A novel mucoadhesive paliperidone-nanoemulsion developed using the ultrasonication method in the treatment of schizophrenia.

: To develop paliperidone mucoadhesive-nanoemulsion (PLP-NE) to enhance brain bioavailability. To evaluate comparative effects of PLP-NE and CS-PLP-NE in the treatment of schizophrenia, followed by a toxicity study of opt-NE. : Oil: oleic acid, surfactant: Tween-80, and co-surfactant: Labrasol were chosen based on the solubility and maximum nanoemulsion area. The ultrasonication technique was applied with the aqueous micro titration method for the development of PLP-NE. The optimization of the method for the excellent PLP-NE was performed using a central composite design based on a five-factor and four-level. Oil (% v/v), (v/v%), ultrasonication intensity in percentage, ultrasonication time in minutes, and temperature (°C) were optimized and used to the independent variables. : The parameters , oil (5%), (10%), ultrasonication time (5.0 min), ultrasonication intensity (25%), and temperature (38 °C) were optimized and used as independent and dependent variables for the development of novel PLP-NE. Based on experimental data, the dependent variables, , globule size (53.90 ± 4.01 nm), % transmittance (92.56% ± 1.06%), PDI (0.218 ± 0.007), and zeta potential (-11.60 ± 0.031 mV), were determined. The smooth near about spherical shaped of PLP-NE globules with, refractive index , 1.62 ± 0.021, viscosity: 39 ± 6 cp with the pH: 7.40 ± 0.089, and content of drug (97.98 ± 0.39%) for optimized-PLP-NE. The optimized PLP-NE with oleic acid, Tween-80, and Labrasol was used to improve brain bioavailability with good permeation the intranasal route. CS-PLP-NE yielded good mucoadhesive property results compared to paliperidone-nanoemulsion, and PLP-S containing a 0.751 minutes retention time with their deuterated-IS (0.806 min) and / of 427.2/207.2 with IS (/: 431.2/211.2) for PLP and PLP-IS. A calibration curve was plotted with a linear range of 1-2000 ng mL with inter- and intraday accuracy (97.03-99.31%) and precision (1.69-50.05%). The results of AUC and for PLP were found to be highly significant ( < 0.001) as an improvement of brain bioavailability in rats intranasal delivery of CS-PLP-NE. Furthermore, the locomotion test, social interaction, and forced swimming test (forced swimming, climbing, and immobility) of a mucoadhesive CS-PLP-NE (intranasally) provided highly significant results with the improvement of behavioral analysis when compared to the PLP-NE and PLP-S studies. : CS-PLP-NE (i.n.) showed highly significant results, , < 0.001 for the improvement of bioavailability of the brain in the treatment of schizophrenia. Optimized-mucoadhesive-CS-based-PLP-NE is safe and shows no toxicity.