Modeling of Effects of Lipids On Dissolution of Poorly Water-Soluble Drugs

Despite the recognized capability of ingested lipids to impact several processes associated with the overall oral absorption of poorly water-soluble drugs, the fate of co-administered drugs remains unclear and unpredictable. The aim of this study is to quantitatively investigate and model the effects of ingested lipids and lipid digestion on dissolution and partitioning of hydrophobic drugs orally delivered in simulated intestinal fluids by means of in vitrolipolysis models.

 An updated in vitro digestion model – comprising a bio-relevant medium, soybean oil as lipid substrate, and lipase/colipase enzymes - 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 were investigated by acid-base titration and correlated to dissolution tests. Kinetics of drug partitioning between colloidal phases (oil, micellar, aqueous) formed during in vitro digestion was tracked by electron paramagnetic resonance (EPR). A model considering pseudo-equilibrium micelle partitioning, interfacial-barrier driven oil partitioning, and oil digestion kinetics was developed and compared to experimental results.

 A film-equilibrium model, in the form of Noyes-Whitney expression, was developed and utilized to predict drug dissolution kinetics in the simulated intestinal fluids with and without lipids. In the model, the influence of interacting colloids on 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 was evaluated based on EPR measurements pre- and during in vitro lipolysis simulations. EPR provided real-time compound tracking measurements being able to quantify the amount of drug present in each phase related to the lipolysis process. After the addition of soybean oil into the bio-relevant medium, EPR spectra of pre-lipolysis samples showed an increasing partitioning of TB into the oil phase up to 30%, over a time scale similar to that of lipid digestion (3 hours), suggesting an interfacial-barrier driven process rather than pure diffusion of drug into the oil phase.

Drug dissolution, partitioning coefficients, and digestion kinetics of digestion were correlated in system-based model enabling prediction of the fate of orally administered drugs during the lipid digestion process and providing insight into their anticipated overall effect on oral absorption.