BDNF for intranasal administration for treatment of sensory nerve deafness

Abstract

The present invention relates to a brain-derived nerve factor (BDNF) for use in the prevention or treatment of sensory nerve deafness in a subject, wherein the BDNF is intranasally administered to the subject.

Description

Technical Field

[0001] The present invention relates to the prevention and treatment of sensorineural hearing loss. Background Art

[0002] Hearing loss is the fourth leading cause of disability worldwide, affecting 430 million people, more than 5% of the world’s population. It is estimated that by 2050, more than 700 million people will suffer from disabling hearing loss (World Health Organization, 2021). https: / / www.who.int / news-room / fact-sheets / detail / deafness- and-hearing-loss. ).

[0003] The term hearing loss refers to a range of hearing conditions that can be divided into two major categories: (i) conductive hearing loss, in which hearing loss is caused by an obstruction or disease of the outer or middle ear that prevents sound energy from being transmitted to the inner ear, and (ii) sensorineural hearing loss (SNHL), which accounts for 90% of all hearing loss cases, in which hearing loss is caused by damage to the inner ear and auditory nerve. In particular, sensorineural hearing loss is primarily characterized by the degeneration of two types of cells: cochlear hair cells, which are the primary mechanoreceptors that convert sound energy into neural signals; and / or auditory neurons, namely spiral ganglion cells (SGCs), which transmit signals from the cochlear hair cells to the auditory nuclei of the brainstem via the auditory nerve.

[0004] Sensorineural hearing loss is usually caused by hair cell degeneration.

[0005] The above two types of cells are strictly connected, and the degeneration of sensory hair cells leads to a decrease in synaptic signals that stimulate spiral ganglion neurons, resulting in neurodegeneration (cochlear synaptopathy) (Cunningham al., N. Engl. J. Med. 2017, 377(25):2465–2473).

[0006] Hair cell degeneration in sensorineural hearing loss can have genetic or non-genetic causes. Non-genetic factors include noise exposure, viral or bacterial infection, ototoxic chemicals (such as chemotherapeutic drugs cisplatin or aminoglycoside antibiotics), autoimmune diseases, and aging (Liu et al, Front. Neurosci. 2022, 16: art. 867453).

[0007] Although hearing loss significantly affects all populations, the only approved treatment option is the cochlear implant (CI) hearing prosthesis, which works by directly stimulating the cell bodies and possibly the central axons of spiral ganglion cells (SGCs), partially restoring the patient's sensory organ function. There are currently no FDA-approved drug treatments for the prevention and treatment of this condition.

[0008] In clinical practice, non-hereditary SNHL is usually treated by administering corticosteroids, particularly dexamethasone and prednisolone. However, this treatment has not been shown to produce satisfactory outcomes.

[0009] Therefore, there is a strongly felt need to develop new, more effective pharmacological treatments that target the inner ear and are able to prevent damage to or replenish the hair cell and neuronal populations in the cochlea and restore hearing function.

[0010] Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family. This signaling molecule has been well documented to have the ability to regulate neuronal plasticity, cell growth, proliferation, cell survival, and long-term memory.

[0011] BDNF has been identified in preclinical and clinical studies as a promising therapeutic approach for the prevention and treatment of SNHL.

[0012] Preclinical studies have shown that BDNF can effectively rescue spiral ganglion neurons after hair cell damage. In addition, in animal models of cochlear synaptopathy, local administration of BDNF to the cochlea has been shown to restore ribbon synapses and their function (Liu et al, Front. Neurosci. 2022, 16: art. 867453, Foster at al, J. Acoust. Soc. Am. 2022, 151 (6): 3937-3946, Foster at al, Pharmacol Res Perspect. 2022, 10 (3): e00970).

[0013] Additionally, a clinical trial is ongoing to evaluate the safety, tolerability, and efficacy of OTO-413 administered as an intratympanic injection for the treatment of speech-in-noise hearing loss (https: / / clinicaltrials.gov / ct2 / show / NCT04129775?term=otonomy&draw=3).

[0014] However, a major challenge in effectively using BDNF to treat hearing disorders is delivering the protein to the inner ear compartment.

[0015] The delivery of drugs, especially large molecules such as proteins, to the inner ear cavity is hampered by the presence of several protective barriers.

[0016] The blood labyrinth barrier (BLB), which separates the inner ear fluid from the blood circulation, limits the possibility of systemic delivery. At the same time, delivery by topical application into the ear is hampered by the barriers between the different chambers of the ear, namely the tympanic membrane (TM) between the outer ear and the middle ear and the round window membrane (RWM) between the middle ear and the inner ear.

[0017] To achieve higher drug concentrations in the middle ear, in ongoing clinical trials using BDNF, intratympanic injections of the protein have been used to deliver BDNF directly into the middle ear for subsequent diffusion across the RWM into the inner ear. However, this delivery route requires an invasive surgical procedure that can be painful for the patient and carries the risk of permanent tympanic membrane perforation.

[0018] In preclinical studies, another approach for delivering BDNF into the inner ear is the implantation of an osmotic minipump into the scala tympani. However, also in this case, the clinical application of this approach is limited by the fact that the patient must undergo an invasive surgical procedure. Summary of the invention

[0019] The present inventors have now unexpectedly discovered that BDNF can be delivered to the inner ear at effective concentrations by intranasal administration.

[0020] Therefore, a first object of the present invention is BDNF for use in preventing or treating sensorineural hearing loss in a subject, wherein the BDNF is administered intranasally to the subject.

[0021] Another object of the present invention is a pharmaceutical composition comprising BDNF and at least one pharmaceutically acceptable excipient for use in preventing or treating sensorineural hearing loss in a subject, wherein said composition is administered intranasally to said subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shown are the concentrations of BDNF in the perilymph at different time points after administration of rhBDNF (BDNF) or phosphate buffered saline (PBS), measured as described in Example 1. *** : p<0.0002 compared with PBS; **** : p<0.0001 compared with PBS.

[0023] Figure 2 Shown are threshold shifts of ABRs at low (6 kHz), medium (12, 16 and 20 kHz) and high (24 and 32 kHz) frequencies in mice treated with vehicle (grey line) or rhBDNF (black line) 7 days after cisplatin treatment compared to those measured on day 0, as measured as described in Example 2. DETAILED DESCRIPTION

[0024] A first object of the present invention is brain-derived neurofactor (BDNF) for use in preventing or treating sensorineural hearing loss in a subject, wherein the BDNF is administered intranasally to the subject.

[0025] As used herein, the terms "treat", "treat", "prevent", and "prevent", respectively, refer to eradication / amelioration or prevention / delay of onset of a disorder or one or more symptoms associated therewith.

[0026] Preferably, the subject is a human subject.

[0027] According to one embodiment, the subject has been diagnosed with sensorineural hearing loss, and the BDNF is used to treat the sensorineural hearing loss by intranasal administration to the subject.

[0028] According to an alternative embodiment, the subject has been identified as being at risk for developing sensorineural hearing loss, and the BDNF is used to prevent the sensorineural hearing loss by intranasal administration to the subject.

[0029] Preferably, the sensorineural hearing loss is sensorineural hearing loss of non-hereditary etiology.

[0030] Preferably, the sensorineural hearing loss of non-genetic etiology is caused by noise exposure, bacterial or viral infection, treatment with ototoxic drugs, autoimmune disease or aging.

[0031] Preferably, the ototoxic drug is selected from chemotherapeutic drugs and aminoglycoside antibiotics, more preferably, it is selected from cisplatin, carboplatin and gentamicin.

[0032] Preferably, the BDNF is human BDNF, more preferably, it is recombinant human BDNF (recombinant human brain-derived neurotrophic factor, rhBDNF).

[0033] Preferably, the BDNF used according to the invention is administered one to three times daily for a treatment period of 7 to 300 days, preferably 60 to 240 days, more preferably 100 to 200 days.

[0034] Preferably, the amount of BDNF administered per time is 5 μg to 1 mg, more preferably 10 μg to 400 μg, even more preferably 15 μg to 200 μg.

[0035] In the case of treating SNHL, the effective amount of BDNF used in each administration, the duration of treatment and the number of daily administrations are selected by the skilled person based on the characteristics of the subject to be treated, the severity of SNHL and based on hearing tests performed during treatment.

[0036] In the case of preventing SNHL, the effective amount of BDNF used in each administration, the duration of treatment and the number of daily administrations are selected by the skilled person based on the characteristics of the subject at risk of developing SNHL and an assessment of the entity and duration of the risk of developing SNHL due to one of the causes.

[0037] Evaluation of the above factors is within the knowledge and expertise of the skilled artisan.

[0038] Another object of the invention relates to a pharmaceutical composition for intranasal administration comprising BDNF as defined above.

[0039] Preferably, the pharmaceutical composition for intranasal administration of the present invention is a liquid intranasal composition.

[0040] Preferably, the pharmaceutical composition according to the present invention comprises an effective amount of BDNF and at least one pharmaceutically acceptable excipient, preferably selected from solvents, thickeners, mucoadhesives, buffers, antioxidants, preservatives and penetration enhancers.

[0041] Preferably, the concentration of BDNF in the liquid intranasal composition according to the present invention is 5 μg / ml to 1 mg / ml, more preferably 10 μg / ml to 400 μg / ml, even more preferably 15 μg / ml to 200 μg / ml.

[0042] Preferably, the solvent is water.

[0043] Preferably, the antioxidant is methionine, more preferably at a concentration of 0.005 mg / ml to 0.02 mg / ml, more preferably at a concentration of 0.01 mg / ml.

[0044] Preferably, the surfactant is Kolliphor P188 (Poloxamer 188), more preferably at a concentration of 0.05% w / v to 0.2% w / v, more preferably at a concentration of 0.1% w / v.

[0045] The term "Kolliphor P188" as used herein refers to Poloxamer 188, a block copolymer which is a synthetic copolymer of ethylene oxide and propylene oxide represented by the following chemical structure:

[0046]

[0047] Wherein the a and b blocks have the following values:

[0048]

[0049] Preferably, the buffer is phosphate buffer.

[0050] Preferably, the penetration enhancer is n-dodecyl-β-D-maltoside, more preferably at a concentration of 0.1% w / v to 1% w / v, more preferably at a concentration of 0.5% w / v.

[0051] A particularly preferred liquid intranasal composition according to the present invention comprises, preferably consists of, BDNF, sodium chloride, phosphate buffer and water.

[0052] Another particularly preferred liquid intranasal composition according to the present invention comprises BDNF, sodium chloride, phosphate buffer, Kolliphor P188 (Poloxamer 188), L-methionine and water, preferably consists of BDNF, sodium chloride, phosphate buffer, Kolliphor P188 (Poloxamer 188), L-methionine and water.

[0053] Another particularly preferred liquid intranasal composition according to the present invention comprises BDNF, sodium chloride, phosphate buffer, Kolliphor P188 (Poloxamer 188), L-methionine, n-dodecyl-β-D-maltoside and water, preferably consists of BDNF, sodium chloride, phosphate buffer, Kolliphor P188 (Poloxamer 188), L-methionine, n-dodecyl-β-D-maltoside and water.

[0054] Preferably, the liquid intranasal composition according to the present invention comprises, preferably consists of, the following components:

[0055] - BDNF, preferably at a concentration of 5 μg / ml to 1 mg / ml, more preferably 10 μg / ml to 400 μg / ml, even more preferably 15 μg / ml to 200 μg / ml,

[0056] -NaH2PO4*H2O, preferably at a concentration of 5 to 8 mg / ml, more preferably at a concentration of 6.9 mg / mL, -NaCl, preferably at a concentration of 5 to 6.5 mg / ml, more preferably at a concentration of 5.84 mg / mL,

[0057] - Poloxamer 188, preferably in a concentration of 0.05% w / v to 0.2% w / v, more preferably in a concentration of 0.1% w / v,

[0058] - L-methionine, preferably at a concentration of 0.005 mg / ml to 0.02 mg / ml, more preferably at a concentration of 0.01 mg / ml,

[0059] - optionally, n-dodecyl-β-D-maltoside, preferably in a concentration of 0.1% w / v to 1% w / v, more preferably in a concentration of 0.5% w / v,

[0060] -water.

[0061] The pharmaceutical composition according to the present invention can be suitably formulated using appropriate methods known in the art or by the methods disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton Pa.

[0062] Preferably, as described above, the pharmaceutical composition of the present invention is used for preventing or treating sensorineural deafness in a subject, wherein the composition is administered intranasally to the subject.

[0063] In another aspect, the invention relates to a method for preventing or treating sensorineural hearing loss in a subject, comprising intranasally administering BDNF to the subject in a therapeutically effective amount as described above.

[0064] Preferably, in the method according to the invention, said BDNF is administered as described above.

[0065] Preferably, the BDNF used in the method of the invention is in the form of a pharmaceutical composition as defined above.

[0066] The present invention will be further described in the following examples, which do not limit the scope of the invention defined in the claims.

[0067] Experimental Section

[0068] Example 1

[0069] The bioavailability of recombinant human BDNF (rhBDNF) in the inner ear (perilymph) after a single intranasal administration was evaluated in 10-week-old C57BL6 mice (Envigo Labs, France).

[0070] The mice were divided into six groups:

[0071] Group 1 (n=4): control group, treated with PBS and sampled at 2 hours after treatment. Groups 2 to 6: rhBDNF-treated groups, perilymph was sampled at different time points: Group 2 (n=4): treated with rhBDNF and sampled at 2 hours.

[0072] Group 3 (n=4): treated with rhBDNF and sampled at 6 hours.

[0073] Group 4 (n=4): treated with rhBDNF and sampled at 12 hours.

[0074] Group 5 (n=4): treated with rhBDNF and sampled at 24 hours.

[0075] Group 6 (n=4): treated with rhBDNF and sampled at 48 hours.

[0076] Animals were treated as follows.

[0077] A micropipette was filled with 10 μl of a solution of rhBDNF (expressed in E. coli of Dompéfarmaceutici SpA) at 2 mg / ml in 50 mM sodium phosphate buffer, 100 mM NaCl, pH 7.2 (Groups 2 to 6) or with PBS (Group 1), and the tip of the filled pipette was placed near the left nostril of the mouse, maintaining a 45 degree angle, and releasing a drop of the contents, which was immediately inhaled by the mouse. After about 2 to 3 seconds, a second drop was released to allow the mouse to inhale through the same nostril. After administration, the mouse was kept in this position for 15 seconds.

[0078] All mice were sacrificed by cervical dislocation at relevant time points and the tympanic bulla was isolated. Each tympanic bulla was opened, the cochlea was washed with PBS, and 1 μl of cochlear perilymph was sampled from each cochlea using a capillary micropipette and immediately frozen in a low-binding Eppendorf tube and stored at −20°C prior to ELISA analysis. The contralateral cochlea was used as a replicate.

[0079] Cochlear perilymph samples were diluted 1 / 10 and 10 μl / well were analyzed by ELISA (Thermo Fisher, Ref. EH42RB).

[0080] The rhBDNF standard reference was diluted to 0, 0.066 ng / mL, 0.160 ng / mL, 0.410 ng / mL, 1.020 ng / mL, 2.560 ng / mL, 6.40 ng / mL and 16 ng / mL to plot a standard curve. The obtained rhBDNF standard curve exhibited a linear regression with an R square of 0.9997 and a slope of 0.1209 ± 0.0005206, allowing interpolation of the curve to determine the rhBDNF concentration in each mouse sample.

[0081] Add standard working solutions of different concentrations to the first two columns: add each concentration to two wells side by side, and add the samples to be analyzed to the other wells (10 μl / well). Cover the plate with the seal provided in the kit and incubate overnight at 4°C. Washing and incubation procedures are performed according to the manufacturer's instructions. At the end of the procedure, add 50 μl of stop solution to each well and immediately determine the optical density of each well using a microplate reader set to 450 nm.

[0082] The analysis results are Figure 1 Reported in.

[0083] from Figure 1 As can be seen in the Figures, a sustained and significant increase in rhBDNF concentration was observed in the perilymph from 2 hours to 48 hours after treatment in the rhBDNF treated group compared to the PBS treated control group. The concentration of rhBNDF reached a peak at 12 hours after administration, with a concentration of 9.91 ng / mL ± 1.02. Then, a decrease in rhBDNF concentration was observed at 24 hours and 48 hours after treatment, with concentrations (mean ± SEM) of 9.33 ng / mL ± 0.59 and 8.20 ng / mL ± 0.47, respectively. The data obtained indicate that intranasal administration of rhBDNF results in the delivery of the protein in the cochlear perilymph, with peak concentrations reached at 12 hours after treatment and accumulated until 48 hours after treatment, indicating that this route of administration is suitable for targeting hearing disorders.

[0084] Example 2

[0085] The efficacy of recombinant human BDNF (rhBDNF) administered by the intranasal route was tested in a cisplatin-induced hearing loss mouse model.

[0086] Specifically, male adult Wistar rats (Catholic University Laboratories, 200 to 250 g) of 2 months old with normal Preyer's reflex were used in this study. A total of 13 animals were subjected to the experiment, which were randomized and assigned to two experimental groups: Group 1: animals treated with cisplatin and phosphate buffer pH 7.2 (vehicle); ("Cis+vehicle" group; n=6), Group 2: animals treated with cisplatin and recombinant hBDNF ("Cis+rhBDNF" group; n=7).

[0087] All animals were treated with cisplatin (Catalog No. P4394, Sigma-Aldrich, St.Louis, MO, USA) at time 0. Specifically, cisplatin was diluted (1 mg / ml) in sterile saline and freshly prepared in dark. In order to promote drug dissolution, the solution was heated and stirred for a period of 20 minutes. Under deep anesthesia, a single cisplatin dose of 12 mg / kg was delivered intraperitoneally (intraperitoneally, ip) in about 30 minutes with an infusion pump (Axon Instruments, Foster City, CA, USA) at a flow rate of 8 ml / hours. Animals were highly hydrated (subcutaneous injection, 15 ml per day) with saline solution to limit cisplatin side effects.

[0088] Then, starting 1 hour after cisplatin treatment (day 0), rhBDNF (expressed in E. coli of Dompéfarmaceutici SpA) (2.4 mg / mL) (Group 2) or vehicle (Group 1) was administered daily by the intranasal route for 7 days. Using the dominant hand (without anesthesia), a micropipette (Gilson) was filled with 40 μl of rhBDNF or vehicle. The tip of the filled pipette was placed in the rat's nostril, maintaining a 45-degree angle. Each application consisted of gradually releasing two single drops of drug or vehicle in the nostrils (40 μl per nostril, 80 μl per animal). The drops were inhaled by the animal, being careful to prevent them from being transferred to the oral opening. The immobilized animals were placed in a supine position to facilitate the entry of the drug into the nostrils and absorption. At the end of each application, the rats were placed in their own cages to allow the nostrils to dry completely.

[0089] To evaluate the effects of hearing loss and rhBDNF administration caused by cisplatin treatment, hearing function was estimated by ABR recordings. In all animals, ABR was measured at low (6kHz), medium (12, 16 and 20kHz) and high (24 and 32kHz) frequencies on days 0 and 7 after the start of treatment. In all animals, bilateral ABR assessments were performed before treatment to ensure normal hearing and reassessed at all time points to evaluate the effects of treatment on hearing.

[0090] ABR recording is carried out as follows. All animals are lightly anesthetized (ketamine, 35mg / kg and medetomidine (medetomidine)-domitor, 0.25mg / kg) and placed in an anechoic chamber. Three stainless steel recording electrodes are subcutaneously inserted into the rear (working (active)) of the test auricle, the top of the skull (reference) and the contralateral auricle (grounding). The TDT System3 (Tucker Davis Technologies, Alachua, FL, USA) data acquisition system controlled by a PC with real-time digital signal processing is used for ABR recording and auditory stimulation generation. From 6 to 32kHz (rise / fall time is 1 millisecond, total duration is 10 milliseconds, and repetition rate is 20 / second) the short pure tone (tone burst) of pure tone is presented in a single ear. The response is filtered (0.3 to 3kHz), digitized and averaged (in 500 discrete samples under each frequency level combination). The threshold is defined as the lowest stimulus level that produces a repeatable waveform-based initialization.

[0091] The results obtained are Figure 2 Shown in.

[0092] As can be seen, in the groups treated with cisplatin and vehicle, an improvement of about 25 dB in threshold shift in all analyzed frequencies was observed, whereas treatment with rhBDNF reduced hearing loss by about 15 dB in low and mid frequencies, and by about 10 dB in high frequencies.

[0093] These data indicate that non-invasive intranasal administration of rhBDNF induced recovery of auditory function in an animal model of cisplatin ototoxicity.

[0094] Example 3

[0095] The present inventors have prepared the following exemplary pharmaceutical compositions obtained according to the preparation methods disclosed below.

[0096] Composition 1

[0097] rhBDNF (0.6 mg / mL)

[0098] 6.9mg / mL NaH2PO4*H2O

[0099] 5.84 mg / mL NaCl

[0100] 1mg / mL Kolliphor P188

[0101] 5mg / mL n-dodecyl-β-D-maltoside

[0102] 0.01mg / mL L-methionine

[0103] ·WFI

[0104] Dissolve 0.69 g NaH2PO4*H2O, 0.58 g NaCl and 0.1 g Kolliphor P188 in 100 mL water. Wait for complete dissolution and then add 0.5 g n-dodecyl-β-D-maltoside under magnetic stirring. After complete dissolution, add 0.001 g L-methionine. Adjust pH to 7 with NaOH.

[0105] After complete dissolution, the composition was filtered using a 0.22 μm filter.

[0106] Neurotrophic factors were added to the composition at a final concentration of 0.6 mg / mL.

[0107] Composition 2

[0108] rhBDNF (0.6 mg / mL)

[0109] 6.9mg / mL NaH2PO4*H2O

[0110] 5.84 mg / mL NaCl

[0111] 5mg / mL n-dodecyl-β-D-maltoside

[0112] 0.01mg / mL L-methionine

[0113] ·WFI

[0114] Dissolve 0.69 g NaH2PO4*H2O and 0.58 g NaCl in 100 mL water. Wait for complete dissolution and then add 0.5 g n-dodecyl-β-D-maltoside under magnetic stirring. After complete dissolution, add 0.001 g L-methionine. Adjust pH to 7 with NaOH.

[0115] After complete dissolution, the composition was filtered using a 0.22 μm filter.

[0116] Neurotrophic factors were added to the composition at a final concentration of 0.6 mg / mL.

Claims

1. Brain-derived neurotrophic factor (BDNF) for use in preventing or treating sensorineural hearing loss in a subject, wherein the BDNF is administered intranasally to the subject.

2. BDNF for use according to claim 1, wherein the sensorineural hearing loss is of non-genetic etiology.

3. The BDNF for use according to claim 2, wherein the sensorineural hearing loss of non-genetic etiology is caused by noise exposure, bacterial or viral infection, treatment with ototoxic drugs, autoimmune disease or aging.

4. The BDNF for use according to claims 1 to 3, wherein the BDNF is human BDNF, more preferably, the BDNF is recombinant human BDNF.

5. BDNF for use according to claims 1 to 4, wherein the BDNF is administered one to three times daily for a treatment period of 7 to 300 days, preferably 60 to 240 days, more preferably 100 to 200 days.

6. BDNF for use according to claims 1 to 5, wherein the amount of BDNF per administration is 5 μg to 1 mg, more preferably 10 μg to 400 μg, even more preferably 15 μg to 200 μg.

7. A pharmaceutical composition comprising, preferably consisting of: - BDNF, preferably at a concentration of 5 μg / ml to 1 mg / ml, more preferably 10 μg / ml to 400 μg / ml, even more preferably 15 μg / ml to 200 μg / ml, -NaH2PO4*H2O, preferably at a concentration of 5 to 8 mg / ml, more preferably at a concentration of 6.9 mg / mL, -NaCl, preferably at a concentration of 5 to 6.5 mg / ml, more preferably at a concentration of 5.84 mg / mL, - Poloxamer 188, preferably in a concentration of 0.05% w / v to 0.2% w / v, more preferably in a concentration of 0.1% w / v, - L-methionine, preferably at a concentration of 0.005 mg / ml to 0.02 mg / ml, more preferably at a concentration of 0.01 mg / ml, - optionally, n-dodecyl-β-D-maltoside, preferably in a concentration of 0.1% w / v to 1% w / v, more preferably in a concentration of 0.5% w / v, -water.

8. The pharmaceutical composition according to claim 7, wherein the BDNF is human BDNF, more preferably, the BDNF is recombinant human BDNF.

9. A pharmaceutical composition comprising BDNF and at least one pharmaceutically acceptable excipient for use in preventing or treating sensorineural hearing loss in a subject, wherein the composition is administered intranasally to the subject.

10. The pharmaceutical composition for use according to claim 9, wherein the BDNF is human BDNF, more preferably, the BDNF is recombinant human BDNF.

11. The pharmaceutical composition for use according to claim 9 or 10, wherein the BDNF is contained in the composition at a concentration of 5 μg / ml to 1 mg / ml, more preferably 10 μg / ml to 400 μg / ml, even more preferably 15 μg / ml to 200 μg / ml.

12. The pharmaceutical composition for use according to claims 9 to 11, comprising BDNF, sodium chloride, phosphate buffer and water, preferably consisting of BDNF, sodium chloride, phosphate buffer and water.

13. The pharmaceutical composition for use according to claims 9 to 12, wherein the sensorineural hearing loss of non-genetic etiology is caused by noise exposure, bacterial or viral infection, treatment with ototoxic drugs, autoimmune disease or aging.

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