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The controlled-release characteristic of drug delivery systems is utilized to increase the residence time of therapeutic agents in the human body. This study aimed to formulate and characterize salsalate (SSL)-loaded chitosan nanoparticles (CSNPs) prepared using the ionic gelation method and to assess their in vitro release and antibacterial and antibiofilm activities. The optimized CSNPs and CSNP–SSL formulation were characterized for particle size (156.4 ± 12.7 nm and 132.8 ± 17.4 nm), polydispersity index (0.489 ± 0.011 and 0.236 ± 132 0.021), zeta potential (68 ± 16 mV and 37 ± 11 mV), and entrapment efficiency (68.9 ± 2.14%). Physicochemical features of these nanoparticles were characterized using UV–visible and Fourier transform infrared spectroscopy and X-ray diffraction pattern. Scanning electron microscopy studies indicated that CSNPs and CSNP–SSL were spherical in shape with a smooth surface and their particle size ranged between 200 and 500 nm. In vitro release profiles of the optimized formulations showed an initial burst followed by slow and sustained drug release after 18 h (64.2 ± 3.2%) and 48 h (84.6 ± 4.23%), respectively. Additionally, the CSNPs and CSNP–SSL nanoparticles showed a sustained antibacterial action against Staphylococcus aureus (15.7 ± 0.1 and 19.1 ± 1.2 mm) and Escherichia coli (17.5 ± 0.8 and 21.6 ± 1.7 243 mm). Interestingly, CSNP–SSL showed better capability (89.4 ± 1.2% and 95.8 ± 0.7%) than did CSNPs in inhibiting antibiofilm production by Enterobacter tabaci (E2) and Klebsiella quasipneumoniae (SC3). Therefore, CSNPs are a promising dosage form for sustained drug delivery and enhanced antibacterial and antibiofilm activity of SSL; these results could be translated into increased patient compliance.

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