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Chemical and enzymatic in vivo degradation of antimicrobial peptides represents a major challenge for their therapeutic use to treat bacterial infections. In this work, anionic polysaccharides were investigated for their ability to increase the chemical stability and achieve sustained release of such peptides. The investigated formulations comprised a combination of antimicrobial peptides (vancomycin (VAN) and daptomycin (DAP)) and anionic polysaccharides (xanthan gum (XA), hyaluronic acid (HA), propylene glycol alginate (PGA) and alginic acid (ALG)). VAN dissolved in buffer of pH 7.4 and incubated at 37 °C showed first order degradation kinetics with a reaction rate constant k obs of 5.5 × 10 -2 day -1 corresponding with a half-life of 13.9 days. However, once VAN was present in a XA, HA or PGA-based hydrogel, k obs decreased to (2.1-2.3) × 10 -2 day -1 while k obs was not affected in an alginate hydrogel and a dextran solution (5.4 × 10 -2 and 4.4 × 10 -2 day -1). Under the same conditions, XA and PGA also effectively decreased k obs for DAP (5.6 × 10 -2 day -1), whereas ALG had no effect and HA even increased the degradation rate. These results demonstrate that the investigated polysaccharides (except ALG for both peptides and HA for DAP) slowed down the degradation of VAN and DAP. DSC analysis was used to investigate on polysaccharide ability to bind water molecules. Rheological analysis highlighted that the polysaccharides containing VAN displayed an increase in G' of their formulations, pointing that the peptides interaction act as crosslinker of the polymer chains. The obtained results suggest that the mechanism of stabilization of VAN and DAP against hydrolytic degradation is conferred by electrostatic interactions between the ionizable amine groups of the drugs and the anionic carboxylate groups of the polysaccharides. This, in turn, results in a close proximity of the drugs to the polysaccharide chain, where the water molecules have a lower mobility and, therefore, a lower thermodynamic activity.