An investigation of the physicochemical mechanisms underlying enhanced oral bioavailability following administration of hydrophobic drugs via lipid-based delivery systems

The dissolution and solubilization process following oral administration of poorly water-soluble compounds is inherently slow, resulting in incomplete absorption and correspondingly low bioavailability. As a result, lipid-based dispersed systems have beer developed as a means of enhancing the transport rate of hydrophobic compounds. The current dissertation focuses on examining the physicochemical mechanism(s) by which mass transport of poorly water-soluble compounds from lipid-based aggregate systems is modulated. We have hypothesized that the mass flux of steroids across a silastic rubber membrane (model lipophilic membrane) does not correlate directly with thermodynamic activity of the solute in the bulk phase of micelle or microemulsion formulations as is commonly suggested in the literature, but instead mass flux rate correlates with diffusivity of the solute in the lipid-based formulations.; Using a model lipid-based drug delivery system and the poorly water-soluble compounds progesterone and estradiol, it was demonstrated that the Miglyol 812/Brij 97/H2O lipid-based formulations do in fact have the potential to significantly alter mass flux of the poorly water-soluble drugs progesterone and estradiol. Thermodynamic activities of the model drugs in lipid-based delivery systems employed in transport studies were directly measured using the Silicone Polymer Uptake Method, revealing that AT alone cannot fully explain transport of poorly water-soluble compounds from the Miglyol 812Brij 97/H2O model lipid-based system.; Diffusivities of progesterone and estradiol in a variety of microemulsion and micellar formulations were measured using the Pulsed Gradient Spin Echo Nuclear Magnetic Resonance technique. A clear correlation between overall diffusivity of drug in lipid-based formulations and transport rate was observed, suggesting that diffusivity seems to play a role in modulating transport from lipid-based formulations. Taken together, these results would seem to add support to the proposal that microemulsion aggregates enhance mass transport by carrying larger amounts of drug across the aqueous boundary layer adjacent to the membrane, enabling a fast replacement of drug that has permeated the membrane, thus diminishing the effect of the aqueous boundary layer on mass transport.