Choline chloride:glycerol deep eutectic solvents assist in the permeation of daptomycin across Caco-2 cells mimicking intestinal bilayer

Abstract

Daptomycin is a cyclic lipopeptide antibiotic used for complicated skin infections and right-sided endocarditis. The oral absorption of daptomycin is limited because of its restricted permeability across the intestinal epithelium, low lipophilicity, low bioavailability due to enzymatic degradation and high molecular weight. This study investigates the enhancement in intestinal absorption of daptomycin using a new class of permeation enhancers. Caco-2 cell-based model, mimicking the intestinal bilayer, was used as an in-vitro mucosal barrier to examine the diffusion of daptomycin. The study explored the potential of deep eutectic solvents (DESs) as oral permeation enhancers, in comparison with sodium caprate, a well-known intestinal permeation enhancer. Safe and non-toxic concentrations of DESs were determined using an MTT assay. Accordingly, a safe and effective concentration range was employed for enhancing the permeation of daptomycin. Diffusion studies performed using RP-HPLC indicated an increase in permeation of daptomycin in the presence of sodium caprate and DESs. Confocal microscopy enabled elucidation of the mechanism of permeation enhancement via reduced expression of cell junction proteins. Both, sodium caprate and DESs lowered the expression of ZO-1 protein, due to the loosening of tight junctions between Caco-2 cells and thus enhanced permeation of daptomycin. Therefore, DESs can be used as safe and effective permeation enhancers for daptomycin and explored for other oral peptide-based therapeutics .