Theoretical and experimental studies of lipid-based formulations

This dissertation consists of two related chapters which are theoretical in nature and one unrelated experimental-based chapter. The central theme for all of these studies is to understand, model, and exploit lipid aggregation patterns to improve the therapeutic ratios of administered drugs. The first chapter examines a lipid aggregation process that occurs in the upper intestines during fat digestion that can have a profound impact on absorption of lipophilic drugs. The agreement between these molecular dynamics computer simulation results and experimentally measured properties of intestinal lipid aggregates illustrates that this technique can be useful to study mixed micelles of bile salts and fatty acids, critical to the understanding of food as well as lipid formulation effects on bioavailability patterns of poorly soluble drugs. The aggregation behavior and structure of these simulated intestinal micelles are presented in this chapter. The work in the second chapter then evaluates a hybrid MD/physiological-based pharmacokinetic model intended to predict gastrointestinal absorption of various drugs. Erratic absorption related to concomitant food intake is a serious problem facing new drug candidates, and the algorithm presented in this work can be applied to predict interactions of drugs with intestinal lipid aggregates and, using this information, forecast the fed to fasted absorption ratios. The model predictions show good agreement with existing clinical data for the selected drugs.;The final chapter deals with near-infrared active thermosensitive liposomes. The lipid-based formulations described in the text demonstrate potential for future applications in image-guided cancer therapy. One of the major goals of this work was the design of a stable, temperature-sensitive liposome formulation resistant to the RES uptake in vivo. Factors such as phase transition temperature, cellular uptake, and release/stability were investigated, and a suitably stable liposome formulation was chosen for optical near-infrared pharmacokinetic studies. Key to the success of this work, the near-infrared imaging validation study demonstrated good correlation between absolute amount of the near-infrared fluorophore, ICG, and the near-infrared image intensity, indicating that this imaging process holds promise as a clinical level non-invasive indicator of liposome biodistribution.