Dimitrijevic, Dejana; (1998) Effects of surfactant systems on metformin transport. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This work has focused on the investigations of carrier and absorption enhancing systems for the hydrophilic drug metformin when delivered orally. The influence of both water-in-oil (W/O) and oil-in-water (O/W) emulsions containing metformin in the aqueous phase on oral metformin bioavailability was studied in the rat. A water-in-isopropyl myristate emulsion stabilised with sorbitan monooleate (Span 80) and bovine serum albumin (BSA), an OAV emulsion stabilised with cholesteryl poly (24) oxyethylene ether (Solulan C24) and Span 80 prepared with soybean oil and an OAV emulsion stabilised with sorbitan monostearate (Span 60) with sesame oil as the continuous phase were formulated, characterised and tested in vivo. The oral administration of emulsions modifies the absorption of metformin in rat. Histological investigations provided some clues as to the cause of increase in metformin absorption. Most likely are changes to the intestinal membrane and, in some cases to the junctional complexes caused by the surface active compounds and fatty acids present in the formulations. Knowledge of the reversibility of these effects was crucial. Allowing the intestinal cells to recover after dosing for three days, suggests that all changes that were detected were, indeed, reversible. The effects of the non-ionic surfactants polysorbate 20, 60, 85, Solulan C24 and a lanolin-based poly(16)oxyethylene ether (Solulan 16) on epithelial integrity of the Caco-2 cells monolayers were studied. The effects of the surfactants on cell permeability were assessed by measurements of the transport of metformin, transepithelial electrical resistance (TEER) and tests for cell viability (determined by the diphenyltetrazolium bromide test). The concentration-dependent effects on TEER correlated with cell viability, i.e. increased TEER and increased cell-monolayer permeability for metformin corresponded to decreased cell viability. The results indicate that the Solulans and polysorbates were active as absorption enhanced in quite different concentration ranges, the former being more effective than the latter. The effects of the surfactants were also assessed by transmission and scanning electron microscopy. The results prove a correlation between the increase of metformin transport caused by the surfactants and toxic effects on cell monolayers. The effects of the most potent surfactants (polysorbate 20, Solulan C24 and 16) were tested in vivo to establish a correlation with in vitro data. It was concluded that the effects of the surfactants used at certain concentrations on the rat intestinal membrane were reversible. Several niosome formulations were prepared in order to assess potential toxic effect of these systems on Caco-2 cell monolayers. It may be concluded that the toxic effect of niosomes is due to the amount of free surfactant present in the niosome suspension. Novel fluorocarbon and hydrocarbon surfactants as potential absorption enhancers were also tested on Caco-2 cell monolayers. All hydrocarbon surfactants and one of the fluorocarbon demonstrated concentration-dependent effects on cell permeability. In general fluorocarbon surfactants seemed to be less toxic, but less potent as absorption enhancers, emphasising the affinity between transport enhancement and toxicity.

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