title: Physicochemical and biopharmaceutical characterization of amorphous solid dispersion of nobiletin, a citrus polymethoxylated flavone, with improved hepatoprotective effects.
abstract: The present study aimed to develop an amorphous solid dispersion (SD) of nobiletin (NOB), a citrus polymethoxylated flavone, with the aim of improving its biopharmaceutical and hepatoprotective properties. SD formulation of NOB (NOB/SD) was prepared by wet-milling and subsequent freeze drying, and its stability and dissolution properties were characterized. The hepatoprotective effects and pharmacokinetic behavior of orally dosed NOB/SD were evaluated in rats. During the storage of NOB/SD for 4 weeks under accelerated conditions, there were no significant transitions in the appearance, particle size, and amorphousity of wet-milled NOB. In comparison with crystalline NOB, the NOB/SD exhibited significant improvement in the dissolution with a 10-fold higher dissolution rate. In a rat model of acute liver injury, repeated treatment with NOB/SD (2 mg NOB/kg) every 4 h led to marked attenuation of hepatic damage as evidenced by decreased ALT and AST, surrogate biomarkers for hepatic injury; however, crystalline NOB was found to be less effective. After oral administration of NOB/SD (2 mg NOB/kg) in rats, compared with crystalline NOB, improved pharmacokinetic behavior was observed with increases of bioavailability and hepatic delivery by ca. 7- and 6-fold, respectively, possibly leading to better hepatoprotection. Given the improved physicochemical and biopharmaceutical properties, the SD formulation strategy might be efficacious for enhancing the therapeutic potential of NOB.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. onoue@u-shizuoka-ken.ac.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Uchida
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: Aiki
authors.initials: A
authors.lastname: Hiza
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tsukaguchi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asakawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kan
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002152:Calorimetry, Differential Scanning; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002957:Citrus; D003460:Crystallization; D004355:Drug Stability; D047309:Flavones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D033362:Powder Diffraction; D020011:Protective Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D047309:Flavones; D020011:Protective Agents; D002251:Carbon Tetrachloride; C008661:nobiletin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: ALT; ANOVA; AST; CCl(4); CYP; Ceq; DLS; DSC; Dissolution; H&E; HPC; Hepatoprotection; NAD; NOB; Nobiletin; Oral absorption; PBS; PLM; PM; PXRD; RH; SD; SEM; SIR; Solid dispersion; UPLC/ESI-MS; alanine aminotransferase; analysis of variance; aspartate aminotransferase; carbon tetrachloride; cytochrome P450; differential scanning calorimetry; dynamic light scattering; equilibrium solubility; hematoxylin and eosin; hydroxypropyl cellulose; nicotinamide adenine dinucleotide; nobiletin; phosphate-buffered saline; physical mixture; polarized light microscopy; powder X-ray diffraction; relative humidity; scanning electron microscopy; selected ion recording; solid dispersion; ultra-performance liquid chromatography equipped with electrospray ionization mass spectrometry