Optimized topical glucocorticoid-therapy of the inner ear

Glucocorticoids are being used for the treatment of a wide variety of inner ear diseases for decades. The limited effectiveness of systemic glucocorticoid therapy and the severe side effects of long term glucocorticoid treatment made researchers concentrate on topical drug delivery to the inner ear. Various approaches aiming at a prolonged glucocorticoid delivery to the inner ear have been evaluated and the application of thermoreversible hydrogels has emerged as one of the most promising of them. At the moment most researchers focus on topical application of dexamethasone - mostly because of its high potency - and a lot of data has been created showing beneficial effects of this glucocorticoid in the setting of various conditions affecting the inner ear, including cochlear implant electrode insertion trauma. Another glucocorticoid, triamcinolone-acetonide, is successfully being used in surgery-protocols aiming at preservation of inner ear function (e.g. in partially deaf patients, who are candidates for residual hearing preserving cochlear implantation, so called electro-acoustic-stimulation), but only limited experimental data are available from literature. In particular, triamcinolone-acetonide has never been applied in a thermoreversible poloxamer 407 hydrogel with the aim of prolonged drug delivery, and a direct comparison of dexamethasone with triamcinolone- acetonide for otoprotective effects has not been performed up to date. Recently, besides glucocorticoids, a rather new group of substances, so-called selective glucocorticoid receptor agonists have been extensively studied, as they could substantially reduce side effects of glucocorticoid therapy. Nevertheless, their effects on the inner ear and their potential otoprotective effects have not been evaluated. We therefore plan to develop poloxamer 407 based hydrogels for the delivery of triamcinolone-acetonide and selective glucocorticoid receptor agonists and to evaluate them in-vitro for gelation properties and drug release. Subsequently we want to determine drug levels in perilymph, liquor and plasma by HPLC to gain insight into distribution profiles of the drugs and to evaluate the hydrogels for ototoxic effects. After having established safety and distribution profiles we plan to evaluate the most promising gels in a guinea pig model of cochlear implantation for otoprotective effects, which will be assessed as a function of hearing measured by compound action potentials and/or auditory brainstem responses. These hydrogels could not only provide new treatment options for patients with steroid-responsive inner ear diseases, but they would also be a helpful tool to unravel the molecular effects of glucocorticoids on the inner ear, which are poorly understood.

The aim of the project Optimized topical glucocorticoid-therapy of the inner ear was to provide a basis for a more efficient topical therapy of patients suffering from hearing loss. One of the main challenges of such therapies is the rapid drainage of fluid medications from the middle ear, which strongly limits the efficacy of active agents. In this project we were able to show that the application of a hydrogel containing triamcinolone-acetonide in the middle ear results in prolonged therapeutic levels of the glucocorticoid in the inner ear. For ease of application, the hydrogel is fluid but solidifies within seconds at body temperature and then resists inactivation by drainage. In a different experimental series, otoprotective effects of the preoperative application of glucocorticoid-hydrogels in the setting of hearing preservation cochlear implantation were shown. If these findings can be confirmed in a clinical study a new treatment regimen might be available for this patient population. In addition to the application before cochlear implantation, such hydrogels could provide new therapeutic options for patients suffering from sudden hearing loss, Menieres disease or noise-induced hearing loss. The use of selective glucocorticoid receptor modulators for the treatment of inner ear disorders, which was also evaluated in the course of this project, did not result in otoprotection. Furthermore, the carbohydrate pattern of the middle ear mucosa was elucidated and potential binding sites for future targeted therapeutics for the ear were identified. In summary, a hydrogel suitable for the sustained delivery of glucocorticoids to the inner ear was developed and characterized. When applied prior to cochlear implantation, this hydrogel protects the inner ear. Additionally, the identification of certain carbohydrates provides the basis for improved bioadhesive therapeutic systems.