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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.
Eur J Pharm Sci. 2017 Mar 01; 99:350-360.EJ

Abstract

PURPOSE

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+Show Affiliations

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.Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.ABITEC Corporation, 501W 1st Avenue, Columbus, OH 43215, United States.Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28024890

Citation

Bu, Pengli, et al. "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." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 99, 2017, pp. 350-360.
Bu P, Ji Y, Narayanan S, et al. 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. Eur J Pharm Sci. 2017;99:350-360.
Bu, P., Ji, Y., Narayanan, S., Dalrymple, D., Cheng, X., & Serajuddin, A. T. (2017). 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. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 99, 350-360. https://doi.org/10.1016/j.ejps.2016.12.018
Bu P, et al. 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. Eur J Pharm Sci. 2017 Mar 1;99:350-360. PubMed PMID: 28024890.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Bu,Pengli, AU - Ji,Yue, AU - Narayanan,Silpa, AU - Dalrymple,Damon, AU - Cheng,Xingguo, AU - Serajuddin,Abu T M, Y1 - 2016/12/24/ PY - 2016/08/02/received PY - 2016/11/27/revised PY - 2016/12/19/accepted PY - 2016/12/28/pubmed PY - 2017/5/27/medline PY - 2016/12/28/entrez KW - Caco-2 cells KW - Cytotoxicity KW - Lipid-based drug delivery system KW - Medium-chain lipid KW - Monoglyceride KW - Permeation enhancement KW - Polysorbate 80 KW - Propylene glycol monoester KW - Surfactant KW - Triglyceride SP - 350 EP - 360 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 99 N2 - PURPOSE: 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. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/28024890/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_ DB - PRIME DP - Unbound Medicine ER -