Preclinical evaluation of thermoreversible triamcinolone acetonide hydrogels for drug delivery to the inner ear

摘要

class="kwd-title">Abbreviations: POX 407, Poloxamer 407; TAAc, Triamcinolone acetonide; DEX, Dexamethasone; POX 188, Poloxamer 188; ORO-test, Oscillation–rotation–oscillation test class="kwd-title">Keywords: Triamcinolone acetonide, Thermoreversible hydrogel, Poloxamer 407, Intratympanic administration, In-vitro release class="head no_bottom_margin" id="idm139856046189184title">AbstractIntratympanic 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 20 s 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.