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Controlled release of dexamethasone to the inner ear from silicone-based implants

Abstract : The ear is the organ responsible for the perception of sound and the sense of balance. The WHO estimated that worldwide 360 million people (over 5 % of the population) are suffering from disabling hearing loss, meaning a loss of 40 dB in the better hearing ear in adults. One of the major strategies to treat hearing loss is to administer steroids, e.g. dexamethasone, systemically. Steroids are used to prevent inflammation and oedema damaging the highly sensitive inner ear hair cells.Unfortunately, drug delivery to the inner ear is very challenging due to the blood-cochlea barrier which is similar to the blood-brain barrier and protects the inner ear from drugs or toxic substances from the blood stream. High doses are often required to reach therapeutic drug concentrations in the inner ear. Thus, local drug delivery seems to be a more promising approach to limit adverse effects due to high systemic blood levels.Nevertheless, a second major hurdle has to be overcome in clinical practice: the small dimensions of the cochlea and its difficult anatomical access. The two semipermeable membranes connecting the middle with the inner ear (the round and oval window) are one possible - but challenging - route to deliver drugs locally to the inner ear. Drug loaded solutions or gels administered with an intra-tympanic injection into the middle ear seem to be a relatively safe and economical therapy for a short or mid-term treatment. Unfortunately, they might be washed away or degraded rapidly and, though, often require repeated applications. Additionally, the anatomy of the ear varies from patient to patient leading to different drug concentrations in the inner ear.For long term treatment, intra-cochlear implants seem to be promising: Since the device is inserted directly into the inner ear, the drug concentration is better controlled and – depending on the formulation – the drug can be released over prolonged periods of time. Nevertheless, this approach is rather invasive so that the benefit for the patient has to be discussed in detail.The purpose of this study was to develop a miniaturized implant being able to deliver dexamethasone directly to the inner ear.To facilitate the development of silicone-based implants loaded with dexamethasone, thin drug loaded films have been prepared and thoroughly characterized in vitro as a model system. Drug release can easily be adjusted by varying the type of silicone used (e.g. type of side chain, degree of crosslinking), or by adding various amounts of PEG 400 or 1000. An analytical solution of Fick’s second law could be used to describe the drug release kinetics from the films and to theoretically predict drug release from dosage forms of arbitrary size and shape.Subsequently, two types of implants have been prepared using the most promising silicone systems. The first system, the Ear Cube implant with a predefined shape consists of a cube on top of a cylinder which stays in contact with the perilymph of the inner ear. The second system, the in situ forming implant adapts perfectly to middle ear anatomy because it cures directly in vivo. It also stays in contact with the inner ear fluids via a hole. Both systems have been characterized in vitro.In vivo, the dexamethasone loaded in situ forming silicone-based implants have been evaluated in mongolian gerbils. Interestingly, dexamethasone was detected within the explanted gerbil cochleae already 20 min after implant formation until at least 30 days.Thus, both implants seem to be a good tool to administer dexamethasone locally to the inner ear in a prolonged and time controlled manner. Further studies should be performed to characterize the Ear Cube implants in vivo. Additionally, both systems could be tested with different types of drug, e.g. gentamicin, to treat also other diseases with this new promising inner ear implants.
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Submitted on : Wednesday, October 5, 2016 - 4:22:11 PM
Last modification on : Friday, August 27, 2021 - 9:50:03 AM
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  • HAL Id : tel-01376802, version 1



Maria Gehrke. Controlled release of dexamethasone to the inner ear from silicone-based implants. Human health and pathology. Université du Droit et de la Santé - Lille II, 2016. English. ⟨NNT : 2016LIL2S004⟩. ⟨tel-01376802⟩



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