title: 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.
abstract: 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 (5mg/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. (1)H 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.
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt.
authors.forename: Ghada Ahmed
authors.initials: GA
authors.lastname: Abdelbary
authors.forename: Mina Ibrahim
authors.initials: MI
authors.lastname: Tadros
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009297:Nasal Mucosa / Q000033:anatomy & histology / Q000187:drug effects; D000077152:Olanzapine; D011060:Poloxalene / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012756:Sheep; D014018:Tissue Distribution
chemical_list: D014150:Antipsychotic Agents; D004337:Drug Carriers; D008823:Micelles; D020442:Poloxamer; D001569:Benzodiazepines; C464484:pluronic block copolymer P123; D011060:Poloxalene; D000077152:Olanzapine