| Popis: |
Oral administration is the preferred route for drug delivery because it has high patient compliance and is cost effective. The aqueous solubility of modern drug candidates is often poor, but a drug delivered orally must dissolve in the intestine so that it can be absorbed into the circulation. Advanced formulations can be used to improve the solubility, but the possible improvement in bioavailability from formulation varies among drug molecules. In vitro methods can be used to assess solubility, but these are slow and consume valuable drug material that is often rare early in development. As a non-destructive alternative, in silico methods have the potential to predict solubility, but methods available are in need of improvement, especially for predictions of drug solubility in intestinal fluid and for refining drug formulations. The goal of this thesis is to use molecular dynamics (MD) simulations to investigate the colloidal structures in intestinal fluids that affect drug solubility, and to simulate processes that affect solubility on the molecular level. Coarse-grained MD simulation protocols for biorelevant media, human and dog duodenal fluids, and lipid-based formulations were established based on concentrations measured in vivo. In the simulations, colloids self-assembled to micelles and vesicles depending on concentration and component input. Simulations with biorelevant media resulted in micelles qualitatively similar to those experimentally measured by small-angle X-rays. The structure of the colloids in the simulations were described in detail, and used to qualitatively assess drug solubility enhancement in model compounds with poor water solubility. These assessments were made by looking at the displacement of drugs and the drugs’ interactions with molecules in small intestinal fluid. The MD simulations were not able replace current solubility-predicting in silico models, but do show that coarse-grained MD simulations can be used for investigating the relevant processes involving intestinal fluids and lipid-based formulations. |
