In-vitro permeability screening of melt extrudate formulations containing poorly water-soluble drug compounds using the phospholipid vesicle-based barrier

Abstract

The phospholipid vesicle-based barrier has recently been introduced as an in-vitro permeation model mimicking gastro-epithelial barriers in terms of passive diffusion of drugs. The aim of this study was to investigate whether the phospholipid vesicle-based barrier was suitable for permeability screening of complex formulations such as solid dispersions. Solid dispersions containing the poorly water-soluble drugs HIV-PI 1 (log P=6.2, molar mass=628.80g/mol) and HIV-PI 2 (log P=5.3, molar mass=720.95g/mol), a hydrophilic polymer and different surfactants were tested with respect to their influence on integrity of the barrier in terms of electrical resistance and permeability for calcein. Furthermore, utilisation of a more biologically relevant medium, Hank's balanced salt solution supplemented with Mg(2+) - and Ca(2+) -ions (HBSS (Mg(2+) , Ca(2+) )), has been tested. Except for the polyoxyl 40 hydrogenated castor oil-containing solid dispersion, no influence on the phospholipid vesicle-based barrier could be observed from the tested samples. Presence of active pharmaceutical ingredients (APIs) in the solid dispersions led to the same results as the corresponding placebo results. First experiments analysing the passive diffusion of both APIs in HBSS (Mg(2+) , Ca(2+) ), evaluated as suitable transport medium, have shown promising results regarding the suitability of the phospholipid vesicle-based barrier for investigation of solid dispersions. The study indicated that the phospholipid vesicle-based barrier was compatible with selected melt extrudate formulations. The model seemed capable to reveal different transport routes in comparison with Caco-2 cell permeability tests.