ABSTRACT
Non-invasive nose-to-brain delivery presents a competitive strategy for effective drug targeting. This strategy can potentially evade the blood-brain barrier (BBB) depending on the pathway the drug and/or drug/micelle composite travels, thereby allowing direct drug delivery to the brain. This delivery strategy was employed for lurasidone, a clinically USFDA-approved neurotherapeutic molecule in bipolar disorders and schizophrenia treatments. The aim of this study was to develop mixed polymeric micelles of lurasidone HCl (LH) for targeted brain delivery via intranasal route. Lurasidone HCl-loaded mixed micelles (LHMM) were prepared by solvent evaporation method and optimized by 32 factorial design to quantify the effects of excipients on micelle size and entrapment efficiency. Fourier transform infrared spectroscopy helped in scrutinizing drug-excipient interactions whereas transmission electron microscopy images showed particle size and shape. Further, LHMM and LHMM hydrogel were evaluated for in vitro diffusion, histopathology, ex vivo permeation, in vivo pharmacokinetics and stability studies. Optimized LHMM exhibited 175 nm particle size and 97.8% entrapment efficiency with improved in vitro drug diffusion (81%). LHMM hydrogel showed 79% ex vivo drug permeation without any significant signs of nasociliary toxicity to sheep nasal mucosa. Single dose in vivo pharmacokinetic studies showed improved therapeutic concentration of drug in the brain post intranasal administration with 9.5 ± 0.21 µg/mL Cmax and T1/2 of 19.1 ± 0.08 h as compared to pure drug. LHMM, when administered by intranasal route, demonstrated significant increase in the drug targeting efficiency as well as potential (%DTE and %DTP) of drug as compared to pure lurasidone. Thus, nanosized mixed micelles were useful in effective brain delivery of lurasidone HCl via intranasal route. Graphical abstract.
