Engineering Chitosan-Coated PLGA Nanoparticles for Sustained Bupivacaine Delivery: Physicochemical Performance and a...

Background/Objectives: Bupivacaine hydrochloride (Bupi-HCl) is a widely used local anesthetic; however, rapid diffusion from the site of administration and concentration-dependent cytotoxicity may limit its local therapeutic efficacy. This study aimed to develop chitosan-coated poly(D, L-lactide-co-glycolide) (PLGA) nanoparticles for sustained Bupi-HCl delivery and to evaluate their physicochemical properties, release behavior, long-term stability, and cytocompatibility with fibroblasts. Methods: Bupi-HCl-loaded chitosan-coated PLGA nanoparticles (Bupi-CS-PLGA NPs) were prepared using a modified double-emulsion solvent-evaporation method and characterized by TEM, DLS, FTIR, DSC, XRD, encapsulation efficiency (EE), drug loading (DL), in vitro release, release kinetic modeling, 12-month physicochemical stability, and a preliminary MTT-based fibroblast cytocompatibility assessment. Results: Bupi-CS-PLGA NPs exhibited a predominantly spherical morphology, a mean particle size of 175.13 ± 8.10 nm, a PDI of 0.195 ± 0.026, and a zeta potential of +24.86 ± 1.90 mV. EE and DL were 80.00 ± 2.14% and 2.60 ± 0.11%, respectively. FTIR findings were consistent with physical incorporation of Bupi-HCl within the PLGA/chitosan matrix without evidence of new chemical bond formation, while DSC demonstrated differences in the thermal profiles of the nanoparticle formulations and XRD showed that Bupi-HCl was not detectable as a separate crystalline phase. The nanoparticles provided sustained Bupi-HCl release over 72 h, reaching approximately 79-80% cumulative release compared with 97-98% for free Bupi-HCl. Among the evaluated kinetic models, Modified Langmuir and RRSBW yielded the highest coefficients of determination (R² = 0.9958 and 0.9952, respectively), while RRSBW showed the lowest total residual value (19.5851). Physicochemical characteristics were maintained during 12 months of storage at refrigerated and room temperatures. Within one experimental run, empty CS-PLGA NPs showed no decrease in MTT-derived signal across the tested concentration range. Bupi-CS-PLGA NPs showed lower MTT-derived signal at 250 and 500 µg/mL than at the two lower particle concentrations (62.5 and 125 µg/mL); particle-related assay interference was not excluded. Because free and encapsulated Bupi-HCl were not evaluated at dose-equivalent concentrations, their cytotoxic potency could not be directly compared, and these single-experiment findings are reported as a preliminary assessment. Conclusions: Bupi-CS-PLGA NPs provided sustained drug release and long-term physicochemical stability, together with a preliminary, assay-limited fibroblast MTT assessment. These findings support further evaluation of this biodegradable nanoparticle system for sustained local delivery of Bupi-HCl.