Title:	The effect of intestinal fluid composition on self-assembly and drug solubility in lipid based formulations.
DNr:	SNIC 2016/1-405
Project Type:	SNIC Medium Compute
Principal Investigator:	Christel Bergström <christel.bergstrom@farmaci.uu.se>
Affiliation:	Uppsala universitet
Duration:	2016-09-28 – 2017-10-01
Classification:	30101 30103
Homepage:	http://www.farmfak.uu.se/farm/lmformul/index.html
Keywords:

Abstract

Oral administration of drugs requires sufficient solubility of the active ingredient in gastric or intestinal fluid to allow complete absorption. Modern drug discovery techniques often generate lead compounds with low aqueous solubility. This translates to an inefficient and expensive drug development process, since time and resources are spent on drug candidates that in the end cannot easily be administered in vivo. This study aims to increase the understanding for the molecular basis in solubilization of poorly soluble compounds in physiological fluids containing lipids. If the mechanisms behind the solubilization in these lipid aggregates could be understood on a molecular level, knowledge-driven decisions about solubility-related issues could be made much earlier during the drug development process. We have previously studied the structural and dynamic features of simple model systems containing two important constituents of intestinal fluid, lecithin (DLiPC) and taurocholate (TCA) (M Holmboe, P Larsson, J Anwar and CAS Bergström, Langmuir, 2016, submitted). The main conclusions from this phase of the project is that spontaneous aggregation of TCH and DLiPC requires intermolecular hydrogen bonding, and that this is an important factor in determining the overall TCH and DLiPC configuration(s). In the case of bilayer systems these intermolecular hydrogen bonds resulted in embedded trans-membrane TCH clusters. Free energy calculations and umbrella sampling techniques revealed that the stability of these trans-membrane TCH clusters was superior when TCH clusters consisted of 3 or 4 TCH per bilayer leaflet. We here want to build on these results and experiences, and simulate using the Martini coarse-grained force-field (for faster screening) a number of lipid-based formulations in isolation, as well as mixtures of common excipients in intestinal fluid (e.g. different lipids, ethoxylated surfactants and cosolvents). By doing a systematic investigation we can readily address the role of composition on drug solubilization. If needed, molecular interaction parameters for some of the more exotic species will be developed simultaneously. As a final goal, the results from these simulations will be compared with available experimental data on both the lipid assemblies alone and assemblies equilibrated with the drug (application submitted for Small angle neutron scattering experiments at the ILL in Grenoble, France).