Effects of Lipids on Absorption of Poorly Water-Soluble Drugs

Introduction Although the capability of ingested lipids to enhance the bioavailability of poorly water-soluble drugs has been experimentally observed and established 1 , the phenomenon is not well understood and is unpredictable. Commercially, lipids could offer valuable opportunities for enabling oral drug delivery, as approximately 4070% of all new drug candidates have been estimated to have very poor water solubility 2 . For this class of drug molecules, whose dissolution in water is likely the limiting step of overall oral absorption, the primary role of ingested lipids and their lipolytic products is to impact the drug dissolution step by forming – with bile components – different colloidal particles, which are able to maintain a larger quantity of hydrophobic drugs in solution via micellar solubilization 3 . Despite increasing numbers of studies demonstrating the positive impact of ingested lipid on several processes associated with the overall absorption of hydrophobic drugs, there is a lack of general in vitro and theoretical models that are able to rationalize and mathematically predict a priori the in vivo performance of drug-lipid systems. In order to investigate the mechanisms by which lipids improve dissolution and the overall absorption of poorly water-soluble drugs, an updated in vitro lipid digestion model 4 has been designed based on knowledge of gastrointestinal contents. Digestion kinetics sensitivity to crucial experimental parameters, including pH, calcium concentration, bile components, and lipid substrate, has been quantitatively investigated based on a 2 4 balanced multifactor design, summarized in Table 1. Preliminary statistical analysis identified the pH as a significant factor for the lipid digestion process. The presence and the size of colloidal species has been evaluated by dynamic light scattering (DLS), which detected the presence of particles with hydrodynamic diameters in the range of 10-200 nm. The kinetics of drug partitioning between colloidal phases formed during in vitro digestion has been tracked by electron paramagnetic resonance (EPR), which showed the ability to detect the drug in aqueous, micellar, and oil phases in real-time. Experimental Method Based on an exhaustive review of the literature pertaining to the knowledge and current models of intestinal contents 5 , the in vitro lipolysis models proposed in this work employ a bio-relevant medium, reflecting gastrointestinal contents in the fed state, which was prepared in maleate buffer (Triz-ma 100 mM, NaCl 65 mM, CaCl2*H2O 10 mM, NaN3 3 mM, and NaOH up to final pH 6.5) and included lecithin and sodium taurodeoxycholate as a model of human bile. The 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 (0, 5, 20, 30, and 50 minutes) during the in vitro lipid digestion experiments and analyzed by DLS and EPR techniques. 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. In the quantitative assessment of system sensitivity to experimental parameters, in vitro lipolysis experiments were performed according to 2 4 multifactor design shown in Table 1. Statistical analysis was carried out by Minitab software 6 to determine the significance of each factor.