Caffeine as a stabilizer in Novel Hydroxypropyl-β-cyclodextrin/Axitinib Drug-Delivery Systems: A computational study

Abstract

Age-related macular degeneration (AMD) is a significant global health concern. Axitinib shows high potential for treating wet AMD, but its lipophilic nature makes it difficult to penetrate the cornea. Cyclodextrins (CDs) are promising drug carriers for axitinib due to their hydrophilic outer surface and lipophilic central cavity. However, lipophilic drug/CD complexes may dissociate in water at the same time. Huang et al. found that caffeine molecules can stabilise lipophilic drug/CD complexes, and caffeine-axitinib-hydroxypropyl-β-cyclodextrin (HPβCD) complexes can decrease lipophilic drug/CD complex dissociation. To investigate the interaction mechanisms between the components of caffeine-axitinib-HPβCD complexes, we employed a combination of computational methods, including Ligand Gaussian Accelerated Molecular Dynamics (LiGaMD), 1D potential of mean force (PMF) profiling, ligand binding kinetics analysis based on Kramers’ rate theory, density functional theory (DFT) calculations, and Interaction Region Identifier (IRI) analysis. Our predicted association rate constan k_on rate constants were similar, but k_off rate values decreased when caffeine was added as a stabilizer. The dissociation rate constan k_off values for axitinib-HPβCD, axitinib-HPβCD-caffeine (primary face), axitinib-HPβCD-caffeine (secondary face), and axitinib-HPβCD-caffeine (primary and secondary faces) were 3.000 ± 0.190 s⁻¹, 1.800 ± 0.210 s^−1, 1.700 ± 0.170 s⁻¹, and 0.50 ± 0.001 s⁻¹, respectively. Our IRI analysis results showed that caffeine attaches to the primary and secondary faces of the axitinib-HPβCD complex via van der Waals forces. As a stabilizer, caffeine helps maintain the integrity of the axitinib-HPβCD complex, thereby slowing down the release of axitinib from HPβCD.