Hydrophobic ion-pairs and lipid-based nanocarrier systems: The perfect match for delivery of BCS class 3 drugs

Membrane permeability of charged BCS class 3 drugs can be tremendously improved by the formation of hydrophobic ion-pairs (HIPs), as the lipophilic character of the drug is strongly improved so that it can move across the phospholipid bilayer of epithelial cells. This effect, however, can in most cases only be observed in in vitro studies, where the destabilizing effect of endogenous counterions on HIPs can be minimized. In vivo results were so far disappointing. Due to the incorporation of HIPs in lipid-based nanocarrier systems such as self-emulsifying drug delivery systems (SEDDS) and oil-in-water nanoemulsions, however, the stability of HIPs in the GI-tract can be substantially improved. As the dielectric constant in the oily droplets is comparatively much lower than that of GI-fluids and endogenous counterions cannot penetrate the oily droplets, HIPs can reach the absorption membrane still in intact form. Moreover, lipid-based nanocarrier systems were shown to be able to move across the mucus gel as well as unstirred water layer and to interact with the absorption membrane via various mechanisms delivering their payload to the systemic circulation. First in vivo studies utilizing the combination of HIPs and lipid-based nanocarrier systems showed a 10- up to 20-fold improved oral bioavailability of different types of drugs providing evidence for the potential of this concept. Within this review so far made achievements in this field and challenges ahead are discussed.