Significantly Increased Aqueous Solubility of Piperine via Nanoparticle Formulation Serves as the Most Critical Factor for Its Brain Uptake Enhancement.

Introduction: Piperine, the major component in Methods: Formulation of piperine nanoparticles (PIP NPs) was developed to enhance its solubility. PIP NPs were prepared using flash nanoprecipitation via a four-stream Multi-Inlet Vortex Mixer, employing an aqueous solution of poloxamer 188 and an ethanolic solution containing piperine and Eudragit L100-55. The process was optimized using the Design of Experiments to minimize the particle size and maximize the encapsulation efficiency of piperine. Additionally, we investigated the impact of administrating PIP NPs via oral and intranasal routes on its systemic and brain uptake. Results: The optimized PIP NPs formulation exhibited a particle size of 171.45±2.38 nm, polydispersity index of 0.27±0.01, zeta potential of -43.71±5.11 mV, encapsulation efficiency of 92.49±1.92% and drug loading of 15.07±0.09%. Fourier-transform infrared spectroscopy confirmed the successful encapsulation of piperine into nanoparticles. The PIP NPs could significantly increase the aqueous solubility of piperine from 0.04 mg/mL to 52.31±0.9 mg/mL and release piperine with a 12.83-fold higher rate than that from piperine suspension. Both oral and intranasal administrations of PIP NPs to C57BL/6 mice at 20 mg/kg demonstrated an increase in AUC Discussion: Our findings suggested that increasing solubility rather than changing the administration route served as the most critical step to enhance the brain uptake of piperine.