Colloidal Interactions in Simulated Intestinal Fluids: Implications for Oral Drug Delivery at the Nanoscale

Oral drug delivery remains the most preferred administration route, and new oral delivery concepts continuously arise to enable oral delivery of new therapeutics. This study investigates how colloidal structures in five simulated intestinal fluids (SIFs) with varying bile salt and phospholipid compositions influence drug solubility, nanoparticle aggregation and cytotoxicity, and mucoadhesion of nanoparticles and polymers. For the poorly water-soluble drugs indomethacin and felodipine, colloidal structure size in SIFs varies with solubility, and felodipine's solubility is influenced by the lipid composition. Nanoparticles, including polymersomes and mesoporous silica nanoparticles with different surface charges, are characterized in each medium. Dynamic light scattering reveals three interaction modalities: interaction, aggregation, and combination, depending on nanoparticle type and fluid composition. Additionally, interaction patterns correlate with Caco-2 cell cytotoxicity. Quartz crystal microbalance with dissipation analysis reveals that both particle and polymer interactions with mucin are significantly altered in SIFs. For nanoparticles, mucin interactions differ depending on the type of nanoparticle. For the polymers, polyethylene oxide completely loses mucin interaction in SIFs, while chitosan retains partial mucoadhesion. These findings emphasize the importance of not only studying drug properties, but also cell compatibility and mucoadhesion of polymers and nanoparticles, in physiologically relevant conditions.