mp9b00889_si_001.pdf (164.21 kB)
Practical Approach to Modeling the Impact of Amorphous Drug Nanoparticles on the Oral Absorption of Poorly Soluble Drugs
journal contribution
posted on 2019-12-06, 15:50 authored by Aaron M. Stewart, Michael E. GrassRecently published studies have proposed that amorphous
drug nanoparticles
in gastrointestinal fluids may be beneficial for the absorption of
poorly soluble compounds. Nanosized drug particles are known to provide
rapid dissolution rates and, in some instances, a slight increase
in solubility. However, in recent studies, the differences observed
in vivo could not be explained solely by these attributes. Given the
high dose and very low aqueous solubility of the study compounds,
rapid equilibration to the drug-saturated solubility in gastrointestinal
fluid would occur independent of the presence of nanoparticles. Alternatively,
it has been proposed that drug nanoparticles (ca. ≤ 200 to
300 nm) may provide a “shuttle” for drug across the
unstirred water layer (UWL) adjacent to the intestinal epithelium,
particularly for low solubility/lipophilic compounds where absorption
may be largely UWL-limited. This transport mechanism would result
in a higher unbound drug concentration at the surface of the epithelium
for absorption. This study evaluates this mechanism using a simple
modification of the effective permeability to account for the effect
of drug nanoparticles diffusing across the UWL. The modification can
be made using inputs for solubility and nanoparticle size. The permeability
modification was evaluated using three published case studies for
amorphous formulations of itraconazole, anacetrapib, and enzalutamide,
where the formation of amorphous drug nanoparticles upon dissolution
resulted in improved drug absorption. Absorption modeling was performed
using GastroPlus to assess the impact of the nanomodified permeability
method on the accuracy of model prediction compared to in vivo data.
Simulation results were compared to those for baseline simulations
using an unmodified effective permeability. The results show good
agreement using the nanomodified permeability, which described the
data better than the standard baseline predictions. The nanomodified
permeability method can be a suitable, fit-for-purpose in silico approach
for evaluating or predicting oral absorption of poorly soluble, UWL-limited
drugs from formulations that produce a significant number of amorphous
drug nanoparticles.