Intensification of quercetin nanobubble formulation and performance by multi-factor optimization and interaction analysis

The natural flavonoid Quercetin (QT) showed a potential for various health benefits, but its pharmaceutical applications are hindered by low solubility, permeability, and limited bioavailability. This research aimed to synthesize, develop and optimize polylactic acid co-glycolic acid (PLGA) nanobubbles using solvent evaporation method as a sustained delivery system for QT, thus improving stability and bioavailability. Through a four-factor, three-level Box Behnken Design, 29 experimental runs were carried out to optimize QT-PLGA nanobubbles. An optimized formulation consisted of 50 mg QT, 250 mg PLGA, and 1.89% <i>w/v</i> PVA. The nanobubbles displayed a particle size of 139.5 ± 6.24 nm, polydispersity index of 0.296 ± 0.19, and zeta potential of -23.0 ± 3.44 mV, with an entrapment efficiency of 59.24 ± 3.08%. Analysis through Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction confirmed no drug-polymer interaction, while scanning electron microscopy revealed a uniform spherical nanoparticle. <i>In vitro</i> studies exhibited an excellent drug release, and stability studies showed no significant changes after one month. <i>In vivo</i> studies in rats demonstrated increased <i>C</i>_max (3.03) and <i>AUC</i>_0-t (5.84), indicating an improved sustained release and absorption. These findings underscored a potential of QT-loaded PLGA nanobubbles to enhance the drug kinetics and bioavailability, offering possibilities for targeted drug delivery and improved therapeutic outcomes.