Self-Assembling Lecithin-Based Mixed Polymeric Micelles for Nose to Brain Delivery of Clozapine: In-vivo Assessment of Drug Efficacy via Radiobiological Evaluation

Abstract

Purpose

The research objective is to design intranasal brain targeted CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) aiming to improve central systemic CLZ bioavailability.

Methods

In our study, intranasal CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) were formulated using soya phosphatidyl choline (SPC) and sodium deoxycholate (SDC) with different CLZ:SPC:SDC ratios via thin film hydration technique aiming to enhance drug solubility, bioavailability and nose to brain targeting efficiency. Optimization of the prepared CLZ-LbPM using Design-Expert® software was achieved showing that M6 which composed of (CLZ:SPC: SDC) in respective ratios of 1:3:10 was selected as the optimized formula. The optimized formula was subjected to further evaluation tests as, Differential Scanning Calorimetry (DSC), TEM, in vitro release profile, ex vivo intranasal permeation and in vivo biodistribution.

Results

The optimized formula with the highest desirability exhibiting (0.845), small particle size (12.23±4.76 nm), Zeta potential of (−38 mV), percent entrapment efficiency of > 90% and percent drug loading of 6.47%. Ex vivo permeation test showed flux value of 27 μg/cm².h and the enhancement ratio was about 3 when compared to the drug suspension, without any histological alteration. The radioiodinated clozapine ([ ¹³¹I] iodo-CLZ) and radioiodinated optimized formula ([ ¹³¹I] iodo-CLZ-LbPM) were formulated in an excellent radioiodination yield more than 95%. In vivo biodistribution studies of [ ¹³¹I] iodo-CLZ-LbPM showed higher brain uptake (7.8%± 0.1%ID/g) for intranasal administration with rapid onset of action (at 0.25 h) than the intravenous formula. Its pharmacokinetic behavior showed relative bioavailability, direct transport percentage from nose to brain and drug targeting efficiency of 170.59%, 83.42% and 117% respectively.

Conclusion

The intranasal self-assembling lecithin based mixed polymeric micelles could be an encouraging way for CLZ brain targeting.

Graphical Abstract