ABSTRACT
This article describes the discovery and characterization of nanocolloidal structures formed between VX-985 (an orally administered inhibitor of hepatitis C virus protease) and the bile salt, sodium taurocholate at concentrations of the latter >4 mM. These complexes (1) distribute narrowly in size around a mean diameter of 260 nm, (2) separate from solution only with ultracentrifugation, and (3) appear to influence the absorption of VX-985 from the intestinal tract in vivo, in rodents and humans. Although the oral bioavailability of suspensions of its solid forms is poor, addition of vitamin E D-alpha-tocopherol polyethylene glycol 1000 succinate to dosing vehicles improves the fraction absorbed of the compound in vivo. In vitro characterization is compatible with the hypothesis that surfactants like D-alpha-tocopherol polyethylene glycol 1000 succinate preclude nanocolloidal structures and increase the bioavailability by increasing the rate of absorption of VX-985. This study, while specific to VX-985, provides a route to circumvent the poor oral bioavailability caused by formation of kinetically stable complexes between bile salts and drug molecules. This study also underscores the importance of characterizing aggregation phenomenon that may be observed in solubility measurements during preclinical formulation development.
Subject(s)
Antiviral Agents/administration & dosage , Drug Carriers/chemistry , Spiro Compounds/administration & dosage , Taurocholic Acid/chemistry , Vitamin E/chemistry , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Biological Availability , Colloids/chemistry , Hepacivirus/enzymology , Hepatitis C/drug therapy , Humans , Intestinal Absorption , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacokinetics , Rats , Solubility , Spiro Compounds/pharmacokineticsABSTRACT
During milling, components are subjected to shear and tensile stresses, which can result in physical phase transformations. The purpose of the work described in this report is to understand the pathway by which two test compounds, d-salicin and γ-indomethacin, undergo a crystalline to amorphous transformation during cryomilling. The results show that the transformation cannot be described by a standard one-phase or two-phase disordering mechanism. In the one-phase model, a continuous set of states exist, linking perfect crystalline with completely amorphous material, whereas the two-phase model of disorder depicts the material as a binary mixture of crystalline and amorphous fractions. Instead, a model is proposed where two one-phase regions, defected crystalline and amorphous regions, are separated by a distinct transition.
