(738a) Studies of Dynamic Nanoscale Structures During in Vitro Lipid Digestion

The recognized capability of ingested lipids to enhance the bioavailability of poorly water-soluble drugs is not well understood and unpredictable. For this class of drug molecules, whose dissolution in water is likely the limiting-step of overall oral absorption, the influence of ingested lipids on oral absorption has been associated with complex, poorly characterized interactions between drugs and several colloidal structures, taking place during lipid digestion . In particular, emulsion droplets, micelles and vesicles influence dissolution kinetics and are able to maintain a larger quantity of hydrophobic drug in solution, increasing the solubilization power of the gastrointestinal (GI) tract contents. In order to investigate the mechanisms by which lipids improve dissolution of poorly water-soluble drugs via micelle/vesicle formation, an updated in vitro lipid digestion model has been designed based on knowledge of gastrointestinal contents. The dynamic system consists of a bio-relevant medium, simulating the GI tract contents in the post-prandial state, in which lipase/co-lipase enzymes and a lipid substrate are added. The digestion kinetics sensitivity to system parameters, including pH, calcium concentration, and lipid substrate, has been characterized. The model is highly sensitive to pH, with production of fatty acids doubling when pH is increased from 6.5 to 7.5. Enhanced rate of digestion is also observed with increasing calcium concentration from 5 mM to 10 mM. The dynamic evolution of colloidal nanostructures formed during the in vitro lipolysis has been monitored by the quasi-elastic light scattering technique, which detected the presence of nanoparticles with hydrodynamic diameters in the range of 10-200 nm. The bio-relevant medium contained micelles with a hydrodynamic diameter less than 20 nm, which suddenly increased to 200 nm after the addition of lipase/co-lipase enzymes and the lipid substrate, indicating the formation of vesicles during the enzymatic hydrolysis of lipids. However, no particular trend, but rather fluctuating particle size over time has been noted during in vitro lipolysis experiments, which may suggest complex kinetics of formation and evolution of different colloidal species as the lipid digestion proceeds. Additional investigation will further characterize these nanostructures and elucidate their role in overall oral absorption.