Harnessing Bile for Drug Absorption through Rational Excipient Selection.

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Physical Chemistry

Background:

• Bioavailability of poorly water-soluble drugs is limited by bile solubilization and solubility at absorption sites.
• Understanding drug-bile interactions is crucial for successful oral formulation development.

Purpose of the Study:

• To investigate the impact of excipients polyethylene glycol-40 hydrogenated castor oil (RH40), amino methacrylate copolymer (Eudragit E), and hydroxypropyl cellulose (HPC) on naporafenib solubility and bile interaction.
• To correlate in vitro findings with in vivo pharmacokinetic performance in beagle dogs.

Main Methods:

• Solubility studies in phosphate-buffered saline (PBS) with and without bile components.
• Nuclear magnetic resonance (NMR) spectroscopy (¹H and 2D ¹H-¹H) to assess drug-bile and drug-excipient interactions.
• Artificial membrane flux studies.
• Pharmacokinetic (PK) studies in beagle dogs.

Main Results:

• Naporafenib solubility improved with RH40 and Eudragit E, but not HPC, in PBS.
• Naporafenib, Eudragit E, and RH40 interacted with bile; HPC did not.
• Eudragit E reduced membrane flux; RH40 shortened supersaturation duration.
• HPC stabilized naporafenib supersaturation and preserved bile solubilization, leading to favorable PK.

Conclusions:

• Excipient choice significantly influences drug-bile interactions and subsequent oral bioavailability.
• HPC demonstrated potential as a formulation excipient for naporafenib by enhancing solubility and preserving bile interaction, leading to improved pharmacokinetics.