title: Development of high-energy amorphous solid dispersion of nanosized nobiletin, a citrus polymethoxylated flavone, with improved oral bioavailability.
abstract: Nobiletin (NOB), a citrus polymethoxylated flavone, attracts attention because of a wide range of pharmacological activities such as anti-inflammation, anticancer, and most notably ameliorative actions on memory impairment and β-amyloid pathology. However, clinical use of NOB could be partly limited due to its poor solubility and bioavailability, which might necessitate high doses in order to reach therapeutic plasma concentrations in the central nervous system (CNS) after oral administration. In the present study, amorphous solid dispersion (SD) of nanosized NOB (NOB/SD) was prepared by wet-milling technique with the aim of improving dissolution behavior and pharmacokinetic properties of NOB. Physicochemical properties of the NOB/SD were characterized with focus on surface morphology, particle size distribution, dissolution, and crystallinity assessment. Wet-milled NOB particles in NOB/SD appeared to be amorphous with a diameter of approximately 270 nm, and there was marked improvement in the dissolution behavior compared with that of crystalline NOB. After oral administration of NOB/SD, higher exposure of NOB was observed with increases of bioavailability and CNS distribution by 13- and sevenfold, respectively, compared with those of crystalline NOB. These findings suggest that an amorphous, nanosized SD could be a viable option for enhancing the bioavailability and CNS delivery of NOB.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Atsushi
authors.initials: A
authors.lastname: Uchida
authors.forename: Haruki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Seto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ogawa
authors.forename: Kayo
authors.initials: K
authors.lastname: Yuminoki
authors.forename: Naofumi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002957:Citrus / Q000737:chemistry*; D047309:Flavones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D010316:Particle Size; D033362:Powder Diffraction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D047309:Flavones; C008661:nobiletin