Hyaluronic Acid Hydrogel Sustains the Delivery of Dexamethasone across the Round Window Membrane

Abstract

Background: The use of intratympanic (IT) steroids for the treatment of inner ear disorders is promising, but the clinical challenges of prolonged middle ear drug application have proven burdensome, and a sustainable delivery system is yet to be developed. Method: In this study, a guinea pig model was used to determine if dexamethasone in combination with a hyaluronic-acid (HA)-based hydrogel is an efficient, stable and sustainable dexamethasone delivery system to the inner ear. For each animal, right and left middle ear bullae were randomly selected to be filled with dexamethasone alone or dexamethasone-HA (Dex-HA) gel. Perilymph samples were collected at different time points and dexamethasone levels were determined using an ELISA. Results: Dexamethasone was measurable in the perilymph samples up to 72 h after treatment. At 24 h after treatment, the perilymph dexamethasone concentrations were significantly higher (p = 0.01) in the ears treated with Dex-HA gel than in those treated with dexamethasone alone. While the perilymph dexamethasone concentration had decreased at 48 h after treatment with Dex-HA gel, the levels were still higher than those observed at 24 h in ears treated with dexamethasone alone. A high variability in dexamethasone concentration was observed between the samples, and the variability between matched ears receiving different treatments was remarkably lower than the variability within each treatment group, suggesting that individual parameters might play a major role in perilymph dexamethasone concentration. There was no statistically significant correlation between dexamethasone concentration and sex, weight or laterality. Conclusions: Our results show that the Dex-HA gel used in this study provides an effective and sustained dexamethasone release mechanism that might be utilized to treat conditions such as sudden sensorineural hearing loss. This could potentially reduce the morbidity and costs associated with IT treatment.

Distribution of Dexamethasone and Preservation of Inner Ear Function following Intratympanic Delivery of a Gel-Based Formulation

“…The measured perilymph drug levels both in this study and those reported by Wang et al [2009] with similar methodology show less variability than prior studies with dex solutions [Parnes et al, 1999;Chandrasekhar et al, 2000;Hahn et al, 2006;Plontke et al, 2008a;Borden et al, 2010]. This is possibly the result of the longer residence time of the drug solution in the middle ear or the sustained drug level provided by the slowly dissolving micronized dex suspension.…”

Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal

“…There have been numerous pharmacokinetic studies of locally-applied corticosteroids in animals (Nomura 1984;Parnes et al 1999;Chandrasekhar et al 2000;Bachmann et al 2001;Hahn et al 2006Hahn et al , 2012Liu et al 2006;Plontke et al 2008b;Yang et al 2008;Wang et al 2009;Borden et al 2011;Salt et al 2011a) and humans (Bird et al 2007;Bird et al 2011), but only a subset of these studies has been analyzed quantitatively to derive an elimination rate. Plontke and analyzed prednisoline data of Bachmann et al (2001) from guinea pigs and found it to be consistent with an elimination half-time from perilymph of 130 min.…”

Intratympanic Steroids in Sudden Sensorineural Hearing Loss: Myth or Magic?

“…Agents such as histamine and hyaluronic acid have been shown to facilitate transport of the corticosteroid across the round window membrane in laboratory studies [22,23]. Intratympanic corticosteroids appear to affect both immune suppression and ion homeostasis [24].…”

“…A 1.5 -2.0 mm microcatheter was placed into the niche and connected to a continuous infusion pump with methylprednisolone (62.5 mg/mL) delivered for 14 days at a rate of 10 microliters per hour 83% of these had improved SDS with 66% returning to normal hearing Borden RC, et al [23] Microcatheter placed near roun window and they perfused methylprednisolone (62.5 mg/ml) continuously at 10 µl/h for 10 d…”