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Molecular dynamics simulations of lipid-based drug delivery systems

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posted on 01.03.2017, 04:35 by Birru, Woldeamanuel Anteneh
Molecular dynamics (MD) simulation is a powerful technique to investigate molecular self-assembly. It can be used to model and understand the interactions of biological membranes, proteins, and lipids. Above their critical micelle concentration (CMC), molecules that are composed of hydrophilic head group and hydrophobic tail group aggregate spontaneously to form a wide variety of assemblies ranging from micelles, rodlike structures, and bilayers to more complex phases such as hexagonal and cubic phases. These self-assembly processes are of fundamental importance in drug discovery and development. In the area of drug discovery and development, it is vital to have an effective means of improving the bioavailability of poorly water-soluble drugs (PWSD). Lipid-based delivery systems (LBDDS) are one of the important approaches of improving the bioavailability of PWSD. The nature of gastrointestinal (GI) fluids strongly influences the absorption of PWSDs. The dissolution rate and the amount of drugs dissolved is determined by the nature of the GI fluids and their solubilisation capacity. Within the GI tract there are endogenous as well as exogenous solubilising components. The endogenous components are secreted from the gall bladder, whereas the exogenous components are those which are administered in the drug formulation as well as resulting from meals. After oral administration, drugs must remain dissolved within the GI tract before partitioning into and then across the enterocyte. Although the self–assembly process of lipids and lipophilic excipients within the GI tract are thought to have a significant influence on drug solubilisation and the degree of drug supersaturation, the molecular understanding of these structures is limited. The first section of this work describes the modification of the GROMOS 53A6 united atom force field particularly for polyethylene glycol (PEG). Then, using MD simulations and experimental methods such as turbidity, particle size measurement, cross-polarized light microscopy and NMR, the current study explores the phase behaviour of (i) the 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), sodium glycochenodeoxycholate (GDX), and water system, and (ii) the 1-palmitoyl-2-hydroxy-sn-glycerol-3-phosphocoline (Lyso PC), GDX and water system and constructs ternary phase diagrams of these mixtures. It also investigates part of the quaternary phase diagram of Lyso PC, glycerol 1-monooleate (GMO), GDX and water, which was used to investigate the structures formed in the intestine after digestion of triglycerides. The solubilisation capacity of the lipidic microenvironment on PWSD has also been investigated using LC-MS and MD simulation. The association structures of these various systems have been modelled and compared to the experimental phase behaviour of the analogous systems. It is indicated in these studies that digestion and digested products have a significant impact on the phase behaviour of the contents of the small intestine and on solubilisation and bioavailability of PWSDs. In summary, this thesis contributes to a better understanding of the performance of lipid-based formulations (LBF) and shines a light on the use of MD simulations as a prediction tool to model LBDDS.


Campus location


Principal supervisor

Colin Pouton

Year of Award


Department, School or Centre

Drug Delivery, Disposition and Dynamics

Degree Type



Faculty of Pharmacy and Pharmaceutical Sciences