(436h) Modeling Impact of Lipids On Orally Delivered Drug Dissolution

Despite the recognized capability of ingested lipids to significantly impact oral absorption of drugs, the fate of co-administered compounds remains unclear and not predictable a priori. The aim of this study is to quantitatively investigate and model the effects of ingested lipids and lipid digestion on dissolution and partitioning of orally delivered drugs by means of in vitro lipolysis models incorporating simulated intestinal fluids.

An updated in vitro digestion model was designed to closely mimic fed state intestinal conditions. The paramagnetic compound TEMPOL benzoate (TB) was selected as a model for poorly water-soluble moderately lipophilic drug (log P = 2.46). Digestion kinetics was investigated by titration and compared with measured dissolution kinetics in the presence and absence of lipids to assess processes likely to significantly impact overall drug absorption kinetics. Drug partitioning between colloidal phases (oil, micellar, aqueous) formed during in vitro digestion was studied by electron paramagnetic resonance (EPR), which provided real-time compound tracking measurements and quantification.

A film-equilibrium drug dissolution model was developed and utilized to predict drug dissolution kinetics in simulated intestinal fluids with and without lipids. In the model, the influence of colloids interacting with drug on drug transport rates was explicitly taken into account, and drug partitioning with micelles was considered as a pseudo-equilibrium process. The impact of lipids and their digestion on dissolution, experimentally evaluated based on EPR measurements pre- and during in vitro lipolysis, was compared with model predictions. Appropriate rate expressions describing lipid digestion, drug dissolution, drug partitioning, and drug transport across the intestinal membrane were assessed and incorporated into a model to predict overall drug absorption. The significance of ingested lipid-drug interactions during digestion to the overall drug absorption is not always obvious and still unpredictable. However, a systems-based model incorporating drug dissolution, drug partitioning, and lipid digestion kinetics might enable prediction of the fate of orally administered drugs during the lipid digestion process and provide insight into their anticipated overall effect on oral absorption. The ability to predict the impact of lipids on oral drug delivery would shed considerable light on the “food effect” on oral drug absorption, a phenomenon of tremendous significance to the pharmaceutical industry and drug development.