Dose-dependent sustained release of dexamethasone in inner ear cochlear fluids using a novel local delivery approach.
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.
Wang
Xiaobo
X
Otonomy Inc., San Diego, CA 92121, USA.
Dellamary
Luis
L
Fernandez
Rayne
R
Harrop
Anne
A
Keithley
Elizabeth M
EM
Harris
Jeffrey P
JP
Ye
Qiang
Q
Lichter
Jay
J
LeBel
Carl
C
Piu
Fabrice
F
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*
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020442:Poloxamer; D003907:Dexamethasone