Sustained Release of Triamcinolone Acetonide from an Intratympanically Applied Hydrogel Designed for the Delivery of High Glucocorticoid Doses

Abstract

The pharmacokinetic properties and tolerability of a triamcinolone acetonide poloxamer 407 hydrogel for intratympanic application were investigated in a guinea pig model. Evaluation of in vivo release kinetics showed very high initial perilymph drug levels, with clinically relevant levels present for a minimum of 10 days. Assessment of auditory brainstem response thresholds showed a minimal, delayed and transient threshold shift, which was apparent on day 3 and resolved by day 10. No relevant histological changes of the middle and inner ear structures were noted, and hair cell counts showed no significant differences between treated and untreated ears. Thus, the triamcinolone-acetonide-loaded poloxamer 407 hydrogel is an effective vehicle for sustained high-dose inner ear glucocorticoid delivery.

Evaluation of the selective glucocorticoid receptor agonist compound A for ototoxic effects

“…Thereafter, each turn of the cochlea was separately embedded in Fluorsave Reagent (Calbiochem, Darmstadt, Germany) and analyzed by means of confocal microscopy. As previously published, hair cells were counted in three randomly selected 200‐μm sections of each turn . The numbers of viable hair cells were expressed as a percentage of their expected total numbers, which were determined for every 200‐μm section by counting the viable hair cells plus the missing hair cells as if they were still in existence.…”

“…As previously published, hair cells were counted in three randomly selected 200-lm sections of each turn. 19 The numbers of viable hair cells were expressed as a percentage of their expected total numbers, which were determined for every 200-lm section by counting the viable hair cells plus the missing hair cells as if they were still in existence. All histopathological examinations were performed blinded to the assigned treatment.…”

Evaluation of Sustained-Release Steroid Hydrogels in a Guinea Pig Model for Noise-Induced Hearing Loss

“…As previously described Honeder et al, 2014], the 20% (w/v) POX407 hydrogel (BASF SE, Germany) was prepared using the cold method. POX407 was dissolved in 10 mM PBS at 4 ° C. Glucocorticoid-containing hydrogels were prepared by suspending either 6%, 30% TAAC (Fagron, Germany) or 6% micronized Dex (Gatt-Koller, Austria) in the POX407 solution using a vortexer followed by storage at 4 ° C overnight.…”

“…Based on these results, our group tested the pharmacokinetic properties and tolerability of a TAAC-loaded POX407 hydrogel and proposed it as a promising vehicle for sustained high-dose inner ear glucocorticoid delivery Honeder et al, 2014]. Otoprotective effects of Dex-loaded POX407 hydrogels were reported in models for cochlear implantation electrode insertion trauma, noise-induced hearing loss as well as acute and chronic cisplatin ototoxicity Harrop-Jones et al, 2016;Honeder et al, 2016].…”

Determination of the glycosylation-pattern of the middle ear mucosa in guinea pigs

“…Although specific antibiotics are administered, the overall clinical effectiveness is limited due to low penetration of the drug to the middle ear mucosa (MEM) ( Coates et al, 2008 ), inaccessibility of the bacteria within the grown biofilm ( Post et al, 2004 ) as well as low symptomatic amendment within the first 24 h ( Glasziou et al, 2004; Rovers et al, 2006 ). To increase the therapeutic outcome and to prolong the contact time of the drug with the infected tissue drug loaded formulations such as thermosensitive hydrogels ( Lee et al, 2004; Li et al, 2014; Honeder et al, 2014 ), ototopical drops ( Kutz et al, 2013 ), implants ( Goycoolea et al, 1992; Goycoolea and Muchow, 1994; Nether et al, 2004 ), micropumps ( Lehner et al, 1997 ), intranasal drug delivery systems ( Chandrasekhar and Mautone, 2004 ), coated middle ear prostheses ( Lensing et al, 2013; Ehlert et al, 2013; Hesse et al, 2013 ), and pellets ( Daniel et al, 2012 ) were developed. Although there are many different therapeutic approaches, a local intratympanic therapy seems to be most beneficial for the treatment of OM as a decrease in side effects provoked by systemic therapy as well as an increase in compliance of the young patients will be expected.…”