Hyaluronic acid-based hydrogels as codelivery systems: The effect of intermolecular interactions investigated by HR-MAS and solid-state NMR Spectroscopy

Hydrogels based on hyaluronic acid and agarose-carbomer, due to their peculiar 3D architecture and biocompatibility, are promising candidates for pharmaceutical strategies based on the codelivery of drugs targeting different diseases. The successful development of these applications requires a precise understanding of drugdrug interactions and their effects on transport and release mechanisms. In this study, such an investigation is carried out on hydrogels loaded with ethosuximide and sodium salicylate at different concentrations. Intermolecular interactions and transport properties are characterized by means of High Resolution Magic Angle Spinning and solid-state Magic Angle Spinning NMR Spectroscopy. At variance with our previous findings on single-drug formulations, the two drugs exhibit closely similar diffusion patterns when co-loaded in the HA-based hydrogels, plausibly due to drug-drug intermolecular interactions. At the highest drug concentrations, where superdiffusion comes into play, we find a fraction of molecules with time-varying diffusion coefficients. A trapping-release mechanism is proposed to explain this observation, which also accounts for the role of drug-hydrogel interactions in drug diffusion motion. The effects of drug-drug interactions on release profiles are finally assessed by means of in vitro release experiments.