Cochlear implant eluting ebselen for treating hearing loss

Abstract

Systems and methods of reducing low frequency hearing loss or preserving low-frequency hearing using an implantable drug delivery device for delivery of an effective amount of ebselen over a period of time to the cochlea of a patient. Systems and methods of manufacturing an implantable cochlear device for effective ebselen delivery.

Description

Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WOCOCHLEAR IMPLANT ELUTING EBSELEN FOR TREATING HEARING LOSSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No.: 63 / 700,548, filed on September 27, 2024, the entire contents of which are incorporated by reference herein. This application also incorporates by reference in its entirety U.S. Patent Application 16 / 300,935 and U.S. Patent No. 12,427,138.TECHNICAL FIELD

[0002] Aspects of the present disclosure relates generally systems and methods of reducing low frequency hearing loss or preserving low-frequency hearing using an implantable drug delivery device for delivery of an effective amount of ebselen over a period of time to the cochlea of a patient. Aspects of the present disclosure also relate to methods of manufacturing implantable cochlear devices for ebselen delivery.BACKGROUND

[0003] Ebselen (2 -Phenyl- l ,2-benzoselenazol-3(27 / )-one) is an anti-inflammatory compound with glutathione peroxidase (GPxl) activity of the following structure:

[0004] GPxl is the dominant catalytic antioxidant enzyme in the mammalian inner ear, and its activity is decreased after noise or ototoxic insult. Several preclinical and clinical studies have demonstrated the safety and efficacy of SPI-1005 (ebselen) at preventing and treating different forms of sensorineural hearing loss. SPI-1005 capsules, containing 200 mg ebselen, have demonstrated the potential for a safe, well tolerated, oral treatment for Meniere’s Disease, a disease for which there are no FDA-approved treatments. Oral Ebselen treatment prevents or reverses the pathologic changes in the cochlea following noise- or ototoxin-induced injury, resulting in improved physiology measured by several types of auditory stimuli. Ebselen is used in the treatment and / or prevention of chemotherapy induced ototoxicity, and treatment and / or prevention of aminoglycoside-induced ototoxicity in patients with cystic fibrosis. Ebselen treatment has further been shown to have use in treating acute lung infections andAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO related conditions or diseases, such as coronavirus-mediated lung injuries. Alternative routes of administration and dosage forms including ebselen are of interest.SUMMARY

[0005] The present disclosure provides a cochlear implantable device that elutes ebselen, and methods of using the same. The device can include a silicone strip including ebselen that is configured to elute a therapeutically effective amount of ebselen when implanted in the ear of a subject in need thereof. Also provided are methods of reducing low frequency hearing loss using the cochlear implantable device. In some embodiments, the method includes implanting the cochlear implantable device in the ear of a subject in need thereof, to elute a therapeutically effective amount of ebselen.

[0006] Accordingly, this disclosure describes embodiments, variations, and examples of devices, systems, and methods for reducing low frequency hearing loss or preserving low- frequency hearing using an implantable drug delivery device for delivery of an effective amount of ebselen over a period of time to the cochlea of a patient. Aspects of the present disclosure also relate to methods of manufacturing implantable cochlear device for ebselen delivery.

[0007] For example, aspects of the present disclosure include an implantable drug delivery device comprising a silicone carrier comprising 1-40 weight % of ebselen or a pharmaceutically acceptable salt thereof, in an amount effective to deliver ebselen over a period of time to the cochlea of a patient. In some embodiments, the device comprises at least 60% of the effective amount of ebselen is delivered by 30 days after implantation. In some embodiments, the device comprises at least 70% of the effective amount of ebselen is delivered by 60 days after implantation. In some embodiments, the amount of ebselen delivered is at least 10 times the amount of a therapeutic dose of ebselen over a period of at least 30 days. In some embodiments, the amount of ebselen delivered is at least 100 times of a therapeutic dose of ebselen over a period of at least 30 days. In some embodiments, the amount of ebselen delivered is at least 1,000 times of a therapeutic dose of ebselen over a period of at least 30 days. In some embodiments, the amount of ebselen delivered is at least 10,000 times of a therapeutic dose of ebselen over a period of at least 30 days.

[0008] In some embodiments, the silicone carrier comprises a silicone strip. In some embodiments, the silicone strip has a length between 0.1mm to 1mm (and ranges therebetween).Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO

[0009] In some embodiments, the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in a patient up to 3 months. In some embodiments, the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in a patient up to 3 months.

[0010] In some embodiments, the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in a patient up to 3 months.

[0011] In some embodiments, the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 3 months.

[0012] In some embodiments, the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in the ear of the patient up to 6 months.

[0013] In some embodiments, the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in the ear of the patient up to 6 months.

[0014] In some embodiments, the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in the ear of the patient up to 6 months.

[0015] In some embodiments, the delivered ebselen reOsults in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 6 months.

[0016] In some embodiments, the ABR threshold shift is a permanent threshold shift.

[0017] In some embodiments, the ABR threshold shift corresponds to threshold-shifts to a plurality of frequencies after a predetermined time period of ebselen delivery.

[0018] In some embodiments, the frequencies comprise at least 1 kHz, 2 kHz, 4 kHz, 6 kHz, 8 kHz, 16 kHz, 20 kHz.

[0019] In some embodiments, the predetermined time period to deliver the effective amount of ebselen is between 2 and 6 months (and ranges therebetween).

[0020] In some embodiments, the weight percentage of ebselen comprises 30%.

[0021] In some embodiments, the device is configured to provide a sustained release of ebselen over the period of time.

[0022] In some embodiments, the device further comprises an adhesive film.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO

[0023] In some embodiments, the silicone strip is attached to a silicon rod.

[0024] In some embodiments, the adhesive film includes a thickness of between 0.1mm to 1mm (and ranges therebetween).

[0025] In some embodiments, the carrier includes a thickness of between 0.1mm and 1mm (and ranges therebetween).

[0026] In some embodiments, the carrier includes a surface area of between 0.1mm2to 8mm2(and ranges therebetween), of which a majority of the surface area is in contact with a surface of the cochlear.

[0027] In some embodiments, the carrier comprises a polymeric matrix comprising polydimethyl siloxane, and tetrapropyl orthosilicate crosslinker.

[0028] In some embodiments, the polymeric matrix comprises 96% poly(dimethyl siloxane) base, 2% tetrapropyl orthosilicate crosslinker, and 2% stannous octoate catalyst.

[0029] In some embodiments, the silicone strip is in contact with a polyimide film.

[0030] In some embodiments, the silicone strip is replaceable.

[0031] In some embodiments, the device is implanted in the ear via intracochlear implantation.

[0032] Aspects of the present disclosure also include a device produced by a process comprising the steps of mixing a concentration of ebselen with a silicone formulation; molding the mixture; and curing the molded mixture. In some embodiments, the process further comprises a demolding process and a post-curing process.

[0033] Aspects of the present disclosure also includes a method of reducing low frequency hearing loss or preserving low frequency hearing, the method comprising: implanting an intracochlear implantable device of any one of claims 1 to 39 in the ear of a subject in need thereof, to elute a therapeutically effective amount of ebselen.

[0034] In some embodiments, the subject is assessed to have reduced hearing loss at one or more low frequencies after implantation.

[0035] In some embodiments, one or more low frequencies are selected from 0.125 kHz, 0.25 kHz, 0.5 kHz, 0.625 kHz, 0.75 kHz, 1 kHz, 1.5 kHz, 2kHz, and 4kHz.

[0036] In some embodiments, the implantable device is implanted for 3 months or longer, and the subject is assessed to have reduced hearing loss after a 3-month period.

[0037] In some embodiments, the implantable device is implanted for 6 months or longer.

[0038] In some embodiments, the implantable device is implanted for 12 months or longer.

[0039] In some embodiments, the silicone strip in the device is replaced one or more times during the administration period.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO

[0040] In some embodiments, the subject is assessed to have reduced hearing based on postimplantation auditory brainstem response (ABR) or pure-tone audiometry (PTA).

[0041] In some embodiments, the implantable device is implanted for 6 months or longer and the silicone strip elutes a therapeutically effective amount of ebselen over a period of 3 to 6 months.

[0042] In some embodiments, the implantation of the silicone strip results in no significant hair cell loss.

[0043] In some embodiments, the subject has residual hearing at risk for permanent loss postimplantation.

[0044] In some embodiments, the subject has Meniere’s disease or sudden sensorineural hearing loss.

[0045] In some embodiments, the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in a patient up to 3 months.

[0046] In some embodiments, the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in a patient up to 3 months.

[0047] In some embodiments, the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in a patient up to 3 months.

[0048] In some embodiments, the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 3 months.

[0049] In some embodiments, the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in the ear of the patient up to 6 months.

[0050] In some embodiments, the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in the ear of the patient up to 6 months.

[0051] In some embodiments, the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in the ear of the patient up to 6 months.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO

[0052] In some embodiments, the eluted ebselen reOsults in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 6 months.

[0053] In some embodiments, the eluted ebselen results in a decrease in low-frequency hearing loss as measured by PTA (pure tone audiometry).

[0054] In some embodiments, the ABR threshold shift is a permanent threshold shift.

[0055] In some embodiments, the ABR threshold shift corresponds to threshold-shifts to a plurality of frequencies after a predetermined time period of ebselen delivery. In some embodiments, the frequencies comprise at least 1 kHz, 2 kHz, 4 kHz, 6 kHz, 8 kHz, 16 kHz, 20 kHz.

[0056] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. The present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0057] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties for all purposes and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Furthermore, where a range of values is provided, it is understood that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the present disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the present disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0058] FIGURES. 1A and IB depict extrapolated ebselen release data from 63-days to 90- days.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO

[0059] FIGURE 2 depicts no significant loss of outer hair cells (OHCs) and inner hair cells (IHCs) from the ebselen elution as shown by immunofluorescent staining.

[0060] FIGURES 3A-H depict threshold shifts (TS) after unilateral intracochlearimplantation in the first GP cohort, as described in Example 1.

[0061] FIGURE 4 depicts OHC loss in both the 0% and 30% CIEBSEL groups, as shown by immunofluorescent staining.

[0062] FIGURES 5A-B depicts threshold shifts (TS) after unilateral intracochlear implantation in the second GP cohort, as described in Example 1.

[0063] FIGURE 6 depicts OHC loss in the vehicle, EBS-10, and EBS-20 groups, as shown by immunofluorescent staining.

[0064] Figures 7A-B illustrate exemplary sample development for both the EO-exposed sample and non-EO exposed sample, according to some embodiments.

[0065] Figure 8 illustrates an exemplary development process according to some embodiments.DETAILED DESCRIPTION

[0066] While various embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions can occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein can be employed.

[0067] Cochlear implants (Cis) are the only approved device that can restore hearing in patients with severe to profound hearing loss. However, the surgical implantation of the electrode array is associated with significant risk of losing residual hearing at low frequencies. Several strategies have been developed to reduce the risk of low-frequency hearing loss including changes in electrode flexibility, electrode placement, and peri-operative pharmacologic treatments aimed at reducing inflammation and fibrosis. Insertion trauma from the electrode array triggers a local inflammatory response that leads to the infiltration of macrophages, immune and non-immune cells, and subsequent fibrosis. Soft surgical techniques as well as mechanically assisted electrode insertion have been developed to reduce this insertional trauma and improve electrode impedance. One pharmacologic strategy involves the incorporation of anti-inflammatory agents directly into or onto the electrode array for intracochlear delivery. Initial preclinical data show that corticosteroids can improve post implantation outcomes, suggesting that local pharmacological treatments may mitigate cochlear damage and the lossAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO of residual hearing. For example, dexamethasone-eluting electrodes have been tested to reduce inflammation and fibrosis, and to improve electrode impedance post implantation. However, improvements in hearing thresholds especially at low-frequencies, and improvements in speech discrimination remain elusive.

[0068] Ebselen (SPI-1005), a novel investigational anti-inflammatory agent, has garnered significant interest and positive preclinical and clinical data in several hearing loss indications. Ebselen functions as a glutathione-peroxidase mimetic, reducing reactive oxygen species (ROS) and improving oxidative stress, both of which are major contributors to inflammation. The unique anti-inflammatory properties of ebselen make it a potential treatment to reduce the loss of residual hearing post-implantation. In prior human studies, ebselen has been delivered orally.EXAMPLES

[0069] The Examples in this section are offered by way of illustration, and not by way of limitation. The examples can represent only some embodiments, and it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein.Example 1

[0070] This study is the first to test a novel formulation of ebselen, embedded in silicone for local delivery into the cochlea of adult GPs.Materials and methods

[0071] CIEBSEL

[0072] To prepare 30% CIEBSEL, approximately 0.39 g ebselen (SPI) was added to 0.91 g silicone formulation comprising 96% polydimethyl siloxane (base), 2% tetrapropyl orthosilicate (crosslinker), and 2% stannous octoate (catalyst). The mixed components were injection-molded, then a 21.5-hour curing process at room temperature (RT) followed by demolding and a 2-hour post-cure at 60°C. Figure 8 illustrates an exemplary development process. In some embodiments, an adhesive is applied to the ebselen-containing strip. In some embodiments, the ebselen-containing strip adheres to a silicone rod before curing. Two sample methods were prepared for in vitro release testing (IVRT). One involved the silicone strip containing 30% ebselen (bare). The other involved adhering the 30% ebselen silicone strip toAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO a thin film backing (Kapton) to mimic adherence to an electrode array. Both sets of samples were sterilized using ethylene oxide (EO) prior to IVRT. Figure 7 illustrates an exemplary sample development for both the EO-exposed sample and non-EO exposed sample. Figure 7A shows an EO exposed sample (bare sample) in which the bare ebselen strip is tested without backing film. In some embodiments, the thickness of the sample strip may be up to 1mm. Figure 7B shows a non-EO exposed sample, with adhesive Kapton backing film. The sample remains attached to the adhesive backing film during IVRT in PBS. In some embodiments, the thickness of the sample may be up to 1mm or 1.3mm. Ebselen was quantitated using a validated HPLC method: column, Waters Sunfire C18, 4.6 X 150mm, 3.5 pm; wavelength, 230 nm; column temperature, 35°C; flow rate, 1.0 mL / min; injection volume, 5 pL; mobile phases, A: 0.05% trifluoroacetic acid (TFA) in water (v / v), B: 0.05% TFA in acetonitrile (ACN); gradient (min (%A:B)): 0 (90: 10), 17 (40:60), 27 (5:95), 30 (5:95), 30.1 (90: 10); diluent water: ACN (40:60 v / v). The method was assessed for linearity (0.3 to 300 pg / mL), R2=0.999. Ebselen was extracted from silicone using tetrahydrofuran stabilized with 400 ppm butylated hydroxy toluene. Please note that the dimensions indicated in the figures are exemplary and correspond to at least some embodiments.

[0073] IVRT

[0074] 30% CIEBSEL (bare and Kapton) were incubated separately 100 in phosphate-buffered saline (PBS) pH 7.4 at 37°C with gentle shaking. At predefined intervals (e.g., 1, 3, 7, 14, 21, 30 and 60 days), 500 pl of the PBS was sampled and replaced with fresh PBS. The released ebselen was quantified using HPLC. Ebselen release data (pg / ml and pM) were analyzed to evaluate the relationship between 30% CIEBSEL (bare and Kapton) and ebselen release kinetics in PBS.

[0075] Mouse cochlear culture

[0076] Cochlear cultures (N=60) were prepared as previously described 24. Neonatal mice were euthanized, and cochleae were collected in ice-cold PBS. Organ of Corti explants were placed onto 1 pm-pore filter membranes (SPLpore) and cultured in Dulbecco's Modified Eagle Medium (DMEM) / F12 supplemented with N2, B27, penicillin, and Fungizone. Cultures were maintained at 37°C in a 5% CO2 incubator. 30% CIEBSEL strips of varying lengths (0.75, 0.375, and 0.187mm) were incubated with the cultures for at least three days.

[0077] Guinea Pigs (GPs)

[0078] GPs (N=60) weighing 250-300 g at baseline (Elm Hill Labs, Chelmsford, MA) were included in this study. GPs were single-housed in a temperature- and humidity-controlled room with a 12 h light-dark cycle and free access to food and water. All procedures adhered to theAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WONIH Guide for the Care and Use of Laboratory Animals and were approved by the IACUC of SPI.

[0079] Auditory Brainstem Response

[0080] GPs were anesthetized with isoflurane, and basal body temperature was maintained at 37°C using a warming pad. Animal health was closely monitored through observation of respiration and circulation. Monaural closed-field Auditory Brainstem Responses (ABRs) were recorded (Intelligent Hearing Systems) before treatment (baseline) and subsequently at 1 week, 1, 2, 3, and 6-months following unilateral intracochlear implantation. Insert 122 ear tips (Nicolet Biomedical, Inc.) were used for sound delivery and sound levels were calibrated using a 0.25-inch microphone. Threshold measurements were performed initially in 20 dB steps, followed by 5 dB steps, and defined by identifying the most robust and reliable peak (I or III) within 0.1 ms. Threshold shifts (TS) were calculated as the difference in thresholds between baseline and follow-up. To reduce bias, a scientist blinded to the treatment groups performed the threshold analysis.

[0081] CIEBSEL implantation

[0082] GPs received isoflurane (5% for induction / 3% for maintenance) while on a warming pad. Using a surgical microscope, a post-auricular incision is made to expose the mastoid bulla. A mastoidectomy was created with a dental drill to expose the round window (RW) of the cochlea. A 0% or 30% CIEBSEL (0.75mm-long, Imm-wide, and O. lmm-thick) strip was inserted into the left cochlea through the RW. A piece of connective tissue was then placed onto the RW. The postl34 auricular incision was closed with 2-0 silk and the GP recovered on a warming pad until sternal.

[0083] Ebselen treatment

[0084] Ebselen was prepared as a stock solution in dimethyl sulfoxide (vehicle) and then diluted in sterile 0.9% (w / w) aqueous sodium chloride solution (vehicle:©.9% NaCl, 1 : 10) to create the working solution for subcutaneous (sc) administration. SC injection ensures safe, reliable dosing for 90 consecutive days. A total of 36 GPs implanted with 30% CIEBSEL unilaterally were randomly divided into three groups at 3-months post-implantation: 12 GPs received vehicle, 12 GPs received ebselen 10 mg / kg / day (EBS-10), and 12 GPs received ebselen 20 mg / kg / day (EBS-20). Each sc dose was administered once daily for 90 days. GPs were weighed daily prior to sc administration.

[0085] Cochlear immunocytochemistry and analysis

[0086] GPs were sacrificed, cochleae were collected, then fixed 144 in 4% PFA overnight, and prepared for 145 whole-mount immunostaining. The bony wall was removed, and theAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO membranous cochlea was isolated. After a 1-hour decalcification in 0.5 M EDTA, tissues were permeabilized and blocked with 0.2% Triton X-100, 1% BSA, and 5% donkey serum in PBS. Tissues were incubated overnight at 4°C with anti-Myosin 7a (1 :200 Proteus Biosciences) and then with Alexa Fluor 594-Donkey anti-Rabbit IgG (Invitrogen) for 2-hours at RT. Cochleae were dissected into four turns, mounted with DAPI to identify nuclei, and imaged using a Nikon Epifluorescence Microscope. Whole mount images of the cochlear base to apex were assembled into photomontages using Adobe Photoshop software. Missing outer hair cells (OHCs) and inner hair cells (IHCs) were identified by the absence of DAPI and Myosin 7a staining in the organ of Corti where OHCs and IHCs should be present. Measurements of OHC loss were recorded (mm) starting from the hook of the cochlea and moving apically.

[0087] Data analysis

[0088] Data analysis was conducted using GraphPad Prism 9. One-way and two-way ANOVAs were applied to data sets with normal distribution and equal sample sizes, while mixed models were applied to data sets that did not. Post-hoc t-tests were performed with Sidak’s (two-way ANOVA) and Tukey’s tests (one-way ANOVA) to identify individual differences at specific time points or treatment group. Statistical significance was defined as *p<0.05, **p<0.01, and ***p<0.001.

[0089] Results

[0090] The 30% CIEBSEL (bare and Kapton) IVRT showed the cumulative amount in micrograms and the percentage of ebselen released from each sample. Ebselen was stable to EO sterilization as determined by HPLC (data not shown). The 30% ebselen bare samples released the majority of ebselen, (70%), by 30-days. The 30% ebselen Kapton samples released the majority of ebselen, (65%), by 63-days. The release data from 63-days to 90-days were extrapolated to estimate the total release over a 90-day period (Figure 1 A, IB).

[0091] Ebselen elution from CIEBSEL strips of varying lengths (0.75, 0.375, and 0.187 mm) was quantitated by HPLC. The corresponding cumulative ebselen released over 3 days in cochlear culture was 5.1 pg / ml (18.6 pM), 2.55 pg / mL (9.3 pM) and 1.27 pg / mL (4.6 pM), respectively. After fixation and immunostaining for Myosin-7a, no significant OHC or IHC loss was observed at any concentration (Figure 2).

[0092] In the first GP cohort (N=24) that received unilateral intracochlear implantation, the TS in the implanted ears were compared. For 0% CIEBSEL (N=12), significant increases in TS were only observed at 6-months: 4-kHz (14.5 ± 5.0 dB, p=0.0119), 8-kHz (11.0 ± 3.4 dB, p=0.0324), 16-kHz (14.0 ± 5.0 dB, p=0.0043), and 32-kHz (21.5 ± 6.6 dB, p=0.0210) (Figure 3A). For 30% CIEBSEL (N=12), significant increases in TS were observed at 1-week: 16-kHzAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO(15.0 ± 4.0 dB, p=0.0041), 24-kHz (20.0 ± 4.7 dB, p=0.0109), and 32-kHz (21.0 ± 4.3 dB, p=0.0092); and at 6-months: 4-kHz (11.4 ± 3.4 dB, p=0.0421), 8-kHz (10.0 ± 3.3 dB, p=0.0285, 16-kHz (21.8 ± 5.0 dB, p=0.0002), 24-kHz (25.45 ± 6 dB, p=0.0005), and 32-kHz (23.6 ± 4.3 dB, p=0.0210) (Figure 3B).

[0093] In the first GP cohort, the TS in nonimplanted ears were also compared. For 0% CIEBSEL (N=12), no significant increase in TS was observed at any frequency at any time point (Figure 3C). However, for 30% CIEBSEL (N=12), significant increases 184 in TS in the nonimplanted ears were 185 observed at multiple frequencies at 6-months: 4-kHz (14.1 ± 5.7 dB, p=0.0055), 24-kHz (11.4 ±186 3.9 dB, p=0.0022), and 32-kHz (13.6 ± 4.6 dB, p=0.0021) (Figure 3D). For 0% CIEBSEL, the implanted-nonimplanted (ATS) was not significant (Figure 3E). However, for 30% CIEBSEL, the ATS was significant at 1-week and 2-months: 4-kHz (4.1 ± 2.6, p=0.0182) and 24-kHz (18.6 ± 4.5 dB, p=0.0266) (Figure 3F). No significant difference between the TS of 0% and 30% CIEBSEL was observed in 4-kHz at 2-months (8.7 ± 2.6 dB vs 1.8 ± 1.1 dB in 0% CIEBSEL, p=0.3089) (Figure 3G). However, in the ATS analysis, significant improvements in 30% CIEBSEL at 4-kHz at 2-months (-6.8 ± 2.7 dB vs 7.9 ± 2.8 dB in 0% CIEBSEL, p=0.0152) and at 6-months (-2.7 vs 12.5 ± 5.6 dB in 0% CIEBSEL, p=0.0110) were observed (Figure 3H). In summary, the 30% CIEBSEL group showed an improvement in ATS at 4-kHz over the 0% CIEBSEL group at 2 months (-14.7 ± 4.7 dB) and at 6-months (-15.2 ± 4.9 dB). No significant differences were observed between males and females after the ATS were calculated. Immunofluorescent myosin-7a staining showed OHC loss (2mm from the hook) in both the 0% and 30% CIEBSEL groups with no significant difference (Figure 4).

[0094] In the second GP cohort (N=36) that all received unilateral intracochlear implantation of 30% CIEBSEL, the TS in the implanted ears were compared between the vehicle (N=12) and ebselen, sc, treatment groups: EBS-10 (N=12) and EBS-20 (N=12). In EBS-10, a significant decrease in TS was observed in the implanted ears at two frequencies compared to vehicle at 6-months post implantation: at 4-kHz (20.0 ± 6.6 dB vs. vehicle 42.5 ± 6.6 dB, p=0.0213) and at 32-kHz (33.75 ± 4.7 dB vs. vehicle 48.3 ± 2.8 dB, p=0.0221) (Figure 5A). In EBS-20, no significant decrease in TS was observed in the implanted ears at any frequency when compared to vehicle 6-months post implantation (Figure 5 A).

[0095] In the second GP cohort, the TS in nonimplanted ears were compared between the vehicle and ebselen treatment groups. In EBS-10, no significant decrease in TS was observed in the nonimplanted ears at any frequency (Figure 5B). However, in EBS-20, a significant decrease in TS was observed in the nonimplanted ears when compared to vehicle at twoAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO frequencies (6-months post-implantation): 4-kHz (6.3 ± 1.5 dB vs. vehicle 20.0 ± 4.1 dB, p=0.0411) and at 8-kHz (5.4 ± 1.9dB vs. vehicle 15.8 ± 3.3 dB, p=0.0480) 6-months postimplantation (Figure 5B).

[0096] Consequently, in EBS-10, ATS were significant at two frequencies when compared to vehicle at 6-month post-implantation: 4-kHz (5.0 ± 4.3 dB vs. vehicle 22.5 ± 6.5 dB, p=0.0338) and 32-kHz (23.8 ± 5.3 vs. vehicle 40.4 ± 2.9 dB p=0.0480) (Figure 5C). The EBS-10 group also showed an improvement in ATS compared to the vehicle group of -17.50 ± 7.3 dB at 4- kHz and -16.7 ± 7.3 dB at 32-kHz, 6-month post-implantation. No significant differences were observed between males and females after the differences in implanted and nonimplanted ears were calculated. Myosin-7a immunofluorescent staining showed OHC loss (2mm from the hook) in most vehicle, EBS-10, and EBS-20 treated cochlea. No significant difference in OHC loss was observed between the groups although the EBS-10 group had less OHC loss (Figure 6).

[0097] Discussion

[0098] Ebselen-eluting silicone strips (CIEBSEL) were developed and tested for the first time both in-vitro and in-vivo. IVRT showed gradual elution of ebselen over 90 days. Exposure to CIEBSEL in cochlear cultures showed no signs of hair cell loss. A GP model of intracochlear implantation demonstrated that 30% CIEBSEL improved residual hearing loss. This effect was enhanced when combined with systemic ebselen administration. CIEBSEL effectively preserved auditory sensitivity at low and high frequencies. Histological analysis showed no significant difference in OHC loss. These findings are consistent with our prior ebselen studies where systemic administration reduced ototoxicity in rats and mice 21,24.

[0099] In our first cohort, the CIEBSEL-implanted ears exhibited smaller TS (approximately 20 dB) over 6 months when compared to the TS reported in other studies (approximately 40 dB) 3. This difference is likely attributable to the shorter length and pliability of the CIEBSEL implant (0.75mm) compared to a stiffer GP electrode array (3-4 mm) due to the incorporated wires and contacts.

[0100] Other studies have shown that deeper insertions can cause greater damage and inflammation, leading to more significant hearing loss 3. In both the 0% and 30% CIEBSEL groups, TS in the implanted cochlea decreased between 1-week and 3 -month post-implantation. However, significant TS were observed at 6 months. This increase in TS, especially at 4, 16, and 32-kHz, may be due to the lack of intracochlear ebselen after 90-days and / or aging. For these reasons, we analyzed the TS in the nonimplanted ears and tested whether systemicAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO ebselen administration could overcome the lack of intracochlear ebselen and the effects of aging.

[0101] In the first cohort, the 0% CIEBSEL group showed no significant TS in the nonimplanted ears. However, in the 30% CIEBSEL group, significant TS were observed in the nonimplanted ears. Although the exact reason for this difference remains unclear, it impacted the 30% CIEBSEL outcomes. To better determine the effects of intracochlear implantation on the individual GP, the TS of the implanted ears were subtracted from the TS of the nonimplanted ears (ATS). Using these differential values, the 30% CIEBSEL group showed significant improvements at 4-kHz vs. the 0% CIEBSEL group at 2- and 6-month postimplantation. In the second cohort, the vehicle group showed a larger TS (>40 dB) than the TS of the first cohort (>20 dB) at 6-months post-implantation. This difference may be due to DMSO-induced ototoxicity especially after chronic dosing. In the EBS-10 group, the TS in the implanted cochlea were significantly reduced at 6 months. In the EBS-10 group, no significant TS were observed in the nonimplanted ear. In the EBS-20 group, the TS in the nonimplanted ears were similar to that observed in the EBS-10 group at 16, 24, and 32-kHz. Interestingly, the TS in the nonimplanted ears of the EBS-20 group were significantly lower than the TS in the vehicle group at 4 and 8-kHz. This observation further supports the otoprotective properties of systemic ebselen treatment in older animals. Although the ATS was greater in the second cohort, treatment with EBS-10 reduced the ATS relative to vehicle, while treatment with EBS- 20 appeared less effective and may have been confounded by higher levels of DMSO in this treatment group. The >15 dB improvement at 4-kHz in the 30% CIEBSEL group may be relevant in future clinical studies involving cochlear implantation. Low frequency hearing is critical for speech discrimination, and this level of improvement may be relevant.

[0102] This study demonstrates that ebselen preserves low-frequency hearing following intracochlear implantation in adult GPs followed for 6 months. The combination of local CIEBSEL and systemic ebselen treatment further improved ABR thresholds.Example 2

[0103] SPI-1005 (ebselen) is a novel anti-inflammatory that improves residual low frequency hearing following cochlear implantation.Method:

[0104] Study goals included developing a novel implantable formulation of ebselen (silicone) that improves low frequency hearing in adult guinea pigs and was conducted from April 2022 to June 2024 under IACUC approval. A series of in vitro & in vivo tests assayed ebselen releaseAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO(IVRT), acute ototoxicity (cochlear cultures), hearing sensitivity (ABR), and chronic ototoxicity (histopathology). 60 neonatal mice cochlear cultures were run for 3-7 days in the presence of 30% ebselen strips. 24 Guinea pigs (GPs) were surgically implanted (unilaterally) with a 0.75mm silicone strip containing ebselen at 0% (control) or 30% (active)concentration into the scala tympani via the RWN. GPs were followed for 180 days and re-assessed at 1- week, 1, 2, 3, and 6-months post-implantation. ABR threshold shifts in the implanted left ear were subtracted from the threshold shift in the un-implanted right ear and that difference was compared between control and active groups at 4, 8, 16, 24 and 32 kHz over 6-months. Cochlear histopathology involved immunofluorescence to determine the length of hair cell loss (mm) in implanted cochlea.Results:

[0105] IVRT showed that 30% strips elute ebselen over a 90-180-day period. Mouse cochlear cultures showed no cell loss after 3-7 days of exposure to ebselen strips. In GPs, ABR threshold shifts were highest at 1-week (20-35 dB) and decreased steadily at 1, 2, and 3 -months (5-10 dB) post-implantation. At 6-months, threshold shifts increased in both active and control guinea pigs. Ebselen implanted GPs showed improvements at 4kHz (15-20 dB) at 2 and 6- months when compared to controls (p-values < 0.05). Hair cell loss was limited to the site of cochlear implantation (2mm) and there was no significant difference between actives and controls.Conclusions:

[0106] These preclinical data show that a novel silicone formulation of ebselen can improve low frequency hearing when compared to controls and support the combination of ebselen with a cochlear implant to improve residual hearing.Example 3Method:

[0107] Sterile CIEBSEL (0% or 30% ebselen) were developed and evaluated by in-vitro release testing (IVRT) and separately in mouse cochlear cultures (N=60) for ototoxicity. First- GP cohort (N=24) was unilaterally-implanted with 0% or 30% CIEBSEL into the scala tympani, and auditory brainstem response (ABR) threshold shifts (4, 8, 16, 24, and 32-kHz) were measured at 1-week, and 1-, 2-, 3-, and 6-months post-implantation. Second-GP cohort (N=36) was unilaterally implanted with 30% CIEBSEL and received ebselen subcutaneously (0, 10, or 20 mg / kg / day) for 3-months (4-6-months) post-implantation. Hair cell loss was assessed by fluorescence microscopy.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WOResult:

[0108] IVRT demonstrated that 30% CIEBSEL gradually eluted ebselen over 90 days and was not ototoxic to cochlear cultures. First-cohort, 30% CIEBSEL showed improved ABR threshold-shifts at 4-kHz at 2-months (-6.8 ± 2.7 dB vs 0% CIEBSEL 7.9 ± 2.8 dB, p=0.010) and at 6-months (-2.7 ± 5.2 dB, vs 0% CIEBSEL 12.5 ± 5.6 dB, p=0.011). Hair-cell loss was confined to the implantation site and was consistent across groups. Second-cohort, 30% CIEBSEL plus ebselen subcutaneously, showed improved threshold-shifts compared to 30% CIEBSEL only at 4-kHz (-22.5 dB, p=0.021) and 32-kHz (-14.6 dB, p=0.022) at 6-months.General Considerations

[0109] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all structure, parameters, dimensions, materials, functionality, and configurations described herein are meant to be an example and that the actual structure, parameters, dimensions, materials, functionality, and configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the claims supported by the present disclosure, and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are also directed to each individual feature, system, article, structure, material, kit, functionality, step, and method described herein. In addition, any combination of two or more such features, systems, articles, structure, materials, kits, functionalities, steps, and methods, if such are not mutually inconsistent, is included within the inventive scope of the present disclosure. Some embodiments may be distinguishable from the prior art for specifically lacking one or more features / elements / functionality (i.e., claims directed to such embodiments may include negative limitations).

[0110] Also, as noted, various inventive concepts are embodied as one or more methods, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts areAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.[OHl] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” The terms “can” and “may” are used interchangeably in the present disclosure, and indicate that the referred to element, component, structure, function, functionality, objective, advantage, operation, step, process, apparatus, system, device, result, or clarification, has the ability to be used, included, or produced, or otherwise stand for the proposition indicated in the statement for which the term is used (or referred to) for a particular embodiment(s).

[0112] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined.

[0113] Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0114] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.”

[0115] “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0116] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one elementAtorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0117] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Claims

Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WOWhat is currently claimed.

1. An implantable drug delivery device comprising a silicone carrier comprising 1-40 weight % of ebselen or a pharmaceutically acceptable salt thereof, in an amount effective to deliver ebselen over a period of time to the cochlea of a patient.

2. The device of claim 1, wherein the device is configured to deliver at least 60% of the effective amount of ebselen within 30 days after implantation.

3. The device of claim 1, wherein the device is configured to deliver at least 70% of the effective amount of ebselen within by 60 days after implantation.

4. The device of claim 1, wherein the device is configured to deliver an amount of ebselen at least 10 times of a therapeutic dose of ebselen over a period of at least 30 days.

5. The device of claim 1, wherein the device is configured to deliver an amount of ebselen within at least 100 times of a therapeutic dose of ebselen over a period of at least 30 days.

6. The device of claim 1, wherein the device is configured to deliver an amount of ebselen at least 1,000 times of a therapeutic dose of ebselen over a period of at least 30 days.

7. The device of claim 1, wherein the device is configured to delivery an amount of ebselen at least 10,000 times of a therapeutic dose of ebselen over a period of at least 30 days.

8. The device of claim 1, wherein the silicone carrier comprises a silicone strip.

9. The device of claim 8, wherein the silicone strip has a length between 0.1mm to 1mm.

10. The device of claim 1, wherein the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in a patient up to 3 months.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO11. The device of claim 1, wherein the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in a patient up to 3 months.

12. The device of claim 1, wherein the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in a patient up to 3 months.

13. The device of claim 1, wherein the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 3 months.

14. The device of claim 1, wherein the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in the ear of the patient up to 6 months.

15. The device of claim 1, wherein the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in the ear of the patient up to 6 months.

16. The device of claim 1, wherein the delivered ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in the ear of the patient up to 6 months.

17. The device of claim 1, wherein the delivered ebselen reOsults in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 6 months.

18. The device of claims 10-17, wherein the ABR threshold shift is a permanent threshold shift.

19. The device of claims 10-18, wherein the ABR threshold shift corresponds to thresholdshifts to a plurality of frequencies after a predetermined time period of ebselen delivery.

20. The device of claim 19, wherein the frequencies comprise at least 1 kHz.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO21. The device of claim 19, wherein the frequencies comprise at least 2 kHz.

22. The device of claim 19, wherein the frequencies comprise at least 4 kHz.

23. The device of claim 19, wherein the frequencies comprise at least 6 kHz.

24. The device of claim 19, wherein the frequencies comprise at least 8 kHz.

25. The device of claim 19, wherein the frequencies comprise at least 16 kHz.

26. The device of claim 19, wherein the frequencies comprise at least 20 kHz.

27. The device of claim 1, wherein the predetermined time period to deliver the effective amount of ebselen is between 2 and 6 months.

28. The device of any of claims 1-27, wherein the weight percentage of ebselen comprises 30%.

29. The device of any of claims 1-28, wherein the device is configured to provide a sustained release of ebselen over the period of time.

30. The device of any of claims 1-29, wherein the device further comprises an adhesive film.

31. The device of any of claims 8-9, wherein the silicone strip is attached to a silicon rod.

32. The device of claim 30, wherein the adhesive film includes a thickness of between 0.1mm to 1mm..

33. The device of claims 8-32 , wherein the carrier includes a thickness of between 0.1mm and 1mm.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO34. The device of any of claims 8-33, wherein the carrier includes a surface area of between 0.1mm2to 8mm2, of which a majority of the surface area is in contact with a surface of the cochlear.

35. The device of any of claims 8 to 34, wherein the carrier comprises a polymeric matrix comprising polydimethyl siloxane, and tetrapropyl orthosilicate crosslinker.

36. The device of any one of claims 8-35, wherein the polymeric matrix comprises 96% poly(dimethyl siloxane) base, 2% tetrapropyl orthosilicate crosslinker, and 2% stannous octoate catalyst.

37. The device of any one of claims 8 to 36, wherein the silicone strip is in contact with a polyimide film.

38. The device of any one of claims 8-37, wherein the silicone strip is replaceable.

39. The device of any one of claims 1-38, wherein the device is implanted in the ear via intracochlear implantation.

40. A device produced by a process comprising the steps of: mixing a concentration of ebselen with a silicone formulation; molding the mixture; and curing the molded mixture.

41. The process of claim 40, further comprising a demolding process and a post-curing process.

42. A method of reducing low frequency hearing loss or preserving low frequency hearing, the method comprising implanting an intracochlear implantable device of any one of claims 1 to 39 in the ear of a subject in need thereof, to elute a therapeutically effective amount of ebselen.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO43. The method of claim 42, wherein the subject is assessed to have reduced hearing loss at one or more low frequencies after implantation.

44. The method of claim 42-43, wherein one or more low frequencies are selected from 0.125 kHz, 0.25 kHz, 0.5 kHz, 0.625 kHz, 0.75 kHz, 1 kHz, 1.5 kHz, 2kHz, and 4kHz.

45. The method of any one of claims 42 to 44, wherein the implantable device is implanted for 3 months or longer, and the subject is assessed to have reduced hearing loss after a 3 -month period.

46. The method of claims 42 to 45, wherein the implantable device is implanted for 6 months or longer.

47. The method of claims 42 to 46, wherein the implantable device is implanted for 12 months or longer.

48. The method of any one of claims 42 to 47, wherein the silicone strip in the device is replaced one or more times during the administration period.

49. The method of any one of claims 42 to 48, wherein the subject is assessed to have reduced hearing based on post-implantation auditory brainstem response (ABR) or pure-tone audiometry (PTA).

50. The method of any one of claims 42 to 49, wherein the implantable device is implanted for 6 months or longer and the silicone strip elutes a therapeutically effective amount of ebselen over a period of 3 to 6 months.

51. The method of any one of claims 42 to 50, wherein the implantation of the silicone strip results in no significant hair cell loss.

52. The method of any one of claims 42 to 51, wherein the subject has residual hearing at risk for permanent loss post-implantation.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO53. The method of any one of claims 42 to 52, wherein the subject has Meniere’s disease or sudden sensorineural hearing loss.

54. The method of claim 42, wherein the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in a patient up to 3 months.

55. The method of claim 42, wherein the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in a patient up to 3 months.

56. The method of claim 42, wherein the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in a patient up to 3 months.

57. The method of claim 42, wherein the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 3 months.

58. The method of claim 42, wherein the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 5 dB from a baseline measurement in the ear of the patient up to 6 months.

59. The method of claim 42, wherein the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 10 dB from a baseline measurement in the ear of the patient up to 6 months.

60. The method of claim 42, wherein the eluted ebselen results in a decrease in auditory brainstem response (ABR) threshold shifts of at least 15 dB from a baseline measurement in the ear of the patient up to 6 months.

61. The method of claim 42, wherein the eluted ebselen reOsults in a decrease in auditory brainstem response (ABR) threshold shifts of at least 20 dB from a baseline measurement in the ear of the patient up to 6 months.Atorney Docket No.: 30956-63787 / WOClient Ref.: 020 WO62. The method of claims 42-61, wherein the eluted ebselen results in a decrease in low- frequency hearing loss as measured by PTA (pure tone audiometry).

63. The method of claims 42-62, wherein the ABR threshold shift is a permanent threshold shift.

64. The method of claims 42-63, wherein the ABR threshold shift corresponds to thresholdshifts to a plurality of frequencies after a predetermined time period of ebselen delivery.

65. The method of claim 64, wherein the frequencies comprise at least 1 kHz.

66. The method of claim 64, wherein the frequencies comprise at least 2 kHz.

67. The method of claim 64, wherein the frequencies comprise at least 4 kHz.

68. The method of claim 64, wherein the frequencies comprise at least 6 kHz.

69. The method of claim 64, wherein the frequencies comprise at least 8 kHz.

70. The method of claim 64, wherein the frequencies comprise at least 16 kHz.

71. The method of claim 64, wherein the frequencies comprise at least 20 kHz.

72. The process of claim 40, wherein the molded mixture has a length up to 7.5mm.

73. The process of claim 40, wherein the molded mixture has a width up to 1mm.

74. The process of claim 40, wherein the molded mixture has a thickness between 0.1mm and 1mm.

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