Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

Abstract

The research objective is to design intranasal (IN) brain targeted CLZ-loaded polymeric nanomicellar systems (PNMS) aiming to improve central systemic CLZ bioavailability. Direct equilibrium method was used to prepare CLZ-PNMS using two hydrophobic poloxamines; Tetronic® 904 (T904) and Tetronic® 701 (T701) and one hydrophilic poloxamer; Synperonic® PE/F127 (F127). Optimization is based on higher percent transmittance, solubilizing efficiency, and in vitro release after 24 h with smaller particle size was achieved using Design-Expert® software. The optimized formula was further evaluated via TEM, ex vivo nasal permeation in addition to in vivo biodistribution using radiolabeling technique of the optimized formula by Technetium-99m (99mTc). The optimized formula M5 has small size (217 nm) with relative high percentage of transmittance (97.72%) and high solubilization efficacy of 60.15-fold following 92.79% of CLZ released after 24 h. Ex vivo nasal permeation showed higher flux of 36.62 μg/cm2.h compared to 7.324 μg/cm2.h for CLZ suspension with no histological irritation. In vivo biodistribution results showed higher values of radioactivity percentage of the labeled optimized formula (99mTc–M5) in brain and brain/blood ratio following IN administration of 99mTc–M5 complex which were greater than their corresponding values following intravenous route. It is obvious that nasal delivery of CLZ-PNMS could be a promising way to improve central systemic CLZ bioavailability.

Keywords

• clozapine
• polymeric nanomicellar systems
• intranasal
• brain targeted
• radiolabeled indicator
• tetronic
• synperonic