Abstract
Aripiprazole (ARP), an atypical antipsychotic, suffers from poor aqueous solubility and extensive hepatic metabolism, resulting in limited brain bioavailability. This study aimed to develop and optimize nanostructured lipid carriers (NLCs) for intranasal delivery of ARP to enhance nose-to-brain transport and improve therapeutic outcomes for schizophrenia. ARP-loaded NLCs were formulated using a high-shear homogenization followed by ultrasonication. A 3² factorial design was employed to optimize the formulation variables. The prepared NLCs were characterized for particle size, polydispersity index, zeta potential, drug loading, and entrapment efficiency. Further evaluations included SEM, in-vitro drug release, ex-vivo permeation, hemolytic activity, nasal ciliotoxicity, and stability studies. The optimized formulation (A4), consisting of 2.5% stearic acid and oleic acid (solid lipid phase), Tween 80 (surfactant), and PEG 400 (co-surfactant), demonstrated favorable physicochemical properties: particle size of 99.6 nm, zeta potential of − 36.7 mV, PDI of 0.249, drug loading of 20.96%, and entrapment efficiency of 96.23%. The in-vitro release showed a biphasic pattern over 72 h, fitting the Fickian diffusion model. Ex-vivo studies confirmed enhanced drug permeation across nasal mucosa. Toxicity studies indicated excellent biocompatibility. Stability studies revealed that the formulation was more stable at 5 ± 0.3 °C compared to higher storage temperatures. The results indicated that the optimized intranasal ARP-NLCs developed in this study offer a novel and promising approach for improved brain targeting in schizophrenia, potentially enhancing therapeutic efficacy and patient adherence by enabling sustained drug release and avoiding first-pass metabolism. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-32985-w.