posted on 2023-07-05, 20:31authored byJonas Schlauersbach, Dominic Werthmüller, Cornelius Harlacher, Bruno Galli, Simon Hanio, Bettina Lenz, Sebastian Endres, Ann-Christin Pöppler, Oliver Scherf-Clavel, Lorenz Meinel
Bile solubilization and apparent solubility at resorption
sites
critically affect the bioavailability of orally administered and poorly
water-soluble drugs. Therefore, identification of drug-bile interaction
may critically determine the overall formulation success. For the
case of the drug candidate naporafenib, drug in solution at phase
separation onset significantly improved with polyethylene glycol-40
hydrogenated castor oil (RH40) and amino methacrylate copolymer (Eudragit
E) but not with hydroxypropyl cellulose (HPC) in both phosphate-buffered
saline (PBS) and PBS supplemented with bile components. Naporafenib
interacted with bile as determined by 1H and 2D 1H–1H nuclear magnetic resonance spectroscopy and
so did Eudragit E and RH40 but not HPC. Flux across artificial membranes
was reduced in the presence of Eudragit E. RH40 reduced the naporafenib
supersaturation duration. HPC on the other side stabilized naporafenib’s
supersaturation and did not substantially impact flux. These insights
on bile interaction correlated with pharmacokinetics (PK) in beagle
dogs. HPC preserved naporafenib bile solubilization in contrast to
Eudragit E and RH40, resulting in favorable PK.