title: Dose-dependent sustained release of dexamethasone in inner ear cochlear fluids using a novel local delivery approach.
abstract: The thermo-reversible triblock copolymer poloxamer 407 was investigated as a drug delivery vehicle for micronized dexamethasone into the middle and inner ears of guinea pigs. The study characterized the gelation and in vitro release kinetics of poloxamer formulations. In vivo, the pharmacokinetic profile of formulations containing varying concentrations of poloxamer and dexamethasone was examined following intratympanic administration. Significant drug levels within the perilymph were observed for at least 10 days, while systemic exposure was minimal. The sustained-release kinetics profile could be significantly modulated by varying the concentrations of both poloxamer and dexamethasone. Assessment of auditory function revealed a small transient shift in hearing threshold, most probably of conductive nature, which resolved itself within a week. No significant histological changes of the round window membrane or cochlea could be noted. Poloxamer 407 thus represents an effective and safe delivery system to achieve sustained release of dexamethasone to the inner ear.
authors.affiliation: Otonomy Inc., San Diego, CA 92121, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Luis
authors.initials: L
authors.lastname: Dellamary
authors.forename: Rayne
authors.initials: R
authors.lastname: Fernandez
authors.forename: Anne
authors.initials: A
authors.lastname: Harrop
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Keithley
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Harris
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ye
authors.forename: Jay
authors.initials: J
authors.lastname: Lichter
authors.forename: Carl
authors.initials: C
authors.lastname: LeBel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Piu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003051:Cochlea / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004594:Electrophysiology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D006309:Hearing / Q000187:drug effects; D006320:Hearing Tests; D010498:Perilymph / Q000187:drug effects*; D020442:Poloxamer / Q000008:administration & dosage / Q000493:pharmacokinetics; D014432:Tympanic Membrane / Q000187:drug effects*
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020442:Poloxamer; D003907:Dexamethasone