Molecular Dynamics Simulations of Self-Assembling Colloids in Fed-State Human Intestinal Fluids and Their Solubilization of Lipophilic Drugs

Abstract

Bioavailability of oral drugs often depends on how soluble the active pharmaceutical ingredient is in the fluid present in the small intestine. For efficient drug discovery and development, computational tools are needed for estimating this drug solubility. In this paper, we examined human intestinal fluids collected in the fed state, with coarse-grained molecular dynamics simulations. The experimentally obtained concentrations in aspirated duodenal fluids from five healthy individuals were used in three simulation sets to evaluate the importance of the initial distribution of molecules and the presence of glycerides in the simulation box when simulating the colloidal environment of the human intestinal fluid. We observed self-assembly of colloidal structures of different types: prolate, elongated, and oblate micelles, and vesicles. Glycerides were important for the formation of vesicles, and their absence was shown to induce elongated micelles. We then simulated the impact of digestion and absorption on the different colloidal types. Finally, we looked at the solubilization of three model compounds of increasing lipophilicity (prednisolone, fenofibrate, and probucol) by calculating contact ratios of drug–colloid to drug–water. Our simulation results of colloidal interactions with APIs were in line with experimental solubilization data but showed a dissimilarity to solubility values when comparing fasted-/fed-state ratios between two of the APIs. This work shows that coarse-grained molecular dynamics simulation is a promising tool for investigation of the intestinal fluids, in terms of colloidal attributes and drug solubility.

Nanoscale Prediction of the Thermal, Mechanical, and Transport Properties of Hydrated Clay on 106- and 1015-Fold Larger Length and Time Scales

“…For example, experiments suggest that artificial cement created by compacting C–S–H nanoparticles has properties analogous to those of conventional cement created by growing C–S–H nanoparticles in situ . Similarly, coarse-grained MD simulations have contributed significant theoretical understanding of self-organization in liquid crystals and colloidal assemblages, , and all-atom MD simulations of this self-organization phenomenon represent a logical next step for properties or processes that are sensitive to atomistic-level details, such as the role of water in ionic liquids or in the oriented aggregation of mineral nanoparticles. , As in all MD simulation efforts, a key requirement is the existence of accurate interatomic potential models, a requirement that is fulfilled by the ClayFF model of hydrated phyllosilicate minerals used in this study. Another requirement is the feasibility of neglecting structural heterogeneities formed by nanoparticle assemblages on length scales larger than those probed by MD simulations (i.e., tens of nanometers), such as interaggregate voids.…”