Improved biopharmaceutical performance of chlorpromazine-nanostructured lipid carriers: In vitro release, pharmacokinetics and toxicity testing

Abstract

Herein, we developed and investigated the capability of chlorpromazine-loaded nanostructured lipid carriers (CPZ-NLCs) for enhanced transportation to the brain tissue via intraperitoneal (i.p) route with antipsychotic and tranquilizing activity. CPZ-NLCs were prepared by microemulsion method followed by particle characterization. Subsequently, in-vitro release, ex-vivo permeation, in-vivo pharmacokinetics were performed. Moreover, neuroleptic activity of CPZ-NLCs was evaluated in lipopolysaccharide (LPS)-induced rat depression-model and compared with CPZ-suspension. Furthermore, the expressions of neuroinflammatory biomarkers, and neuroinflammation were assessed. The optimized CPZ-NLCs had spherical shape with particle size (278 nm), zeta-potential (33.2 mV), PDI (0.411), and EE (89.1 %). CPZ-NLCs exhibited sustained drug release behavior and a significantly higher C_max (4.67 ± 0.28 μg/mL) and AUC (137.29 ± 8.18 μg h/mL) in the brain-tissues when compared with CPZ-suspension. In addition, CPZ-NLCs showed a significantly augmented anti-psychotic and antidepressant activity in LPS-induced depressed rats. Similarly, reduced expression of neuroinflammatory biomarkers (cyclo-oxygenase-2 and p-NF-κB) were observed in CPZ-NLCs treated rats, with no neurodegenerative and neuroinflammatory changes in the brain tissues. The outcomes of this study suggested that NLCs can be employed for the site-specific brain-targeted transportation of various active pharmaceutical entities with augmented pharmacological properties in depression and psychosis.