Principles of inner ear sustained release following intratympanic administration

• Published in: The Laryngoscope Vol. 121; no. 2; p. 385
• Main Authors: Wang, Xiaobo, Dellamary, Luis, Fernandez, Rayne, Ye, Qiang, LeBel, Carl, Piu, Fabrice
• Format: Journal Article
• Language: English
• Published: United States 01.02.2011
• Subjects: Animals; Delayed-Action Preparations - administration & dosage; Dexamethasone - administration & dosage; Dexamethasone - pharmacokinetics; Ear, Inner - drug effects; Guinea Pigs; Methylprednisolone - administration & dosage; Methylprednisolone - pharmacokinetics; Poloxamer - administration & dosage; Steroids - administration & dosage; Steroids - pharmacokinetics; Tympanic Membrane
• ISSN: 1531-4995
• DOI: 10.1002/lary.21370

Previous studies revealed that intratympanic administration of the steroid dexamethasone in poloxamer 407 hydrogel, a class of thermoreversible polymers, resulted in significant and durable exposure in the inner ear. Interestingly, varying the concentrations of the poloxamer vehicle and of the steroid impacted the pharmacokinetic profile of dexamethasone in the perilymphatic compartment. Here, the respective contributions of different vehicles (aqueous solution, poloxamer hydrogel) and steroid drugs (dexamethasone, methylprednisolone) were investigated. In particular, various forms of the steroids, discriminated by their aqueous solubility, were compared. In vitro studies characterized the gelation profile and drug release kinetics of the various formulations. The inner ear pharmacokinetic profile of the different formulations was investigated in guinea pigs. Drugs formulated in poloxamer 407 shared significantly more prolonged exposure than those formulated in aqueous solutions both in vitro and in vivo in the inner ear. Furthermore, drugs with low aqueous solubility yielded increased degree and duration of exposure in the inner ear relative to water-soluble drugs. The inner ear pharmacokinetic profile of drugs administered intratympanically is not only highly dependent upon the nature of the vehicle but also upon the physicochemical properties of the drug delivered.