Overcoming the Bile Salt-Mediated Formation of Nanocolloids That Inhibit Oral Absorption of VX-985

• Published in: Journal of pharmaceutical sciences 2019-02, Vol.108 (2), p.821-831
• Main Authors: Song, Bin, Bransford, Philip, Peresypkin, Andrey, Medek, Ales, Mudunuri, Praveen, Randles, Edward G., Dworakowski, Wojciech, Kumar, Santosh, Snyder, Phillip W.
• Format: Article
• Language: English
• Subjects: absorption; Administration, Oral; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; bioavailability; Biological Availability; colloids; Colloids - chemistry; Drug Carriers - chemistry; drug delivery systems; food effects; formulation vehicle; Hepacivirus - enzymology; Hepatitis C - drug therapy; Humans; Intestinal Absorption; nanoparticles; permeability; Protease Inhibitors - administration & dosage; Protease Inhibitors - pharmacokinetics; Rats; Solubility; Spiro Compounds - administration & dosage; Spiro Compounds - pharmacokinetics; Taurocholic Acid - chemistry; Vitamin E - chemistry
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2018.10.036

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.