Mechanistic modelling of intestinal drug absorption - The in vivo effects of nanoparticles, hydrodynamics, and colloidal structures.

Particle size reduction is a traditional approach to increase the intestinal absorption of active pharmaceutical ingredients with poor intestinal solubility, by increasing the particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on drug absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various drug concentrations and in the presence or absence of CS. The increase in absorption rate was explained as a direct consequence of the increased drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the drug had partitioned. Further simulations supported the conclusion that the model can be applied during drug development to provide a priori assessments of the potential benefits of nanoformulations.