Computational Modeling of the Intestinal Drug Delivery EnvironmentMuch research has been conducted on the influence of different drug delivery technologies such as cyclodextrins, lipid-based systems and polymeric systems on drug bioavailability. Often, when such technologies are utilized in practice, a device containing the drug and delivery agent is formulated by trial and error, resulting in an iterative formulation process. Understanding the mechanistic processes involved in drug delivery and the influence of system parameters on them can greatly streamline formulation development.
Since oral drug delivery is the most convenient of the administration routes, it has been widely used. Oral bioavailability depends on absorption in the GI tract as well as metabolism, distribution and excretion of the drug from the body. Dissolution, precipitation and permeation through the intestinal membrane are the key processes affecting oral drug absorption. Our goal is to develop models of oral drug delivery with mathematical expressions for these key processes that incorporate parameters representing physical and chemical properties of the drug to be delivered, the drug delivery device, and the intestinal environment. Our focus to date has been on predicting the influence of solubilizing agents (e.g. cyclodextrins, lipids) on drug absorption and bioavailability. Different dosing schemes have been considered, including dosing saltforms vs. neutral drugs or pre-formed complexes with cyclodextrins vs. physical mixtures. The influence of modeling the GI tract as a single compartment vs. a more physiological representation as a series of compartments on predicted bioavailabiltiy enhancement using solubilizing agents has also been studied. Experimental validations of key process in the model and comparison of predictions with in vivo data are conducted in parallel with model development.
Self-emulsifying drug delivery systems (SEDDS) have shown great promise for enhancing oral bioavailability of water insoluble drug compounds but have been employed in only few oral pharmaceutical products in recent years. This is due to lack of understanding of how and when these drug delivery systems "work" or not. This is also due to lack of confidence in prediction of in vivo performance of emulsion-based drug delivery systems from in vitro testing. Most reported studies in which emulsion-based oral drug delivery is employed investigate single or small sets of drug-oil-surfactant combinations and do not focus on quantitative understanding of how these systems function to enhance oral absorption. The goal of this project is to gain a quantitative understanding of how properties of a given drug, lipid and surfactant, formulated in a specific way, interact with the biological environment to enable oral absorption. For this approach, formation and properties of emulsions, oil/surfactant/drug interactions (statistical methods), emulsion drug release kinetics, digestion kinetics and intestinal permeability are being addressed.