title: Preclinical evaluation of thermoreversible triamcinolone acetonide hydrogels for drug delivery to the inner ear.
abstract: Intratympanic glucocorticoid therapy aims to reduce the side effects associated with systemic long-time therapy of inner ear diseases or traumata after cochlear implantation. For that purpose, thermoreversible hydrogels being fluid at room temperature but solid at body temperature are known to be appropriate drug delivery systems. In this work, the two key parameters sol-gel transition time and temperature of Poloxamer 407 (POX 407) based hydrogels containing oto-compatible micronized triamcinolone acetonide (TAAc) were evaluated by rheological experiments varying the concentrations of the different compounds. A 20% POX 407 hydrogel in PBS containing 30% TAAc emerged as the most appropriate formulation. Oscillation-rotation-oscillation studies at two temperature levels were found to be an useful in-vitro test system for the hydrogel which revealed sufficient storage stability at 4 °C, injectability of the sol, solidification within 20s at body temperature and persistent stiffness indicating prolonged adhesion at the round window membrane. According to the in-vitro release studies using the Transwell™ system, absorption of the poor water soluble TAAc is partly due to the low amount of dissolved drug but predominantly due to micellar transport resulting in a cumulative release of 262.6±13.4 μg TAAc within one week followed by a sustained release of 193.1±8.3 μg TAAc within the next three weeks. Thus, the formation of POX 407 micelles is the basis not only for gel formation but also absorptivity of TAAc. All in all, fine tuned rheological experiments and absorption studies emerged as useful tools for preclinical evaluation of intratympanally administered hydrogels.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Engleder
authors.affiliation: Department of Otorhinolaryngology, Medical University of Vienna, Währinger Gürtel 18, 1090 Vienna, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Honeder
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Klobasa
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Department of Otorhinolaryngology, Medical University of Vienna, Währinger Gürtel 18, 1090 Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Arnoldner
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria. Electronic address: franz.gabor@univie.ac.at.
authors.forename: Franz
authors.initials: F
authors.lastname: Gabor
mesh_terms: D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D065546:Drug Liberation; D007758:Ear, Inner / Q000187:drug effects*; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000737:chemistry; D020100:Hydrogels; D008954:Models, Biological; D044367:Phase Transition; D020442:Poloxamer / Q000737:chemistry*; D012212:Rheology; D044366:Transition Temperature; D014222:Triamcinolone Acetonide / Q000008:administration & dosage* / Q000737:chemistry; D014783:Viscosity
chemical_list: D004337:Drug Carriers; D005938:Glucocorticoids; D020100:Hydrogels; D020442:Poloxamer; D014222:Triamcinolone Acetonide
keywords: In-vitro release; Intratympanic administration; Poloxamer 407; Thermoreversible hydrogel; Triamcinolone acetonide