sciences, College of Liberal Arts and Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.
authors.forename: Silpa
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: ABITEC Corporation, 501W 1st Avenue, Columbus, OH 43215, United States.
authors.forename: Damon
authors.initials: D
authors.lastname: Dalrymple
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States. Electronic address: serajuda@stjohns.edu.
authors.forename: Abu T M
authors.initials: AT
authors.lastname: Serajuddin
mesh_terms: D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D004655:Emulsions / Q000737:chemistry* / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D050178:Monoglycerides / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011136:Polysorbates / Q000737:chemistry*; D019946:Propylene Glycol / Q000737:chemistry; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D004655:Emulsions; D005227:Fatty Acids; D008055:Lipids; D050178:Monoglycerides; D004364:Pharmaceutical Preparations; D011136:Polysorbates; D013501:Surface-Active Agents; D014867:Water; D019946:Propylene Glycol
keywords: Caco-2 cells; Cytotoxicity; Lipid-based drug delivery system; Medium-chain lipid; Monoglyceride; Permeation enhancement; Polysorbate 80; Propylene glycol monoester; Surfactant; Triglyceride