Computational Models of the Gastrointestinal Environment. 2. Phase Behavior and Drug Solubilization Capacity of a Type I Lipid-Based Drug Formulation after Digestion

Lipid-based drug formulations can
greatly enhance the bioavailability of poorly water-soluble drugs.
Following the oral administration of formulations containing tri-
or diglycerides, the digestive processes occurring within the gastrointestinal
(GI) tract hydrolyze the glycerides to mixtures of free fatty acids
and monoglycerides that are, in turn, solubilized by bile. The behavior
of drugs within the resulting colloidal mixtures is currently not
well characterized. This work presents matched in vitro experimental
and molecular dynamics (MD) theoretical models of the GI microenvironment
containing a digested triglyceride-based (Type I) drug formulation.
Both the experimental and theoretical models consist of molecular
species representing bile (glycodeoxycholic acid), digested triglyceride
(1:2 glyceryl-1-monooleate and oleic acid), and water. We have characterized
the phase behavior of the physical system using nephelometry, dynamic
light scattering, and polarizing light microscopy and compared these
measurements to phase behavior observed in multiple MD simulations.
Using this model microenvironment, we have investigated the dissolution
of the poorly water-soluble drug danazol experimentally using LC-MS
and theoretically by MD simulation. The results show how the formulation
lipids alter the environment of the GI tract and improve the solubility
of danazol. The MD simulations successfully reproduce the experimental
results showing the utility of MD in modeling the fate of drugs after
digestion of lipid-based formulations within the intestinal lumen.