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Intestinal Lipoidal Nanostructures - A Lipid Bridge to Increased Drug Delivery

Periodic Reporting for period 3 - INTESTINANOS (Intestinal Lipoidal Nanostructures - A Lipid Bridge to Increased Drug Delivery)

Reporting period: 2018-09-01 to 2020-02-29

My research program explores molecular interplay between drug, dosage form and the complex environment of the gastrointestinal tract (GIT). Drug molecules currently being discovered to cure e.g. CNS diseases, cancer and the metabolic syndrome show poor water solubility and 70-90% of recently discovered drugs have too poor solubility to allow absorption after oral intake. For such compounds the dosage form can significantly improve the absorption. My long-term goal is to establish a computational platform that predicts, from molecular structures and computational tools, the development potential of drug molecules to well-functioning orally administered medicines. A major gap in our understanding of drug performance in the intestine is the poor knowledge of the dynamics of solubilizing lipoidal nanostructures (micelles, vesicles, oil droplets) present in the fluid. This project explores restructuring of these lipoidal nanostructures in response to intake of food or dosage forms, enzymatic digestion, absorption and transit along the GIT. Novel experimental tools are developed to reveal the impact of these nanostructures on drug solubilization, supersaturation and likelihood of precipitation in vivo, all being important for drug absorption. The experimental results are fed into in silico models making use of Molecular Dynamics simulations to develop a computational platform predicting drug performance in the dynamic intestinal milieu. The novel tools designed herein will allow dosage forms that improve performance and increase drug absorption after oral administration to, for the first time, be designed by computational means. The results of this project, in particular the novel in silico tools exploring rearrangement of lipoidal nanostructures, are highly important to related areas such as GIT disease models and food processing but also have wider applications in e.g. studies of intracellular vesicle rearrangements and transport processes in plants.
Mid-way through this project we have already made significant progress. We have developed a novel experimental technique to explore drug absorption after being formulated as lipid-based formulations. Computer-wise we have set up a work flow of importance for the development of a virtual human intestine and produced computational simulations of interindividual variability of fasted state human intestinal fluid. This computational protocol allows us to relatively rapidly set up human intestinal fluids that reflects a population and it is now used to explore the fed state. The available boxes for fasted state are now used to explore processes of improtance for formulated drugs, such as solubilization, importance of digestion and molecular interactions between the lipid aggregates composed of bile and excipients.
Our digestion-absorption system enables physiologically relevant studies not only of the lipid-based formulations but is also useful for other formulation strategies as well as for studies of e.g. food processing, performance of nutrition solutions, nutraceuticals and functional foods (to mention a few). The approach towards the virtual intestine is the first of its kind. We now have established virtual intestinal fluids representing six healthy volunteers with differences in bile secretion. These are now used to explore drug release, dissolution, and solubility, lipid digestion and impact of food. By capturing the interindividual variability in the computer we now make it possible to computationally predict the formulation performance in vivo. The latter is expected to result in improved understanding of these complex physical systems but will also result in the possibility to optimize the formulation in silico (similar to what currently is done in the medicinal chemistry field through computer-aided drug design). Finally the combination of improved in silico and in vitro tools is expected to increase the selection of optimised formulations. When this comes true the number of animal and human studies will be lowered, since these should then only be performed to validate the in silico and in vitro results. In addition the cost for drug development will be decreased through smarter dosage forms being selected based on the understaning obtained from the computational platform.