Chitosan-Glycerophosphate Hydrogel-A Local Drug Delivery System For Inner Ear Applications

PartⅠA Sustained Local Dexamethasone Delivery System for Inner Ear ApplicationsObjectives/Hypothesis:Glucocorticosteroid has been widely used for the treatment of inner ear diseases in the clinic. However, Systemic drug administration increases the likelihood of systemic toxicities and side effects and creates an inequality in drug concentration with higher circulating levels in the serum but lower local levels at the inner ear where the drug is needed. So much interest has been generated in developing a system for local drug delivery to the inner ear for the treatment of inner diseases, such as Meniere's disease and sudden idiopathic or noise-induced hearing loss. Intratympanic injection has overcome some risks and limitations of systemic drug delivery, while there remains a considerable amount of variability in clinical outcomes among those patients treated with intratympanic injections. So there is a clear need for a versatile system which capable of safely and efficiently delivering a sustained dose of the drugs. This system would allow to treat patients by using a single application. The present study investigates the effectiveness of a controlled and sustained local Chitosan-Glycerophosphate hydrogel system on the delivery of dexamethasone into the inner ear and its influences on the inner ear functions.Methods:In vitro:dexamethasone release and Chitosan-Glycerophosphate-hydrogel matrix degradation were characterized. In vivo:dexamethasone laden hydrogel was placed directly in the round window niche of mice. By collecting perilymph and plasma at different time points and analyzing the samples with high performance liquid chromophotography and mass spectrometry, we characterized the drug release of this drug delivery system. The safety of hydrogel on auditory function was also evaluated.Results:We developed a Chitosan-Glycerophosphate-hydrogel which is prepared in a liquid state at room temperature. At body temperature, it undergoes a phase transition becoming solid. In vitro:dexamethasone laden hydrogel released almost half of the dexamethasone it contained over 7 consecutive days with concurrent degradation of the hydrogel matrix to 15.3% of its starting weight. In vivo:Elevated levels of dexamethasone were detected in perilymph for 7 days following a single hydrogel application. In post-operative day 2, there was a little increase in hearing thresholds, and by post-operative day 10, the hearing thresholds returned to baseline.Conclusions:Chitosan-Glycerophosphate-hydrogel provides sustained and controlled drug release of dexamethasone within the inner ear of mice. The surgical procedure and administration of CGP-hydrogel to mouse ears is safe. This novel system provides a unique approach for sustained local drug delivery for inner ear therapy. PartⅡA Controlled and Sustained Local Gentamicin Delivery System for Inner Ear ApplicationsObjectives/Hypothesis:Intratympanic gentamicin injection has gained popularity worldwide for the treatment of Meniere's disease, However, this delivery system remains a considerable amount of variability in clinical outcomes among those patients treated with intratympanic gentamicin injection as unstable portions of the gentamicin contact with the round window membrane (RWM) and enter the fluids of the inner ear by diffusing across the RWM. The present study investigates the effectiveness of a controlled and sustained local hydrogel system on the delivery of gentamicin into the inner ear and its superiority for the treatment of Meniere's disease.Methods:Ultrastructure of hydrogel loaded with/without gentamicin was explored in vivo. Gentamicin was applied to the ear of mice either through intratympanic gentamicin injection or in the hydrogel system. Kinetics curves, hearing and balance functions were examined to study how the hydrogel system affected the gentamicin delivery and inner ear functions.Results:The micrographs and spectra analyses showed different structures between the blank hydrogel and drug-laden hydrogel. The two gentamicin-delivery methods yielded different kinetics curves. The hydrogel system achieved sustained-release over a 7-day period with a flat plateau phase from day 1 to day 3 and slow decent in the subsequent days. The intratympanic gentamicin injection curve dramatically declined after the peak concentration at day 1 and almost eliminated by day 3. Hydrogel system yielded noticeable balance dysfunction with no significant hearing changes. In contrast, intratympanic gentamicin injection exhibited no significant influences on the inner ear functions after applying the same dosage of 40μg gentamicin.Conclusions:The hydrogel system established in this research has been proved to be much more sustained, consistent and efficient than traditional intratympanic gentamicin injection for the transportation of gentamicin into the inner ear and hence offers new outlook for Meniere's disease's therapy.