Abstract: Monitoring of Dissolution of Poorly Water-Soluble Drugs During In Vitro Lipolysis by Electron Resonance Spectroscopy (2011 Annual Meeting)

Wednesday, October 19, 2011: 1:50 PM

212 B (Minneapolis Convention Center)

Selena Di Maio¹, David E. Budil² and Rebecca L. Carrier¹, (1)Chemical Engineering, Northeastern University, Boston, MA, (2)Chemistry and Biological Chemistry, Northeastern University, Boston, MA

The recognized capability of ingested lipids to enhance the bioavailability of poorly water-soluble drugs[1]is not well understood and is 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 nanostructures, taking place during lipid digestion[2]. 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 quantitatively investigate how lipid digestion impacts dissolution of poorly water-soluble drugs via micelle/vesicle formation, an updated in vitro lipid digestion model has been designed, consisting of a bio-relevant medium, which reflects gastrointestinal contents in the fed state. Lipid digestion experiments were initiated by adding lipase/colipase enzymes and a lipid substrate – simple triglycerides (TG) or partially digested lipids (lipid mixture). The extent of lipid digestion was monitored indirectly by recording the volume of NaOH added during the experiment to titrate the fatty acids (FA) formed from the TG hydrolysis. Samples were collected at specific time intervals before and during the in vitro lipid digestion experiments and analyzed by dynamic light scattering (DLS), and electron paramagnetic resonance (EPR), to characterize respectively: size of colloidal particles, and dynamic drug partitioning between phases (aqueous, micellar, and oil). In lipolysis experiments coupled with EPR, the drug model (Tempol Benzoate) was also added to the bio-relevant medium and tracked between phases as the digestion proceeded. DLS analysis showed that the bio-relevant medium contained micelles with a hydrodynamic diameter less than 10 nm, which suddenly increased to 200 nm after the beginning of the lipid digestion, in agreement with previous in vivo studies concerning size of colloidal nanoparticles in human intestinal fluids[3]. Before the addition of lipase, EPR spectra showed an increasing partitioning of the model drug Tempol Benzoate over time, initially added to the bio-relevant medium, into the oil and micellar phases over a time scale similar to that of lipid digestion. Interestingly, results showed that drug partitioning into the oil and the micellar phases further increased over time despite the parallel digestion, and therefore decreasing amount of the soybean oil. This might suggest a higher partitioning into the micellar phase as colloidal particles evolve from micelles to vesicles during the lipid digestion process. Multi-components EPR spectra analysis is being used to quantitatively resolve the amount of drug in each phase (aqueous, oil, micellar) over time. The kinetics of digestion, drug dissolution and partitioning, and, in future studies, drug absorption will be correlated in mathematical models enabling prediction of the overall oral absorption of drug molecules in the presence of lipids.