title: Distribution of dexamethasone and preservation of inner ear function following intratympanic delivery of a gel-based formulation.
abstract: Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated. The gel is liquid at room temperature, allowing IT injection, but transitions to a gel at body temperature, providing a prolonged residence time in the middle ear. A 50-μl volume of control or dex-containing gel (dex-gel) was injected through the tympanic membrane of guinea pigs. Cochlear function was assessed with cochlear action potential and acoustic emission thresholds measured immediately, 6 or 24 h after IT gel injection. After 6- or 24-hour treatment with dex-gel, perilymph drug gradients along the cochlea were assessed by taking samples sequentially from the apex, and endolymph was sampled from the basal turn. Control gel injections caused small changes in sound field calibrations and functional measures for low-frequency stimuli, consistent with an induced conductive loss. Within 24 h, responses returned to normal. Twenty-four hours after dex-gel injection, low-frequency changes remained as the dex-gel was retained better in the middle ear, but there was no indication of high-frequency loss. While perilymph sample data showed that dex gradients were substantially lower than after single injections of dex solution, quantitative analysis of this result suggests that some dex may have entered the perilymph through the thin bone in the apical region of the cochlea. Endolymph levels of dex remained lower than those in the perilymph. This study confirms that a poloxamer hydrogel-based dex formulation provides an effective method for a prolonged delivery, providing a more uniform distribution of drug in the inner ear.
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, St. Louis, Mo., USA. salta @ ent.wustl.edu
authors.forename: Alec N
authors.initials: AN
authors.lastname: Salt
authors.forename: Jared
authors.initials: J
authors.lastname: Hartsock
authors.forename: Stefan
authors.initials: S
authors.lastname: Plontke
authors.forename: Carl
authors.initials: C
authors.lastname: LeBel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Piu
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007758:Ear, Inner / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005782:Gels / Q000008:administration & dosage / Q000493:pharmacokinetics; D006168:Guinea Pigs; D008297:Male; D014432:Tympanic Membrane / Q000187:drug effects* / Q000502:physiology
chemical_list: D005782:Gels; D003907:Dexamethasone