Brain targeting of olanzapine via intranasal delivery of core–shell difunctional block copolymer mixed nanomicellar carriers: In vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies

Olanzapine (OZ) is atypical antipsychotic drug that suffers from low brain permeability due to efflux by P-glycoproteins and hepatic first-pass metabolism. The current work aimed to develop OZ-loaded micellar nanocarriers and investigate their nose-to-brain targeting potential. OZ-loaded (5 mg/ml) micelles (F1–F12) were prepared, using a Pluronic® mixture of L121 and P123, adopting thin-film hydration method. The micelles were evaluated for turbidity, particle size, morphology, drug-entrapment efficiency (EE%), drug-loading characteristics, in vitro drug release and ex vivo nasal toxicity in sheep. The in vivo biodistribution and pharmacokinetic studies in the brain/blood following intravenous (i.v.) and intranasal (i.n.) administrations of technetium-labeled OZ-loaded micelles and OZ-solution were evaluated in rats. Spherical micelles ranging in size from 18.97 to 380.70 nm were successfully developed. 1H NMR studies confirmed OZ incorporation into micelle core. At a drug:Pluronic® L121:Pluronic® P123 ratio of 1:8:32 (F11), the micelles achieved a conciliation between kinetic and thermodynamic stability, high drug-EE%, controlled drug-release characteristics and evoked minor histopathological changes in sheep nasal mucosa. The significantly (P < 0.05) higher values for F11 micelles (i.n.); brain/blood ratio (0.92), drug targeting index (5.20), drug targeting efficiency (520.26%) and direct transport percentage (80.76%) confirm the development of a promising non-invasive OZ-loaded nose-to-brain delivery system.

(1) Olanzapine (OZ)-loaded micellar nanocarriers (F11), (2) histopathological assessment of the local toxicity on the sheep nasal mucosa, (3) minor changes in the olfactory epithelium of the sheep nasal mucosa, (4) estimation of 99mTc-OZ biodistribution and pharmacokinetics in the brain and the blood of male Wister albino rats, and (5) Oz concentration in male Wister albino rat brain at different time intervals following administration of intranasal 99mTc-OZ solution, intranasal 99mTc-F11 micellar nanocarriers and intravenous 99mTc-F11 micellar nanocarriers, mean ± S.D., n = 3.Figure optionsDownload high-quality image (193 K)Download as PowerPoint slide