Brain-Targeted Intranasal Delivery of Zotepine Microemulsion: Pharmacokinetics and Pharmacodynamics

The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% w/w of oil (Capmul MCM C8, monoglycerides, and diglycerides of caprylic acid), 50% w/w of S-mix (Labrasol and Transcutol HP, and 40% w/w of water resulting in a globule size of 124.6 +/- 3.52 nm with low polydispersity index (PDI) (0.212 +/- 0.013) and 2.8-fold higher permeation coefficient through porcine nasal mucosa compared to pure drug). In vitro cell line studies on RPMI 2650, Beas-2B, and Neuro-2A revealed ZTP-ME as safe. ZTP-ME administered intranasally showed higher AUC(0-t24) (18.63 +/- 1.33 h x mu g/g) in the brain by approximately 4.3-fold than oral ME (4.30 +/- 0.92 h x mu g/g) and 7.7-fold than intravenous drug solutions (2.40 +/- 0.36 h x mu g/g). In vivo anti-schizophrenic activity was conducted using catalepsy test scores, the formulation showed better efficacy via the intranasal route; furthermore, there was no inflammation or hemorrhage in the nasal cavity. The results concluded that the ZTP microemulsion as a safe and effective strategy could greatly enhance brain distribution by intranasal administration.

Automated summary

The aim of this study was to enhance the solubility, bioavailability, and efficacy of zotepine through brain-targeted intranasal delivery of microemulsion. The optimized microemulsion formulation showed promising physicochemical properties and significantly increased drug distribution in the brain when administered through the intranasal route.