(189y) Comparison of Oral Drug Dissolution between Medium and Long Chain Unsaturated and Saturated Triglycerides: A Modeling-Based Approach

An increasing number of drugs emerging from discovery pipelines are lipophilic, poorly water-soluble drugs. When co-administered with food, these drugs can exhibit either a positive or a negative effect of food on absorption and bioavailability. Modeling such a food effect successfully would be very valuable, as it would allow for an improved understanding of food related pharmacokinetic effects and ensure better co-dosing or formulation decisions when advancing towards clinical trials. Lipids in food are particularly significant in affecting the bioavailability of poorly soluble drugs. Our group previously developed a model of the impact of lipids on oral drug dissolution and bioavailability[i], with these initial efforts focused on studying and predicting the effects of soybean oil, a mixture of many different lipid molecules, as a model lipid vehicle.

The goal of this study is to more accurately model lipolysis and drug dissolution during the dynamic digestion of structurally diverse lipids, representing the variety of lipids available in our foods. This model may then be combined with an absorption model to more accurately predict the bioavailability of drugs under fed conditions with different meal constituents. The modeling framework incorporates lipolysis kinetic parameters, drug solubility data, and partition parameters which are experimentally measured. Thus, in vitro experiments are employed to obtain kinetic digestion and partitioning modeling parameters that highlight the differences between medium and long chain, unsaturated and saturated, and solid and liquid triglycerides. These differences ultimately affect pharmacokinetics of lipophilic drug co-dosed with lipids. For our experiments, we employ Griseofulvin as a model drug known to have a positive food effect.

Experiments were performed using a simulated fed state intestinal solution consisting of a buffer, (CaCL₂), a bile salt (NaTDC), and phospholipid. The lipid is added to the fed state solution (after melting for lipids solid at room temperature) and sonicated to form microparticles, which are stabilized due to the amphiphilic character of the bile salt and phospholipid. The bile salt and the phospholipid also form bile micelles that assist in drug dissolution by allowing for drugs to partition into the micelles. Pancreatin extract is added to begin digestion. As digestion occurs, the digestion products, mainly monoglycerides and fatty acids, partition into the micelles and the micelles grow allowing for higher concentrations of drug to partition into them. In vitro digestion experiments with unsaturated lipid, triolein (long chain length: C18 - liquid) and saturated lipids, tristearin (long chain length: C18 - solid) and tricaprylin (medium chain length: C8 - liquid) were conducted. As expected, the medium chain triglyceride exhibits faster drug dissolution kinetics than longer chain triglycerides. Initial experiments also show that saturated triglyceride exhibit slower digestion and lower drug solubility than the unsaturated triglycerides. With all three lipids, a significant increase in drug solubility was observed when lipid was introduced into solution as compared to fed state solution without lipid present, in concurrence with the positive food effect observed with griseofulvin when co-dosed with lipids. The mechanistic mathematical model is currently under development and initial results show successful prediction of triolein lipolysis and its impact on drug dissolution and overall absorption.

[i] F. Buyukozturk, S. Di Maio, D. E. Budil, R. L. Carrier. Phram. Res. 2013, 30, 3131