mp2c01009_si_001.pdf (2.92 MB)
Harnessing Bile for Drug Absorption through Rational Excipient Selection
journal contributionposted on 2023-07-05, 20:31 authored by Jonas 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.
substantially impact fluxoverall formulation successamino methacrylate copolymer1 supbile interaction correlatednaporafenib supersaturation durationdrug candidate naporafenibh –< supnaporafenib interactedsoluble drugspoorly waterpolyethylene glycolorally administeredhydroxypropyl celluloseharnessing bileeudragit edrug absorptionbuffered salinebile componentsbeagle dogsapparent solubility