Effects of absorption enhancer surfactants on culture models of intestinal and vascular barriers

Abstract

Surfactants used in pharmaceutical products have several advantageous properties; they improve drug absorption and dissolution, and protect active molecules. However, adverse effects are also observed during the application of different surface active agents which necessitates the investigation of registered surfactants and novel absorption enhancer candidates. Cremophor RH40 and EL are widely used excipients in oral and intravenous drug formulations. Studies indicate that Cremophors, especially EL, have toxic side effects, but few data are available on endothelial and epithelial cells which form biological barriers and are directly exposed to these molecules. In our investigation human intestinal epithelial and vascular endothelial cells were treated with Cremophor RH40 and EL in clinically relevant concentrations and their toxic effect was monitored by several methods. Cremophors caused concentration- and time-dependent damage in both epithelial and endothelial cells. Endothelial cells were more sensitive to surfactant treatment than epithelial cells, and Cremophor EL was more toxic than RH40 in both cell types. Our results support and complement the previously experimentally described toxic effects of Cremophor EL which may be related to the clinically recognized side-effects of medicines containing Cremophor EL. Sucrose fatty acid esters are increasingly investigated as novel excipients in pharmaceutical research and some of them are registered in Pharmacopoeias both in the European Union and in the United States. Several studies documented their advantageous properties but few data are available on their toxicity profile, mode of action and efficacy on intestinal epithelial models. Three water soluble sucrose esters, palmitate (P-1695), myristate (M-1695), laurate (D-1216), and two reference absorption enhancers, Tween 80 and Cremophor RH40 were tested on human Caco-2 intestinal epithelial cells. Sucrose esters in non-toxic concentrations significantly reduced resistance and impedance of cells, but not reference surfactants. All excipients increased permeability for drugs and fluidized plasma membrane, but did not visibly open tight junctions. Tween 80 but not sucrose esters inhibit P-glycoprotein. Our data indicate that in addition to their dissolution increasing properties sucrose esters can enhance drug permeability through both the transcellular and paracellular routes but this effect is unrelated to P-glycoprotein inhibition. The presented results demonstrate the differences between the cellular actions of various non-ionic surfactant excipients, which can be important for the development of new pharmaceutical formulations and drug delivery systems.