4-Phenyl-tetrahydropyridine derivatives for the treatment of hearing disorders

Abstract

The present invention relates to 4-phenyl-tetrahydropyridine derivatives for use in the treatment of hearing disorders, in particular in the treatment of unilateral or bilateral sensorineural hearing loss and / or cochlear synaptopathy, optionally accompanied by tinnitus. The present invention also relates to pharmaceutical compositions allowing transtympanic administration of 4-phenyl-tetrahydropyridine derivatives and to pharmaceutical compositions for use in the treatment of hearing disorders, in particular in the treatment of unilateral or bilateral sensorineural hearing loss and / or cochlear synaptopathy, optionally accompanied by tinnitus.

Description

[Technical field]

[0001] The present invention relates to 4-phenyl-tetrahydropyridine derivatives for use in the treatment of hearing disorders, in particular in the treatment of unilateral or bilateral sensorineural hearing loss and / or unilateral or bilateral cochlear synaptic disorders, optionally accompanied by unilateral or bilateral tinnitus. The present invention also relates to pharmaceutical compositions allowing transtympanic administration of 4-phenyl-tetrahydropyridine derivatives and to pharmaceutical compositions for use in the treatment of hearing disorders, in particular in the treatment of unilateral or bilateral sensorineural hearing loss and / or unilateral or bilateral cochlear synaptic disorders, optionally accompanied by unilateral or bilateral tinnitus. [Background technology]

[0002] Among hearing disorders, sensorineural hearing loss (SNHL) is the most common type of permanent hearing loss, accounting for approximately 90% of reported hearing losses. In most cases, SNHL is caused by either aging (presbycusis) or exposure to excessive noise levels or ototoxic chemicals, which damage the inner and outer hair cells, resulting in temporary or permanent hearing loss (elevated hearing thresholds). There is currently no available drug therapy for SNHL, and hearing medical devices (such as hearing aids or cochlear implants) are the only solution to help patients hear.

[0003] In addition to the destruction of cochlear hair cells, excessive exposure to noise can also cause the destruction of synaptic connections between inner hair cells and the auditory nerve fibers of spiral ganglion neurons, known as excitotoxicity. The severed spiral ganglion neurons then gradually die and disappear over time. The result is cochlear synaptopathy, which may be a hidden form of hearing loss or be associated with hearing loss. Patients suffering from cochlear synaptopathy have reduced speech-in-noise intelligibility. Furthermore, cochlear synaptopathy is often associated with the development of tinnitus and / or hyperacusis. However, there is currently no available treatment for cochlear synaptopathy.

[0004] It is therefore an object of the present invention to provide a means for treating hearing disorders such as hearing loss, cochlear synaptic disorders, and tinnitus, particularly hearing loss that is sensorineural hearing loss.

[0005] In the prior art, WO 9848802 describes the use of tetrahydropyridine derivatives to prepare medicaments for treating diseases that cause demyelination, such as multiple sclerosis. However, there is no suggestion in the prior art that 4-phenyl-tetrahydropyridine derivatives can lead to improvement of hearing function.

[0006] Nevertheless, the present inventors have surprisingly found that 4-phenyl-tetrahydropyridine derivatives, such as paliproden and xaliproden, exhibit beneficial effects resulting in improved hearing function, improved speech intelligibility in quiet, improved speech intelligibility in noise, and are accompanied by reduced auditory brainstem response (ABR) threshold shifts following noise exposure. Summary of the Invention

[0007] The present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment of a hearing disorder in a subject, Formula (I) is [ka] (I) During the ceremony: R1 is a halogen atom, a CF3 group, a (C1-C4) alkyl group or a (C1-C4) alkoxy group; R2 and R3 are independently a hydrogen atom or a (C1-C3) alkyl group; A is: a phenyl radical substituted by a substituent X, X being: (a) a group selected from (C3-C6)cycloalkyl, (C3-C6)cycloalkylmethyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkylamino, and cyclohexenyl; or (b) a group selected from phenyl, phenylmethyl, phenylcarbonyl, phenoxy, phenylamino, N-(C1-C3)alkylphenylamino, phenylthio, phenylsulfinyl, and phenylsulfonyl a phenyl radical, - 1-naphthyl or 2-naphthyl radicals, which are unsubstituted or substituted in the 5-, 6-, 7- and / or 8-positions by one or two hydroxyl groups, one or two (C1-C4)alkoxy groups, or a 6,7-methylenedioxy group; It is.

[0008] Preferably, R1 is a CF3 group.

[0009] Preferably, at least one of R2 and R3 is a hydrogen atom, and more preferably, R2 and R3 are each a hydrogen atom.

[0010] Preferably, A is a biphenyl radical or an unsubstituted 2-naphthyl radical.

[0011] Preferably the salt is the hydrochloride or fumarate salt of the compound of formula (I).

[0012] Advantageously, the compound is administered to the subject by oral route or by transtympanic route.More advantageously, the compound is administered to the subject by oral route or by transtympanic route, where transtympanic route administration consists of injection between the tympanic membrane and the round window through the tympanic membrane.Even more preferably, the compound is administered to the subject by transtympanic route, where transtympanic route administration consists of injection between the tympanic membrane and the round window through the tympanic membrane through the round window.

[0013] Advantageously, the compound is administered by the transtympanic route at a dose ranging from 10 μg to 400 mg, between once a month and once every 12 months.Preferably, said administration by the transtympanic route consists of an injection between the tympanic membrane and the round window, using a needle through the tympanic membrane.

[0014] Preferably, the hearing disease is selected from the group consisting of unilateral or bilateral hearing loss, unilateral or bilateral tinnitus, unilateral or bilateral hyperacusis, hidden hearing loss, such as cochlear synaptopathy with normal thresholds, reduced speech intelligibility, unilateral or bilateral temporary hearing threshold shift, central auditory processing disorder, unilateral or bilateral auditory recruitment, acoustic neuroma, unilateral severe hearing loss, excitotoxicity, ototoxicity, such as drug-induced ototoxicity, and any combination thereof. More preferably, the hearing disease is selected from the group consisting of unilateral and bilateral hearing loss, such as unilateral and bilateral sensorineural hearing loss, unilateral or bilateral tinnitus, unilateral or bilateral hyperacusis, hidden hearing loss, such as cochlear synaptopathy with normal thresholds, and reduced speech intelligibility.

[0015] Preferably, the hearing disease is unilateral or bilateral sensorineural hearing loss selected from the group consisting of unilateral or bilateral noise-induced sensorineural hearing loss, unilateral or bilateral inflammation-induced sensorineural hearing loss, unilateral or bilateral sudden idiopathic sensorineural hearing loss, unilateral or bilateral ototoxic chemical-induced sensorineural hearing loss, and unilateral or bilateral age-induced sensorineural hearing loss, such as presbycusis. More preferably, the hearing disease is unilateral or bilateral sensorineural hearing loss selected from the group consisting of unilateral or bilateral noise-induced sensorineural hearing loss and unilateral or bilateral age-induced sensorineural hearing loss.

[0016] Preferably, the hearing disease is unilateral or bilateral inflammation-induced sensorineural hearing loss caused by a chronic inflammatory disease, more preferably the chronic inflammatory disease is selected from the group consisting of diabetes, chronic kidney disease, inflammatory bowel disease, and rheumatoid arthritis.

[0017] Preferably, the hearing disorder is unilateral or bilateral hearing loss with a tonal audiometric threshold of more than 30 dB at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus. More preferably, the hearing disorder is unilateral or bilateral hearing loss with a tonal audiometric threshold of 30 dB to 70 dB at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus, the tonal hearing threshold being measured by auditory brainstem response or pure tone audiometry.

[0018] Preferably, the hearing disorder is selected from the group consisting of labyrinth dysfunction, vestibular neuronitis, acute unilateral vestibular neuropathy, benign paroxysmal positional vertigo, central vertigo, Meniere's disease, Meniere's syndrome, and any combination thereof.

[0019] In one embodiment, the subject is fitted with at least one hearing device.

[0020] Advantageously, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to the subject during cochlear surgery, for example during cochlear implant surgery.

[0021] Advantageously, the subject is a mammal having a tympanic membrane, preferably said mammal having a tympanic membrane is selected from the group consisting of humans, cats, dogs, and non-human primates, more preferably said mammal having a tympanic membrane is a dog.

[0022] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to the present invention or a pharma- ceutically acceptable salt and / or solvate thereof and at least one pharma- ceutically acceptable excipient selected from the group consisting of poloxamers, polyethoxylated castor oils, phospholipids, triglycerides, and any combination thereof.

[0023] The present invention also relates to a transtympanic pharmaceutical composition comprising a combination of a compound of formula (I) according to the invention or a pharma- ceutically acceptable salt and / or solvate thereof and a mixture of a polyoxyethylated triglyceride and a poloxamer, said pharmaceutical composition being a thermoreversible gel.

[0024] The present invention further relates to a pharmaceutical composition for use in treating an auditory disorder in a subject, said pharmaceutical composition comprising a compound of formula (I) according to the invention or a pharma- ceutically acceptable salt and / or solvate thereof and at least one pharma- ceutically acceptable excipient. Preferably, said auditory disorder is as defined herein.

[0025] definition In the present invention, the following terms have the following meanings:

[0026] "About" before a number or numeral refers to plus or minus 10% of the amount of that number or numeral. In one embodiment, "about" before a number or numeral refers to plus or minus 5% of the amount of that number or numeral.

[0027] "Active agent" refers to an agent that has a therapeutic effect. The agent may be a chemical or a biological agent. Preferably, the active agent is a chemical. The therapeutic effect may be prevention, delay, reduction in the severity and / or frequency of at least one symptom associated with a pathological condition, or suppression of at least one symptom associated with a pathological condition, or prevention, slowing or suppression of the underlying cause of a pathological condition, or amelioration or repair of damage.

[0028] "Alkyl" by itself or as part of another substituent refers to a linear, saturated hydrocarbyl group. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, n-hexyl, iso-hexyl, and tert-hexyl. Preferred alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and tert-butyl. "Cycloalkyl" by itself or as part of another substituent refers to a cyclic, saturated hydrocarbyl group. "Alkoxy" refers to -O-alkyl. "Cycloalkoxy" refers to -O-cycloalkyl. "Cycloalkylamino" refers to -NH-cycloalkyl.

[0029] "Audiometry threshold" or "tone hearing threshold" or "hearing threshold" or "threshold" refers to the sound level below which the human ear cannot detect any sound, i.e., the "threshold" is the hearing level at which the test stimulus is barely audible. Audiometric thresholds can be measured objectively, for example, by auditory brainstem h-response, or subjectively by pure-tone hearing tests. "ABR threshold" refers to the threshold measured by auditory brainstem response. "Pure-tone hearing threshold" refers to the threshold measured by pure-tone hearing tests. "Normal threshold" is -10 to 15 dB. "Elevated threshold" refers to a threshold of 16 dB or higher.

[0030] "Auditory brainstem response" or "ABR" refers to auditory evoked potentials extracted from ongoing electrical activity in the brain and recorded via electrodes placed on the scalp.

[0031] "Buffer" refers to a mixture of a weak acid and its conjugate base, or a weak base and its conjugate acid, which, when a small amount of a strong acid or base is added thereto, can maintain a constant pH of a pharmaceutical composition. In one embodiment, the buffer is a phosphate buffer. In one embodiment, the buffer is a bicarbonate buffer. A "phosphate buffer" is a buffer that contains a phosphate or a derivative thereof as a buffering agent. A "bicarbonate buffer" is a buffer that contains a bicarbonate or a derivative thereof as a buffering agent.

[0032] "Buffering agent" refers to a specific chemical that exists in both acidic and basic forms in a buffer solution, allowing the pH of the pharmaceutical composition to be maintained constant. In one embodiment, the buffering agent is a phosphate or a derivative thereof. In another embodiment, the buffering agent is a bicarbonate or a derivative thereof.

[0033] "Chronic disease" refers to a long-term, progressive illness, often with the threat of disability and serious complications. A chronic disease progresses more or less rapidly over a period of at least several months, particularly at least 3 months.

[0034] "Chronic inflammatory disease" refers to a chronic disease that includes among its causes and / or symptoms and / or consequences a chronic inflammatory response affecting one or more organs or tissues, which chronic inflammatory response lasts for at least 3 months. In one embodiment, the chronic inflammatory disease is selected from the group consisting of rheumatoid arthritis, chronic inflammatory bowel disease (IBD) (consisting of Crohn's disease (CD) and ulcerative colitis (UC)), type 1 diabetes, type 2 diabetes, chronic kidney disease (CKD), psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, inflammatory myopathy, systemic lupus erythematosus, Gougereau-Sjogren's syndrome, scleroderma, and thyroiditis. In a preferred embodiment, the chronic inflammatory disease is selected from the group consisting of rheumatoid arthritis, Crohn's disease, ulcerative colitis, type 1 diabetes, type 2 diabetes, and chronic kidney disease. In a more preferred embodiment, the chronic inflammatory disease is type 2 diabetes.

[0035] "Cochlear hair cells" refers to hair cells distributed in the tonal tissue along the cochlea. They code a wide range of sound frequencies, from high to low frequency sounds, respectively, from the base to the tip of the cochlea; they include inner hair cells and outer hair cells. "Inner hair cells" (IHCs) code sound waves into electrical signals that are sent via the auditory nerve to the cochlear nucleus in the brainstem, then transmitted through the central auditory system, and finally to the auditory cortex; they are essential for hearing, and code a wide range of sound intensities by gradually recruiting a variety of type I afferent nerve fibers, ranging from high spontaneous and low threshold nerve fibers that code low intensity sounds to low spontaneous and high threshold nerve fibers that code high intensity sounds. "Outer hair cells" (OHCs), which connect to type II afferent and efferent nerve fibers, amplify low intensity sounds through adaptive contraction activities, and are therefore involved in hearing sensitivity. OHCs are more sensitive than IHCs to damage induced by excessive noise levels and / or ototoxic chemicals.

[0036] "Cochlear synaptopathy" refers to a hearing disorder. This is due to a decrease in the number of synapses between the IHCs and the nerve fibers of the spiral ganglion neurons (SGNs). The cause of cochlear synaptopathy can be exposure to excessive noise levels, which causes the destruction of synaptic connections between the inner hair cells of SGNs and the auditory nerve fibers due to the release of excess glutamate (known as excitotoxicity), and then the severed SGNs die and gradually disappear. Cochlear synaptopathy is characterized by changes in speech intelligibility; patients with cochlear synaptopathy have difficulty accurately processing speech information in the presence of background noise, i.e., they have a deficit in speech intelligibility in noise. Advantageously, the subject with cochlear synaptopathy can be a human being between 40 and 65 years of age.

[0037] Cochlear synaptopathy can be either a covert form of hearing loss (ie, cochlear synaptopathy with normal thresholds) or one that is associated with hearing loss (ie, cochlear synaptopathy associated with elevated thresholds).

[0038] Patients with "cochlear synaptopathy with normal thresholds" have normal hearing thresholds. Cochlear synaptopathy with normal thresholds is a hidden form of hearing loss, also called sub-clinical form of hearing loss. Cochlear synaptopathy with normal thresholds is a hearing disorder characterized by altered speech intelligibility while hearing is preserved at normal thresholds. Thus, patients with cochlear synaptopathy with normal thresholds have difficulty accurately processing speech information in the presence of background noise, i.e., they have normal hearing thresholds but a deficit in speech intelligibility in noise.

[0039] Patients with "cochlear synaptopathy associated with elevated thresholds" have elevated hearing thresholds, particularly hearing thresholds between 16 and 40 dB. Cochlear synaptopathy associated with elevated thresholds is a hearing loss accompanied by changes in speech intelligibility. Patients with cochlear synaptopathy associated with elevated thresholds have difficulty accurately processing speech information in the presence of background noise, i.e., deficits in speech intelligibility in noise, and elevated hearing thresholds.

[0040] "Comprising" or "comprise" is to be interpreted in an open and inclusive sense, but is not limited to this. In one embodiment, "comprising" means "consisting essentially of." In one embodiment, "comprising" means "consisting of," which is to be interpreted as being limited.

[0041] "Three consecutive frequencies" refers to three consecutive frequencies selected from the following frequencies: 0.25 kHz, 0.5 kHz, 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz, 8 kHz, 12 kHz and 16 kHz. Preferably, the three consecutive frequencies are selected from the following frequencies: 0.25 kHz, 0.5 kHz, 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz and 8 kHz. For example, the three consecutive frequencies are: -0.5kHz, 1kHz, and 2kHz (corresponding to the audio frequency range); -1kHz, 2kHz, 4kHz (corresponding to the mid-frequency range); -4kHz, 6kHz, and 8kHz (corresponding to the high frequency range); -8kHz, 12kHz, 16kHz (corresponding to the extended high frequency range) may be selected from the group consisting of:

[0042] "dB SPL" refers to decibels relative to the sound pressure threshold of human hearing. "dB SPL RMS" refers to the average dB SPL measurement. SPL = Sound Pressure Level. RMS = Root Mean Square.

[0043] "Dose" refers to the amount of active agent administered at one time. In one embodiment, two oral doses are administered to one subject at an interval of 8 hours to one week, preferably at an interval of 12 hours to 24 hours, more preferably at an interval of about 24 hours. In one embodiment, two transtympanic doses are administered to one subject at an interval of 1 week to 12 months, for example at an interval of 1 week, 12 weeks, 1 month, 3 months, 6 months, or 12 months; preferably, two transtympanic doses are administered to one subject at an interval of 1 month. Advantageously, the human dose is a standard human dose for a male weighing 70 kg.

[0044] "Tympanic membrane" refers to the membrane that separates the outer ear from the middle ear.

[0045] "Excipient" refers to any inactive ingredient required for the formulation of an active agent in a suitable dosage form. In one embodiment, "excipient" refers to any and all solvents, diluents, carriers, fillers, bulking agents, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonicity agents, thickening or emulsifying agents, stabilizers, absorption enhancers, flavoring agents, preservatives, antioxidants, buffers, gelling agents, solubilizers, or any combination thereof. Excipients are, by definition, inert, but for the sake of clarity, the term "excipient" according to the present invention is expressly stated to refer to non-ototoxic excipients.

[0046] "X~Y" refers to a range of values ​​between X and Y, where the area of ​​X and Y is included in the range.

[0047] "Gel" refers to a three-dimensional network (forming a matrix) of solid elements diluted in a liquid (acting as a foaming agent). Gels do not exhibit flowability in the stable state and have properties ranging from soft and ductile to hard and brittle. "Thermoreversible gel" refers to a gel that has a melting point above which it becomes a viscous fluid and flows, and below which it is in a gel state, and the junctions of said thermoreversible gels are thermally reversible.

[0048] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0049] "Hearing disorder" refers to a disorder that affects hearing or the ear (e.g., an ear infection such as otitis externa). In one embodiment, "hearing disorder" refers to a disorder that affects hearing. A disorder that affects hearing may affect hearing thresholds or speech intelligibility, such as speech intelligibility in noise.

[0050] "Hearing loss" refers to a hearing disorder characterized by an elevation in hearing threshold of 16 dB or more. Hearing loss can be temporary or permanent. Slight hearing loss is characterized by a threshold between 16 and 25 dB. Mild hearing loss is characterized by a threshold between 26 and 40 dB. Moderate hearing loss is characterized by a threshold between 41 and 55 dB. Moderately severe hearing loss is characterized by a threshold between 56 and 70 dB. Profound hearing loss is characterized by a threshold between 71 and 90 dB. Profound hearing loss is characterized by a threshold of 91 dB or greater.

[0051] "Hidden forms of hearing loss" or "subclinical forms of hearing loss" refer to hearing disorders characterized by changes in speech intelligibility while hearing is maintained at normal thresholds. Thus, patients with hidden forms of hearing loss, such as cochlear synaptopathy with normal thresholds, have difficulty accurately processing speech information in the presence of background noise, i.e., they have normal hearing thresholds but deficits in speech intelligibility in noise.

[0052] A "lipid-based solution" refers to a solution in which the solvent comprises at least one lipid. Preferably, the solvent comprises at least 20% of at least one lipid, more preferably at least 40%, and even more preferably at least 50%, by weight of the total solvent.

[0053] "Mucooadhesive" refers to a substance or composition that adheres to the mucous membrane of the ear. In one embodiment, "mucoadhesive" refers to a substance or composition that adheres to the mucous membrane of the middle ear.

[0054] "Ototoxic chemical" refers to a chemical that, when absorbed into the bloodstream of a subject, can induce hearing loss in a subject. Ototoxic chemicals can be solvents (e.g., butanol, carbon disulfide, ethanol), heavy metals (e.g., arsenic, lead, manganese), asphyxiants (e.g., acrylonitrile, carbon monoxide, hydrogen cyanide), or pharmaceuticals (e.g., platinum-based antineoplastics, aminoglycosides). In one embodiment, "ototoxic chemical" refers to an ototoxic pharmaceutical, such as a platinum-based antineoplastic or an aminoglycoside.

[0055] "Palirodene" refers to the chemical molecule 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, of the following chemical formula: [ka]

[0056] A "pharmaceutical composition" refers to a combination of at least one active agent and at least one pharma- ceutically acceptable excipient.

[0057] "Pharmaceutically acceptable" refers to something that is generally safe, non-toxic and not biologically, physiologically or otherwise undesirable to mammals, particularly humans, dogs, cats, and non-human primates.

[0058] "Phenylcarbonyl" refers to -CO-phenyl. "Phenoxy" refers to -O-phenyl. "Phenylamino" refers to -NH-phenyl. "Phenylthio" refers to -S-phenyl. "Phenylsulfinyl" refers to -SO-phenyl. "Phenylsulfonyl" refers to -SO2-phenyl.

[0059] "Placebo" or "vehicle" refers to a pharmaceutical composition that contains only a pharma- ceutically acceptable excipient(s) and no active agents.

[0060] "Poloxamer" refers to a block terpolymer of polyethylene glycol-polypropylene glycol-polyethylene glycol.

[0061] "Poloxamer 188" is a poloxamer with an average molecular weight of 8,400 g / mol.

[0062] "Poloxamer 407" is a poloxamer with an average molecular weight of 12,600 g / mol, two PEG block lengths of approximately 101 repeat units, and a propylene glycol block length of approximately 56 repeat units.

[0063] "Pure tone audiometry" refers to the measurement of an individual's hearing sensitivity to calibrated pure tones.

[0064] "Residual hearing" refers to the physiological hearing in a patient with hearing loss, and therefore does not take into account the eventual hearing gain induced by the hearing aid if the patient has a hearing aid such as a cochlear implant.

[0065] "Salt of a compound" refers to an acid or base addition salt of the compound described above. Acid addition salts are formed with pharma- ceutically acceptable organic or inorganic acids; base addition salts are formed when an acid proton present in the compound is replaced by a metal ion or coordinated with a pharma- ceutically acceptable organic or inorganic base. In one embodiment, the acid addition salt is an acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isothiocyanate, ... The base addition salt is selected from the group consisting of thionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. In one embodiment, the base addition salt is selected from the group consisting of aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts. According to a preferred embodiment, the salt is selected from the group consisting of besylate, fumarate, and hydrochloride / chloride salts.

[0066] "Sensorineural hearing loss" or "SNHL" refers to the most common type of hearing disease in adults due to loss of function of the sensory hair cells in the cochlea. The cause of SNHL can be exposure to excessive noise levels and / or ototoxic chemicals, such as platinum-based antineoplastic drugs and aminoglycosides, which cause damage to the inner and outer hair cells, resulting in temporary or permanent hearing loss.

[0067] A "solvate of a compound" refers to a molecular complex comprising a compound and one or more pharma- ceutically acceptable solvent molecules. A "hydrate of a compound" refers to a molecular complex comprising a compound and one or more pharma- ceutically acceptable solvent molecules, where the solvent is water.

[0068] A "subject" or "patient" refers to a mammal, where "mammal" refers to a human or non-human mammal. Preferably, "subject" refers to a mammalian animal having a tympanic membrane. In one embodiment, "subject" refers to a human (male or female). According to a preferred embodiment, "subject" refers to a human aged 18 years or older, preferably aged 40 years or older, preferably aged 50 years or older, more preferably aged 65 years or older. In particular, "subject" may refer to a human aged 40 to 65 years. In another embodiment, "subject" refers to a non-human mammal, preferably a non-human mammal selected from the group consisting of cats, dogs, horses, and non-human primates such as monkeys. According to a preferred embodiment, "subject" refers to a non-human mammal selected from the group consisting of cats and dogs, more preferably, "subject" refers to a non-human mammal, where the non-human mammal is a dog.

[0069] A "sustained release composition" refers to a composition that allows for release of its active agent(s) over an extended period of time, preferably at least 12 hours, more preferably at least 24 hours, and even more preferably at least one week.

[0070] A "therapeutically effective amount" or "effective amount" of an active agent or composition refers to a nontoxic but sufficient amount of the active agent or composition to produce the desired therapeutic effect.

[0071] "Tinnitus" refers to a hearing disorder in which the patient hears intermittent or continuous non-existent noises that are not caused by sounds from the outside world and therefore cannot be heard by anyone other than the patient. Such noises can be ringing, buzzing, humming, hissing, throbbing, musical or singing sounds. Tinnitus is a common problem; it affects about 15% of people.

[0072] "Transtympanic administration" or "intratympanic administration" or "administration via the transtympanic route" refers to administration of an active agent or composition through the ear canal and across the tympanic membrane.

[0073] In one embodiment, transtympanic administration consists of administering an active agent or composition in the ear canal, where the active agent or active agent of the composition can pass through the tympanic membrane, for example by diffusion. The formulation of the active agent or composition may be any formulation suitable for administration in the ear canal. Preferably, the formulation of the active agent or composition is selected from the group consisting of a semi-solid formulation, a gel formulation and a liquid formulation. The liquid formulation may be selected from the group consisting of a suspension, an emulsion and a solution. The gel formulation may be selected from the group consisting of a thermoreversible gel, a hydrogel, a glycerin-based gel, a binding gel, a cross-linked gel and an alginate-based gel. The formulation of the active agent or composition may be a systemic administration formulation, a diffusion administration formulation or an erodible formulation. More preferably, the formulation of the active agent or composition is selected from the group consisting of a gel formulation and a liquid formulation, for example an ear gel or ear drops.

[0074] In another embodiment, transtympanic administration consists of an injection between the tympanic membrane and the cochlear window using a needle through the tympanic membrane. After transtympanic injection, the injected substance diffuses through the cochlear window into the cochlea. Preferably, the gauge of the needle is between 21 and 33, more preferably between 21 and 30, more preferably between 24 and 30, even more preferably between 25 and 30, even more preferably between 25 and 27, even more preferably between 25 and 26. In particular, the gauge of the needle may be selected from the group consisting of 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33. More preferably, the needle is a 26 gauge needle (= 26G needle). Advantageously, the needle is selected from the group consisting of a transtympanic injection needle and a spinal needle. Even more advantageously, the needle is a transtympanic injection needle. For example, the needle may be the product "MediPlast ENT, Otorhinolaryngology, Transtympanic Injection Needle, Single Use, 0.4x90mm with Luer Lock" sold by Mediplast®. Preferably, the formulation of the active agent or composition is selected from the group consisting of a semi-solid formulation, a gel formulation and a liquid formulation. The liquid formulation may be selected from the group consisting of a suspension, an emulsion and a solution. The solution may be a mucoadhesive solution, in particular a lipid-based mucoadhesive solution. The gel formulation may be selected from the group consisting of a thermoreversible gel, a hydrogel, a glycerin-based gel, a binding gel, a cross-linked gel and an alginate-based gel. The formulation of the active agent or composition may be a systemic administration formulation, a diffusion administration formulation or an erodible formulation.

[0075] More preferably, the formulation of the active agent or composition is selected from the group consisting of a gel formulation and a liquid formulation.More preferably, the formulation of the active agent or composition is selected from the group consisting of a thermoreversible gel and a solution; the solution is in particular a mucoadhesive solution, more particularly a lipid-based mucoadhesive solution.

[0076] "Treating" or "treatment" refers to any action that prevents, delays, reduces, or inhibits the severity and / or frequency of at least one symptom associated with a pathological condition, or prevents, slows, or inhibits the underlying cause of a pathological condition, or allows for amelioration or repair of damage. In one embodiment, "treatment" refers to curative treatment. In another embodiment, "treatment" refers to prophylactic treatment. In another embodiment, "treatment" refers to prophylactic and / or curative treatment.

[0077] "Unilateral or bilateral" refers to a hearing disorder that can affect either one ear (which is a unilateral hearing disorder) or both ears (which is a bilateral hearing disorder). Unilateral hearing disorders can affect either the right or left ear.

[0078] "Xaliproden" refers to the chemical molecule 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, having the following chemical formula: [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] Compounds for Use Formula (I)

[0080] The present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment of a hearing disorder in a subject.

[0081] The present invention also relates to a method of treating a hearing disorder by administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof.

[0082] The present invention also relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment of a hearing disorder in a subject.

[0083] The present invention also relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof for the treatment of a hearing disorder in a subject.

[0084] Formula (I) is: [ka] (I) During the ceremony: R1 is a halogen atom, a CF3 group, a (C1-C4) alkyl group or a (C1-C4) alkoxy group; R2 and R3 are independently a hydrogen atom or a (C1-C3) alkyl group; A is: a phenyl radical substituted by a substituent X, where X is: (a) a group selected from (C3-C6)cycloalkyl, (C3-C6)cycloalkylmethyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkylamino, and cyclohexenyl; or (b) a group selected from phenyl, phenylmethyl, phenylcarbonyl, phenoxy, phenylamino, N-(C1-C3)alkylphenylamino, phenylthio, phenylsulfinyl, and phenylsulfonyl a phenyl radical which is - 1-naphthyl or 2-naphthyl radicals, either unsubstituted or substituted in the 5-, 6-, 7- and / or 8-positions by one or two hydroxyl groups, one or two (C1-C4)alkoxy groups, or a 6,7-methylenedioxy group; It is.

[0085] Preferably, R1 is a CF3 group.

[0086] Preferably, at least one of R2 and R3 is a hydrogen atom. More preferably, R2 and R3 are each a hydrogen atom.

[0087] Preferably, A is a biphenyl radical or an unsubstituted 2-naphthyl radical.

[0088] According to one embodiment, in the above formula (I): R1 is a halogen atom, a CF3 group, or a (C1-C4)alkoxy group; R2 and R3 are independently a hydrogen atom or a (C1-C3) alkyl group; A is: a phenyl radical substituted with a substituent X, where X is a group selected from phenyl, phenylmethyl, phenylcarbonyl, phenoxy, phenylamino, N-(C1-C3)alkylphenylamino, phenylthio, phenylsulfinyl and phenylsulfonyl; or - 1-naphthyl or 2-naphthyl radicals, either unsubstituted or substituted in the 5-, 6-, 7- and / or 8-positions by one or two hydroxyl groups, one or two (C1-C4)alkoxy groups, or a 6,7-methylenedioxy group; It is.

[0089] According to one embodiment, in the above formula (I): R1 is a halogen atom, a CF3 group, or a (C1-C4)alkoxy group; R2 and R3 are independently a hydrogen atom or a (C1-C3) alkyl group; A is: -biphenyl; or -unsubstituted 1-naphthyl or 2-naphthyl radical, preferably unsubstituted 2-naphthyl radical It is.

[0090] According to one embodiment, in the above formula (I): R1 is a halogen atom, a CF3 group, or a (C1-C4)alkoxy group; R2 and R3 are independently a hydrogen atom or a (C1-C3) alkyl group; A is biphenyl.

[0091] According to one embodiment, in the above formula (I): R1 is a halogen atom, a CF3 group, or a (C1-C4)alkoxy group; R2 and R3 are independently a hydrogen atom or a (C1-C3) alkyl group; A is an unsubstituted 2-naphthyl radical.

[0092] According to a preferred embodiment, formula (I) is: [ka] It is. According to this embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, also known as palylodene, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0093] According to another preferred embodiment, formula (I) is: [ka] It is. According to this embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, also known as xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0094] Advantageously, the salts are selected from the group consisting of the hydrochloride, fumarate and besylate salts of the compounds of formula (I), and even more advantageously, the salts are selected from the group consisting of the hydrochloride and fumarate salts of the compounds of formula (I).

[0095] According to a preferred embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is the fumarate salt of 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, also known as palylodene fumarate.

[0096] According to another preferred embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is the hydrochloride salt of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, also known as xaliproden hydrochloride.

[0097] Indications According to the present invention, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined above is for use in the treatment of a hearing disorder in a subject.

[0098] According to one embodiment, the hearing disease is selected from the group consisting of unilateral or bilateral hearing loss, unilateral or bilateral tinnitus, hidden hearing loss such as cochlear synaptopathy with normal threshold, otosclerosis such as non-obstructive and obstructive otosclerosis with oval window and cochlear otosclerosis, acoustic neuroma, unilateral severe hearing loss, ototoxicity such as drug-induced ototoxicity, labyrinth dysfunction, vestibular neuronitis, excitotoxicity, autoimmune inner ear disease, acute unilateral vestibular neuropathy, benign paroxysmal positional vertigo, central vertigo, Meniere's disease, Meniere's syndrome, unilateral or bilateral auditory recruitment, diplopia, unilateral or bilateral hyperacusis, unilateral or bilateral temporary hearing threshold shift, central auditory processing disorder, and any combination thereof.

[0099] Advantageously, the unilateral or bilateral hearing loss is selected from the group consisting of unilateral or bilateral sensorineural hearing loss, unilateral or bilateral cochlear synaptic damage associated with elevated thresholds, and unilateral or bilateral mixed conductive and sensorineural hearing loss.Preferably, the unilateral or bilateral sensorineural hearing loss is selected from the group consisting of unilateral or bilateral noise-induced sensorineural hearing loss, unilateral or bilateral inflammation-induced sensorineural hearing loss, unilateral or bilateral sudden idiopathic sensorineural hearing loss, unilateral or bilateral ototoxic chemical-induced sensorineural hearing loss, and unilateral or bilateral age-induced sensorineural hearing loss, such as presbycusis.More preferably, the unilateral or bilateral sensorineural hearing loss is selected from the group consisting of unilateral or bilateral noise-induced sensorineural hearing loss, unilateral or bilateral age-induced sensorineural hearing loss, such as presbycusis, and unilateral or bilateral inflammation-induced sensorineural hearing loss. The unilateral or bilateral inflammation-induced sensorineural hearing loss may be induced by chronic inflammatory disease. More preferably, the unilateral or bilateral sensorineural hearing loss is selected from the group consisting of unilateral or bilateral noise-induced sensorineural hearing loss and unilateral or bilateral age-induced sensorineural hearing loss such as presbycusis. Preferably, the unilateral or bilateral cochlear synaptopathy associated with elevated threshold is selected from the group consisting of unilateral or bilateral noise-induced cochlear synaptopathy associated with elevated threshold, unilateral or bilateral inflammation-induced cochlear synaptopathy associated with elevated threshold, and unilateral or bilateral age-induced cochlear synaptopathy associated with elevated threshold. In particular, the unilateral or bilateral noise-induced cochlear synaptopathy associated with elevated threshold may be induced by chronic noise exposure. In particular, the unilateral or bilateral inflammation-induced cochlear synaptopathy associated with elevated threshold may be induced by chronic inflammatory disease.

[0100] According to a preferred embodiment, the hearing disease is selected from the group consisting of unilateral and bilateral sensorineural hearing loss, unilateral and bilateral cochlear synaptopathy associated with elevated thresholds, unilateral or bilateral tinnitus, cochlear synaptopathy with normal thresholds, acoustic neuroma, sudden idiopathic hearing loss, drug-induced hearing loss, unilateral severe hearing loss, excitotoxicity, ototoxicity, drug-induced ototoxicity, labyrinth dysfunction, vestibular neuronitis, acute unilateral vestibular neuropathy, benign paroxysmal positional vertigo, central vertigo, Meniere's disease and Meniere's syndrome.

[0101] According to a preferred embodiment, the hearing disease is selected from the group consisting of unilateral or bilateral hearing loss, unilateral or bilateral tinnitus, hidden hearing loss such as cochlear synaptopathy with normal thresholds, otosclerosis such as non-obstructive and obstructive otosclerosis with oval window and cochlear otosclerosis, acoustic neuroma, unilateral severe hearing loss, ear infection, drug-induced ototoxicity, excitotoxicity, acute unilateral vestibular neuropathy, ototoxicity such as vestibular neuronitis, and any combination thereof.

[0102] According to a more preferred embodiment, the hearing disease is selected from the group consisting of unilateral or bilateral hearing loss, unilateral or bilateral tinnitus, hidden hearing loss such as cochlear synaptopathy with normal threshold, unilateral severe hearing loss, acute unilateral vestibular neuropathy, vestibular neuronitis, unilateral or bilateral auditory recruitment, diplopia, unilateral or bilateral hyperacusis, unilateral or bilateral temporary hearing threshold shift, central auditory processing disorder, and any combination thereof.

[0103] According to a more preferred embodiment, the hearing disorder is selected from the group consisting of unilateral or bilateral tinnitus, unilateral or bilateral auditory recruitment, diplopia, unilateral or bilateral hyperacusis, unilateral or bilateral temporary hearing threshold shift, central auditory processing disorder, and any combination thereof, which hearing disorders fall under the classes H93.1 and H93.2 of the International Classification of Diseases ICD-10, 2019 Edition.

[0104] According to a more preferred embodiment, the hearing disorder is selected from the group consisting of unilateral or bilateral hearing loss, unilateral or bilateral tinnitus, hidden hearing loss such as cochlear synaptic disorder with normal thresholds, and any combination thereof.

[0105] According to a more preferred embodiment, the hearing disease is selected from the group consisting of unilateral or bilateral hearing loss, unilateral or bilateral tinnitus, hidden hearing loss such as cochlear synaptopathy with normal threshold, and any combination thereof, where the unilateral or bilateral hearing loss is selected from the group consisting of unilateral or bilateral sensorineural hearing loss, unilateral or bilateral mixed conductive and sensorineural hearing loss, and unilateral or bilateral cochlear synaptopathy associated with elevated threshold.Preferably, the hearing disease is unilateral or bilateral hearing loss, where the unilateral or bilateral hearing loss is selected from the group consisting of 1) unilateral or bilateral sensorineural hearing loss, such as noise-induced sensorineural hearing loss or age-induced sensorineural hearing loss, such as presbycusis, and 2) unilateral or bilateral cochlear synaptopathy associated with elevated threshold, such as noise-induced cochlear synaptopathy associated with elevated threshold or age-induced cochlear synaptopathy associated with elevated threshold.

[0106] According to a more preferred embodiment, the hearing disease is selected from the group consisting of unilateral or bilateral sensorineural hearing loss such as noise-induced sensorineural hearing loss or age-induced sensorineural hearing loss such as presbycusis, unilateral or bilateral cochlear synaptopathy associated with elevated thresholds, unilateral or bilateral tinnitus, hidden hearing loss such as cochlear synaptopathy with normal thresholds, and any combination thereof.

[0107] According to a more preferred embodiment, the hearing disorder is selected from the group consisting of unilateral or bilateral sensorineural hearing loss, such as noise-induced sensorineural hearing loss or age-induced sensorineural hearing loss, such as presbycusis, unilateral or bilateral tinnitus, and any combination thereof.

[0108] According to a more preferred embodiment, the hearing disorder is a combination of unilateral or bilateral sensorineural hearing loss, such as noise-induced sensorineural hearing loss or age-induced sensorineural hearing loss, and unilateral or bilateral tinnitus.

[0109] According to a more preferred embodiment, the hearing disorder is a combination of unilateral or bilateral tinnitus and hidden hearing loss, such as cochlear synaptic disorder with normal thresholds.

[0110] According to a more preferred embodiment, the hearing disease is a combination of unilateral or bilateral sensorineural hearing loss, such as noise-induced sensorineural hearing loss or age-induced sensorineural hearing loss, and hidden hearing loss, such as cochlear synaptic disorder with normal thresholds.

[0111] According to a more preferred embodiment, the hearing disease is a combination of unilateral or bilateral sensorineural hearing loss, such as noise-induced sensorineural hearing loss or age-induced sensorineural hearing loss, and unilateral or bilateral cochlear synaptic damage associated with elevated thresholds.

[0112] According to a more preferred embodiment, the hearing disorder is a combination of unilateral or bilateral tinnitus and unilateral or bilateral cochlear synaptopathy associated with elevated thresholds.

[0113] According to a more preferred embodiment, the hearing disease is unilateral or bilateral sensorineural hearing loss, preferably the unilateral or bilateral sensorineural hearing loss is selected from noise-induced sensorineural hearing loss and age-induced sensorineural hearing loss such as presbycusis.

[0114] According to a more preferred embodiment, the hearing disorder is unilateral or bilateral tinnitus.

[0115] According to a more preferred embodiment, the hearing disease is a hidden hearing loss, such as a cochlear synaptic disorder with normal thresholds.

[0116] According to a more preferred embodiment, the hearing disorder is a unilateral or bilateral cochlear synaptic disorder associated with elevated thresholds.

[0117] Preferably, the hearing disorder according to the present invention is not induced by a decrease or increase in TGF-β (transforming growth factor β).

[0118] Preferably, the hearing disorder according to the present invention is not caused by a demyelinating disease or demyelination of the auditory nerve.

[0119] In one embodiment, the hearing disease according to the present invention is inflammation-induced unilateral or bilateral sensorineural hearing loss caused by a chronic inflammatory disease, preferably the chronic inflammatory disease is selected from the group consisting of diabetes, preferably type 2 diabetes, chronic kidney disease, inflammatory bowel disease, and rheumatoid arthritis.

[0120] In one embodiment, the hearing disease according to the present invention is inflammation-induced unilateral or bilateral cochlear synaptic damage associated with elevated thresholds caused by a chronic inflammatory disease, preferably the chronic inflammatory disease is selected from the group consisting of diabetes, preferably type 2 diabetes, chronic kidney disease, inflammatory bowel disease, and rheumatoid arthritis.

[0121] In another embodiment, the hearing disorder according to the present invention is a sensorineural hearing loss not caused by diabetes, chronic kidney disease, inflammatory bowel disease or rheumatoid arthritis, preferably the hearing disorder according to the present invention is a sensorineural hearing loss not caused by a chronic inflammatory disease.

[0122] In another embodiment, the hearing disease according to the present invention is a unilateral or bilateral cochlear synaptopathy associated with elevated thresholds not caused by diabetes, chronic kidney disease, inflammatory bowel disease, or rheumatoid arthritis, preferably the hearing disease according to the present invention is a unilateral or bilateral cochlear synaptopathy associated with elevated thresholds not caused by chronic inflammatory disease.

[0123] According to one embodiment, the hearing disorder is unilateral or bilateral hearing loss with a tonal hearing threshold of more than 30 dB at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus, the tonal hearing threshold being measured by auditory brainstem response or pure tone audiometry. According to a preferred embodiment, the hearing disorder is unilateral or bilateral hearing loss with a tonal hearing threshold of 30 dB to 70 dB at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus, the tonal hearing threshold being measured by auditory brainstem response or pure tone audiometry. According to another embodiment, the hearing disorder is unilateral or bilateral hearing loss with a tonal hearing threshold of 71 dB or more at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus, the tonal hearing threshold being measured by auditory brainstem response or pure tone audiometry. According to a preferred embodiment, the hearing disorder is a bilateral hearing loss with a tonal hearing threshold of 71 dB or more at three consecutive frequencies, the tonal hearing threshold being measured by auditory brainstem response or pure tone audiometry. According to another embodiment, the hearing disorder is a unilateral or bilateral hearing loss with a tonal hearing threshold of more than 91 dB at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus, the tonal hearing threshold being measured by auditory brainstem response or pure tone audiometry. According to a preferred embodiment, the hearing disorder is a unilateral hearing loss with a tonal hearing threshold of 91 dB or more at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus, the tonal hearing threshold being measured by auditory brainstem response or pure tone audiometry.

[0124] Advantageously, the subject wears at least one hearing device. The subject may wear one hearing device. The subject may wear two hearing devices. Indeed, among other advantages, administering a compound of formula (I), such as pariloden or xaliproden, or its pharma- ceutically acceptable salt and / or solvate, to a subject wearing at least one hearing device results in improved speech intelligibility in noise.

[0125] According to another embodiment, the compound of formula (I) or its pharmacologic acceptable salt and / or solvate is administered to the subject during cochlear surgery, for example during cochlear implant surgery.Indeed, administering the compound of formula (I), for example pariloden or xaliproden, or its pharmacologic acceptable salt and / or solvate to the subject during cochlear surgery, for example during cochlear implant surgery, allows better preservation of residual hearing and / or promotion of post-operative rehabilitation (better and / or faster post-operative rehabilitation).Indeed, cochlear implant surgery is generally safe; however, the risk of cochlear implant surgery includes loss of residual hearing.

[0126] The inventors have surprisingly found that administering a compound of formula (I), such as parilodene or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, results in an improvement in hearing function, as achieved by a reduction in pure-tone hearing threshold and / or ABR threshold shift of at least 10 dB at three consecutive frequencies.

[0127] Furthermore, the inventors have surprisingly found that administering a compound of formula (I), such as parilodene or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, results in an improvement in speech intelligibility in quiet, as achieved by a 10% improvement in word recognition score (number of words correctly identified in a list of 50 words presented at 30 dB above the hearing threshold).

[0128] Furthermore, the inventors have surprisingly found that administering a compound of formula (I), such as parilodene or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, results in an improvement in speech intelligibility in noise, achieved by a 4 dB reduction in the SNR (signal-to-noise ratio) required to achieve 50% correct word understanding.

[0129] Furthermore, the inventors have surprisingly found that administering a compound of formula (I), such as pariloden or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, exhibits beneficial effects following noise exposure accompanied by a reduction in ABR threshold shifts.

[0130] Administration The compound of formula (I), such as palyloden or xaliproden, or its pharma- ceutically acceptable salts and / or solvates, may be administered to a subject by any suitable administration route. Preferably, the compound of formula (I), such as palyloden or xaliproden, or its pharma- ceutically acceptable salts and / or solvates, is administered to a subject by any suitable administration route for the compound to reach the inner ear. More preferably, the suitable route for the compound to reach the inner ear is a route selected from the group consisting of a systemic route and a local route. The systemic route may be selected from the group consisting of an oral route, an intraperitoneal route, an intravenous route, an intramuscular route, an intraarterial route, and a subcutaneous route. The local route may be selected from the group consisting of a supratympanic route, a transtympanic route, an intrabullar route, an intracochlear route, and a round window pit route.

[0131] Thus, a compound of formula (I), such as parilodene or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, may be administered to a subject by a route of administration selected from the group consisting of the epitympanic route, the transtympanic route, the intrabullous route, the intracochlear route, the round window pit route, the oral route, the intraperitoneal route, the intravenous route, the intramuscular route, the intraarterial route and the subcutaneous route.

[0132] Advantageously, the compound of formula (I), such as pariloden or xaliproden, or its pharma- ceutically acceptable salts and / or solvates, is administered to the subject by transtympanic or oral route.More advantageously, administration by transtympanic route consists of injection between the tympanic membrane and the round window, using a needle through the tympanic membrane.

[0133] In one embodiment, the compound of formula (I), such as pariloden or xaliproden, or its pharma- ceutically acceptable salt and / or solvate, is administered to the subject by transtympanic route. In a preferred embodiment, the compound of formula (I) or its pharma-ceutically acceptable salt and / or solvate is administered to the subject by transtympanic route in one ear, such as the right ear or the left ear. In another preferred embodiment, the compound of formula (I) or its pharma-ceutically acceptable salt and / or solvate is administered to the subject by transtympanic route in both ears. Advantageously, administration by transtympanic route consists of injection between the tympanic membrane and the round window, using a needle through the tympanic membrane.

[0134] In another embodiment, the compound of formula (I), such as palyloden or xaliproden, or its pharma- ceutically acceptable salts and / or solvates, is administered to the subject by oral route, which has the advantage of promoting compliance by the subject and ease of administration, especially when the subject is a non-human mammal, such as a cat or dog.

[0135] According to one embodiment, the compound of formula (I), such as parilodene or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, is administered to the subject by the transtympanic route at a dose per ear ranging from 10 μg to 400 mg, preferably from 0.1 mg to 10 mg, more preferably from 1 mg to 10 mg, even more preferably from 4 mg to 6 mg, and even more preferably about 5 mg. Advantageously, administration by the transtympanic route consists of an injection between the tympanic membrane and the round window using a needle through the tympanic membrane.

[0136] According to one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to a subject via the transtympanic route at a dose per ear ranging from 10 μg to 400 mg, preferably from 0.1 mg to 20 mg, more preferably from 1 mg to 20 mg, even more preferably from 8 mg to 12 mg, and even more preferably about 10 mg.

[0137] According to one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to a subject by the transtympanic route at a dose per ear in the range of 10 μg to 400 mg, preferably 1 mg to 30 mg, more preferably 5 mg to 25 mg, even more preferably 17 mg to 23 mg, and even more preferably about 20 mg.

[0138] According to one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to a subject via the transtympanic route at a dose per ear ranging from 10 μg to 400 mg, preferably from 1 mg to 300 mg, more preferably from 50 mg to 200 mg, even more preferably from 100 mg to 150 mg, and even more preferably about 125 mg.

[0139] According to one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered in an amount of about 10 μg, 0.1 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg mg, 5.75mg, 6mg, 6.25mg, 6.5mg, 6.75mg, 7mg, 7.25mg, 7.5mg, 7.75mg, 8mg, 8.25mg, 8.5mg, 8.75mg, 9mg, 9.25m g, 9.5mg, 9.75mg, 10mg, 10.25mg, 10.5mg, 10.75mg, 11mg, 11.25mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg, 14mg , 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 25mg, 30mg, 35mg, 40 mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150 The compound is administered to a subject via the transtympanic route at a dose of 100 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg per ear.

[0140] The above doses may be administered in one ear, for example the right or left ear, once a month to once every 12 months.The above doses may be administered in both ears, for example the right or left ear, once a month to once every 12 months.

[0141] Advantageously, administration by the transtympanic route consists of an injection between the tympanic membrane and the round window using a needle through the tympanic membrane.

[0142] According to one embodiment, the compound of formula (I), such as palyloden or xaliproden, or its pharma- ceutically acceptable salts and / or solvates, is administered to the subject by oral route in a dose ranging from 100 μg to 4 mg, preferably from 1 mg to 4 mg, more preferably from 2 mg to 4 mg, and even more preferably about 3 mg, said dose being administered twice a day to once a week, advantageously said dose being administered once a day. This oral dose may in particular be administered to humans.

[0143] According to one embodiment, the compound of formula (I) or its pharma- ceutically acceptable salts and / or solvates is administered by oral route at a dose ranging from 1 mg / kg / day to 10 mg / kg / day, preferably from 3 mg / kg / day to 7 mg / kg / day, more preferably about 5 mg / kg / day, said dose being administered twice a day to once a week, advantageously said dose being administered once a day. This oral dose may in particular be administered to non-human subjects.

[0144] According to one embodiment, the compound of formula (I), such as paliprodene or xaliprodene, or a pharma- ceutically acceptable salt and / or solvate thereof, is administered in micronized form.

[0145] According to one embodiment, the compound of formula (I), such as paliprodene or xaliprodene, or a pharma- ceutically acceptable salt and / or solvate thereof, is administered in the form of a spray.

[0146] In one embodiment, the subject is a mammalian animal having a tympanic membrane. In a preferred embodiment, the mammalian animal having a tympanic membrane is a human. In another preferred embodiment, the mammalian animal having a tympanic membrane is a non-human animal, preferably a non-human mammalian animal having a tympanic membrane selected from the group consisting of cats, dogs, horses, and non-human primates such as monkeys.

[0147] In a more preferred embodiment, the subject is a dog.

[0148] In a more preferred embodiment, the subject is a human, advantageously over 40 years of age.

[0149] In a more preferred embodiment, the subject has diabetes (type 1 diabetes or type 2 diabetes, preferably type 2 diabetes).

[0150] Pharmaceutical Compositions The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt and / or solvate thereof and at least one pharma- ceutically acceptable excipient selected from the group consisting of poloxamers, polyethoxylated castor oils, phospholipids, triglycerides, and any combination thereof.

[0151] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt and / or solvate thereof, said pharmaceutical composition being a thermoreversible gel, preferably said pharmaceutical composition being a transtympanic pharmaceutical composition.

[0152] Advantageously, said pharmaceutical composition is a transtympanic pharmaceutical composition, i.e. a pharmaceutical composition intended to be administered by the transtympanic route.

[0153] In one embodiment, the pharmaceutical composition comprises 0.1 to 15 mg of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof per mL of the pharmaceutical composition.

[0154] In one embodiment, the pharmaceutical composition comprises 0.1-15 mg of palipiloden or a pharma- ceutically acceptable salt and / or solvate thereof per mL of the pharmaceutical composition.

[0155] In one embodiment, the pharmaceutical composition comprises 0.1 to 15 mg of xaliproden or a pharma- ceutically acceptable salt and / or solvate thereof per mL of the pharmaceutical composition.

[0156] According to one embodiment, the at least one pharma- ceutically acceptable excipient is selected from the group consisting of a poloxamer, a polyethoxylated castor oil, a triglyceride, a combination of a phospholipid and a triglyceride, and any combination thereof.

[0157] According to one embodiment, the at least one pharma- ceutically acceptable excipient is selected from the group consisting of poloxamers, triglycerides, and any combination thereof. According to one embodiment, the at least one pharma-ceutically acceptable excipient is selected from the group consisting of poloxamers, triglycerides, combinations of phospholipids and triglycerides, and any combination thereof. In one embodiment, the triglycerides are polyoxyethylated.

[0158] According to one embodiment, the at least one pharma- ceutically acceptable excipient is at least one poloxamer, preferably said poloxamer is selected from the group consisting of poloxamer 407, poloxamer 188, and any combination thereof.

[0159] According to a preferred embodiment, the at least one pharma- ceutically acceptable excipient is a mixture of polyoxyethylated triglycerides obtained by reacting castor oil with ethylene oxide in a molar ratio of 1:35.For example, the at least one pharma-ceutically acceptable excipient may be the commercial product Cremophor EL® (whose CAS number is 61791-12-6).

[0160] According to a preferred embodiment, the at least one pharma- ceutically acceptable excipient is a combination of a poloxamer and a mixture of polyoxyethylated triglycerides, preferably a mixture of polyoxyethylated triglycerides obtained by reacting castor oil, such as Cremophor EL®, with ethylene oxide in a molar ratio of 1:35.More preferably, the pharmaceutical composition comprising said excipient is a thermoreversible gel.

[0161] According to a preferred embodiment, the at least one pharma- ceutically acceptable excipient is a combination of poloxamer 407 and a mixture of polyoxyethylated triglycerides, preferably a mixture of polyoxyethylated triglycerides obtained by reacting castor oil, such as Cremophor EL®, with ethylene oxide in a molar ratio of 1:35.

[0162] According to another preferred embodiment, the at least one pharma- ceutically acceptable excipient is a combination of Poloxamer 407, Poloxamer 188 and a mixture of polyoxyethylated triglycerides, preferably a mixture of polyoxyethylated triglycerides obtained by reacting castor oil, such as Cremophor EL®, with ethylene oxide in a molar ratio of 1:35.

[0163] According to another preferred embodiment, the at least one pharma- ceutically acceptable excipient is: - 7% w / w to 15% w / w of poloxamer 407, - 7% w / w to 12% w / w of poloxamer 188, and - a combination of a mixture of polyoxyethylated triglycerides, between 17% w / w and 20% w / w, preferably about 20% w / w, preferably a mixture of polyoxyethylated triglycerides obtained by reacting castor oil, such as Cremophor EL®, with ethylene oxide in a molar ratio of 1:35; Contains or consists of: The percentages herein are expressed relative to the total amount of the pharmaceutical composition.

[0164] According to one embodiment, at least one pharma- ceutically acceptable excipient is a combination of phospholipids and triglycerides.Preferably, said combination of phospholipids and triglycerides comprises phosphatidylcholine and medium-chain triglycerides, such as caprylic / capric triglycerides.For example, said combination of phospholipids and triglycerides can be the commercial product Phosal® 53 MCT.

[0165] According to one embodiment, the compound of formula (I) or its pharma- ceutically acceptable salts and / or solvates is in micronized form in the pharmaceutical composition.

[0166] According to one embodiment, the compound of formula (I), such as paliprodene or xaliprodene, or a pharma- ceutically acceptable salt and / or solvate thereof, is in the form of a spray in the pharmaceutical composition.

[0167] According to one embodiment, the pharmaceutical composition is a sustained release composition.

[0168] In one embodiment, the pharmaceutical composition has a viscosity of 500-5000 mPa·s (or cP). In a preferred embodiment, the pharmaceutical composition has a viscosity of 600-800 mPa·s, preferably 650-800 mPa·s, preferably 650-750 mPa·s, more preferably about 700 mPa·s. In another preferred embodiment, the pharmaceutical composition has a viscosity of 4000-5000 mPa·s, preferably 4500-5000 mPa·s, more preferably about 4750 mPa·s. Viscosity is the kinematic viscosity, measured in a viscometer using the capillary method at 25°C.

[0169] Such pharmaceutical compositions allow the compound of formula (I) or its pharma- ceutical acceptable salts and / or solvates, such as pariloden or xaliproden, to be administered by transtympanic administration, in particular by injection between the tympanic membrane and the round window with a needle through the tympanic membrane. This transtympanic administration, in particular by injection between the tympanic membrane and the round window with a needle through the tympanic membrane, allows higher concentrations of the compound of formula (I), such as pariloden or xaliproden, or its pharma- ceutical acceptable salts and / or solvates (greater than 500 ng / mL, i.e., about 1 μM) to be reached in the inner ear fluid than oral concentrations, and has the advantage of reducing systemic exposure compared to oral administration.

[0170] Administration of the mucoadhesive composition by transtympanic route, particularly by injection between the tympanic membrane and the cochlear window using a needle through the tympanic membrane, allows the composition to adhere to the mucous membrane of the ear, particularly the mucous membrane of the middle ear. The active agent then diffuses through the cochlear window into the cochlea. Thus, the mucoadhesive properties of the composition ensure that the active agent reaches the cochlea. Excipients such as polyethoxylated castor oil, triglycerides, and combinations of triglycerides and phospholipids can impart mucoadhesive properties to the composition.

[0171] Without being bound by any theory, it is believed that the viscosity of the pharmaceutical composition according to the present invention is responsible for the composition being able to remain in the middle ear longer after injection between the tympanic membrane and the cochlear window using a needle through the tympanic membrane.Thus, this allows the compound of formula (I), such as pariloden or xaliproden, or its pharma-ceutically acceptable salt and / or solvate, to diffuse longer through the cochlear window into the cochlea, ensuring that a larger amount of the compound of formula (I), such as pariloden or xaliproden, or its pharma-ceutically acceptable salt and / or solvate, reaches the cochlea.

[0172] Pharmaceutical Compositions for Use The present invention also relates to a pharmaceutical composition for use in treating a hearing disorder in a subject, said pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt and / or solvate thereof, and at least one pharma- ceutically acceptable excipient.

[0173] The present invention also relates to a method for treating an auditory disorder by administering to a subject in need thereof an effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt and / or solvate thereof, and at least one pharma- ceutically acceptable excipient. The present invention also relates to the use of the pharmaceutical composition for the manufacture of a medicament for treating an auditory disorder in a subject, said pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt and / or solvate thereof.

[0174] The present invention also relates to the use of a pharmaceutical composition for treating a hearing disorder in a subject, said pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt and / or solvate thereof.

[0175] Advantageously, the hearing disorder is as defined herein above.

[0176] The pharmaceutical composition may be administered to a subject by any suitable route of administration. Preferably, the pharmaceutical composition is administered to a subject by any suitable route of administration for delivering the compound of formula (I) or its pharma- ceutically acceptable salt and / or solvate to the inner ear. More preferably, the suitable route for delivering the compound of formula (I) or its pharma- ceutically acceptable salt and / or solvate to the inner ear is a route selected from the group consisting of systemic and local routes. The systemic route may be selected from the group consisting of oral, intraperitoneal, intravenous, intramuscular, intraarterial and subcutaneous routes. The local route may be selected from the group consisting of epitympanic, transtympanic, intrabullous, intracochlear and round window pit routes.

[0177] Thus, the pharmaceutical composition may be administered to a subject by a route of administration selected from the group consisting of a supratympanic route, a transtympanic route, an intrabullous route, an intracochlear route, a round window pit route, an oral route, an intraperitoneal route, an intravenous route, an intramuscular route, an intraarterial route, and a subcutaneous route.

[0178] Advantageously, said pharmaceutical composition is administered to the subject by the transtympanic route or by the oral route. More advantageously, administration by the transtympanic route consists of an injection between the tympanic membrane and the round window using a needle through the tympanic membrane.

[0179] According to a first embodiment, the pharmaceutical composition is administered to a subject by a transtympanic route. Preferably, the pharmaceutical composition is administered by a transtympanic route in one ear, for example the right or left ear. Alternatively, the pharmaceutical composition is administered to a subject by a transtympanic route in both ears. Advantageously, administration by a transtympanic route consists of an injection between the tympanic membrane and the round window with a needle through the tympanic membrane. Preferably, the pharmaceutical composition administered to a subject by a transtympanic route is, in part, as defined above under "pharmaceutical composition" herein.

[0180] According to a second embodiment, the pharmaceutical composition is administered to a subject by oral route. Preferably, the pharmaceutical composition administered to a subject by oral route is in a galenical form selected from the group consisting of drinkable suspension, granules, capsules and tablets. Preferably, the at least one pharmaceutically acceptable excipient of the pharmaceutical composition administered to a subject by oral route is selected from the group consisting of lactose monohydrate, microcrystalline cellulose, corn starch, citric acid, hypromellose, croscarmellose sodium, magnesium stearate, methylcellulose and gum arabic. More preferably, the at least one pharmaceutically acceptable excipient of the pharmaceutical composition administered to a subject by oral route is selected from the group consisting of lactose monohydrate, microcrystalline cellulose, corn starch, citric acid, hypromellose, croscarmellose sodium, magnesium stearate, methylcellulose and gum arabic. - Lactose monohydrate, microcrystalline cellulose, corn starch as diluents; - Citric acid as an antioxidant, - hypromellose as a binder, - Croscarmellose sodium as a disintegrant, magnesium stearate as a lubricant, and -Methylcellulose or gum arabic as a suspending agent Includes a combination of.

[0181] Oral galenical forms may be coated with an aqueous film coating system comprising polyvinyl alcohol, such as Opadry® II (eg Opadry® II 32K28708 white).

[0182] Administration of a pharmaceutical composition comprising a compound of formula (I), such as paliporene or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, to a subject by oral route enables said compound of formula (I), such as paliporene or xaliproden, or a pharma- ceutically acceptable salt and / or solvate thereof, to reach a concentration in the inner ear fluid of greater than 5 ng / mL (i.e., about 10 nM).

[0183] All the features described above for the compound for use (part "compound for use") and for the pharmaceutical composition (part "pharmaceutical composition") also apply mutatis mutandis to the pharmaceutical composition for use. In particular, all the features described above with respect to the compound of formula (I) or its pharma- ceutically acceptable salts and / or solvates, the indications, the administration (particularly the route of administration, the dose, the form of the compound of formula (I) or its pharma- ceutically acceptable salts and / or solvates, the subject), the concentration of the compound of formula (I) or its pharma- ceutically acceptable salts and / or solvates in the pharmaceutical composition, the excipients, the form of the compound of formula (I) or its pharma- ceutically acceptable salts and / or solvates in the pharmaceutical composition, the sustained release properties, and the viscosity of the pharmaceutical composition apply mutatis mutandis to the pharmaceutical composition for use. [Brief description of the drawings]

[0184] [Figure 1] Figure 1 shows the pharmacokinetic profiles of palyloden in plasma (1A) and IEF (1B), and xaliproden in plasma (1C) and IEF (1D) following administration of 30 mg / kg palyloden and 20 mg / kg xaliproden by single oral gavage to male Wistar rats. Mean concentrations and standard deviations (ng / ml) are reported on a logarithmic scale over time for each compound and matrix. [Diagram 2]Figure 2 shows the pharmacokinetic profiles of palyloden in plasma (2A) and IEF (2B), and xaliproden in plasma (2C) and IEF (2D) after a single transtympanic administration of 243 μg palyloden and 192 μg xaliproden by injection between the tympanic membrane and the round window with a needle through the tympanic membrane into the middle ear of male Wistar rats. Concentration means and standard deviations (ng / mL) are reported on a logarithmic scale over time for each compound and matrix. [Diagram 3] 3 shows the pharmacokinetic profiles of palyloden in plasma (3A) and IEF (3B), and xaliproden in plasma (3C) and IEF (3D) after a single transtympanic administration of 300 μg palyloden and 150 μg xaliproden by injection between the tympanic membrane and the round window with a needle through the tympanic membrane into the middle ear of male Wistar rats. Concentration means and standard deviations (ng / mL) are reported on a logarithmic scale over time for each compound and matrix. [Figure 4] FIG. 4 is a histogram showing hearing threshold shifts (in dB) for control rats (sham, non-trauma vehicle, and trauma vehicle groups) and rats treated with pariloden or xaliproden at 1 day (4A) or 7 days (4B) after noise exposure and treatment compared to baseline (before noise exposure). [Diagram 5] FIG. 5 is a histogram showing a comparison of hearing recovery (in dB) achieved on days 1 to 7 after noise-trauma and transtympanic treatment in control rats (sham and trauma vehicle groups) and rats treated bilaterally with pariloden or xaliproden. [Figure 6]FIG. 6 shows histograms showing the number of CtBP2 spots (presynaptic elements) per inner hair cell (6A), Homer (postsynaptic elements) per inner hair cell (6B), and colocalized ribbons per inner hair cell (6C) detected and counted after immunolabeling of dissociated cochleae harvested on day T+28 after noise exposure in control rats (sham, trauma, and trauma vehicle groups) compared with rats treated bilaterally with pariloden or xaliproden immediately after noise exposure. [Figure 7] Figure 7 shows histograms showing the number of CtBP2 spots (presynaptic elements) per inner hair cell (7A), Homer (postsynaptic elements) per inner hair cell (6B), and colocalized ribbons per inner hair cell (6C) detected and counted after immunolabeling of dissociated cochleae harvested on day T+28 after noise exposure in control rats (sham, trauma NaCl, and trauma vehicle groups) compared with rats treated bilaterally with pariloden or xaliproden 2 days after noise exposure. [Figure 8] Figure 8 is a representative panel showing a single image acquired at 25 kHz encoding the cochlear region for one animal from each group (sham, trauma NaCl, trauma vehicle, trauma parilloden, and trauma xaliproden). Differences are shown for CtBP2 (presynaptic elements) labeled in green, Homer (postsynaptic elements) labeled in red, and the number of colocalized ribbons integrated in yellow, in the different treatment groups. [Figure 9] Figure 9 is a histogram showing the hearing threshold shift (in dB) of control mice (sham and trauma groups) and mice treated with pariroden, 1 day (9A) or 35 days (9B) after noise exposure, relative to baseline (pre-noise exposure), with treatment administered immediately following measurements on day 1. The recovery of hearing thresholds (in dB) achieved from days 1 to 35 after treatment is compared for control mice (sham and trauma groups) and mice treated bilaterally with pariroden (9C). [Figure 10]Figure 10 is a histogram showing DPOAE amplitude shifts (in dB) in control mice (sham and trauma groups) and mice treated with pariroden, 1 day (10A) or 35 days (10B) after noise exposure, relative to baseline (pre-noise exposure), with treatment administered immediately following measurements on day 1. Amplitude recovery (in dB) achieved from days 1 to 35 after treatment is compared for control mice (sham and trauma groups) and mice treated bilaterally with pariroden (10C). [Figure 11] FIG. 11 shows histograms comparing ABR wave I amplitude (μV), i.e., auditory nerve fiber activity, in control mice (sham and trauma groups) and mice treated bilaterally with Paliroden at 1 day (top) versus 35 days (bottom) after noise exposure at all tested frequencies: 16 kHz (11A), 25 kHz (11B), 32 kHz (11C), 40 kHz (11D) and 45 kHz (11E). [Figure 12] FIG. 12 shows histograms comparing ABR wave I amplitude (μV), i.e., auditory nerve fiber activity, in control mice (sham and trauma groups) and mice treated bilaterally with Paliroden at 35 days after noise exposure at high frequencies of 25 kHz (12A), 32 kHz (12B), 40 kHz (12C) and 45 kHz (12D) in a subset of responding animals. [Figure 13] FIG. 13 shows histograms showing the number of CtBP2 spots (presynaptic elements) per inner hair cell (13A), Homer (postsynaptic elements) per inner hair cell (13B), and colocalized ribbons per inner hair cell (13C) detected and counted after immunolabeling of dissociated cochleae harvested on day T+35 after noise exposure in control mice (sham and trauma groups) compared to mice treated bilaterally with Paliroden.

[0185] Working Example The present invention is further illustrated by the following examples.

[0186] Example 1: Inner ear exposure of palyloden and xaliproden following oral administration to male Wistar rats material and method Two compositions were prepared: Composition A and Composition B. Composition A is - 6 mg / mL (free base equivalent) of the fumarate salt of 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (=palilodene fumarate) and - 0.6% w / v methylcellulose based on the total volume of the solution It is an aqueous solution containing Composition B is - 4 mg / mL (free base equivalent) of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (=xaliproden hydrochloride) and - Gum arabic, 10% w / v based on the total weight of the solution It is an aqueous solution containing

[0187] Composition A and Composition B were administered to male Wistar rats (5 animals per active agent and time point) as follows.

[0188] Composition A was administered once at time T0 to 15 male Wistar rats by oral gavage injection at a dose of 5 mL of composition A per kilogram of animal, i.e., 30 mg of palyloden fumarate per kilogram of animal. The palyloden concentration in rat plasma and in rat inner ear fluid (IEF) was measured at six time points, with five rats used at each time point for concentration measurements (in plasma and optionally in IEF). The time points for concentration measurements in rat plasma are T0+1 h, T0+2 h, T0+4 h, T0+6 h, T0+8 h, and T0+24 h. As part of the final procedure, which includes taking cochlear samples from both ears of the rats and collecting inner ear fluid, the time points for concentration measurements in rat inner ear fluid are T0+2 h, T0+4 h, and T0+24 h. The bioanalytical method was validated in both matrices (lithium heparin plasma and cochlear fluid) over the range of 0.25–500 ng / mL in plasma and 0.25–100 ng / mL in cochlear fluid.

[0189] Composition B was administered once at time T0 to 15 other male Wistar rats by oral gavage injection at a dose of 5 mL of composition B per kilogram of animal, i.e. 20 mg of xaliproden hydrochloride per kilogram of animal. The xaliproden concentrations in rat plasma and in rat inner ear fluid (IEF) were measured at six time points, with five rats used at each time point for concentration measurements (in plasma and optionally in IEF). The time points for concentration measurements in rat plasma are T0+1 h, T0+2 h, T0+4 h, T0+6 h, T0+8 h, and T0+24 h. As part of the final procedure, which includes taking cochlear samples from both ears of the rats and collecting inner ear fluid, the time points for concentration measurements in rat inner ear fluid are T0+2 h, T0+4 h, and T0+24 h. The bioanalytical method was validated in both matrices (lithium heparin plasma and cochlear fluid) over the range of 0.25–500 ng / mL in plasma and 0.25–500 ng / mL in cochlear fluid.

[0190] result The results are shown in FIG. 1 and in Tables 1 and 2 below:

[0191] [Table 1]

[0192] [Table 2]

[0193] As shown in Tables 1 and 2 and Figure 1, the palyloden and xaliproden salts can cross the blood-labyrinth barrier and reach the inner ear when administered by the oral route. They are present in the IEF at concentrations ranging from about 2 ng / mL to about 20 ng / mL (approximately 4 nM to 40 nM).

[0194] Example 2: Compositions of Paliloden and Xaliproden for Transtympanic Administration (by injection between the tympanic membrane and the cochlear window using a needle through the tympanic membrane)

[0195] material and method Eight compositions suitable for transtympanic injection were prepared: four thermoreversible gel compositions and four lipid-based mucoadhesive solutions. These eight compositions were prepared using both palyloden fumarate and xaliproden hydrochloride as the active agents.

[0196] The four thermoreversible gel compositions that make up Paliroden are as follows: [Table 3]

[0197] The four thermoreversible gel compositions containing xaliproden are as follows: [Table 4]

[0198] The four lipid-based mucoadhesive solutions that make up Paliroden are: [Table 5]

[0199] The four lipid-based mucoadhesive solutions containing xaliproden are as follows: [Table 6]

[0200] result The solubility of each of palyloden and xaliproden in the compositions was measured, and the results are shown in the following table: [Table 7]

[0201] Thus, the formulated thermoreversible gel compositions and lipid-based mucoadhesive solutions contained a significant portion of palyloden or xaliproden in solution, compared to the solubility of less than 0.1 mg / mL in water for both molecules, which allows one to predict that palyloden or xaliproden will be able to cross the round window membrane and enter the inner ear when administered in 2P-8P or 2X-8X compositions, respectively.

[0202] Among the thermoreversible gel compositions, the maximum solubility of palyloden and xaliproden was obtained in compositions 4P and 4X, respectively, which were shown to gel in less than 10 minutes at 37° C. and can be used below 25° C. with a 26G needle for transtympanic injection.

[0203] Among the lipid-based mucoadhesive solutions, the maximum solubility of pariloden and xaliproden was obtained in compositions 7P, 8P and 7X, 8X, respectively. Compositions 7P and 7X had viscosity values ​​of 600-750 mPa.s (cP). Compositions 8P and 8X had viscosity values ​​of up to 5000 mPa.s (or cP). Compositions 7P, 8P, 7X, and 8X were shown to be able to pass through a 26G needle for transtympanic injection.

[0204] Example 3: Pharmacokinetic profile of palyloden and xaliproden in the cochlear fluid of male Wistar rats after transtympanic injection with a lipid-based mucoadhesive solution

[0205] material and method Composition 7P and Composition 7X described in Example 2 were administered to male Wistar rats (5 animals per active agent and time point) as described below.

[0206] At time TO, 15 rats were administered 30 μL of composition 7P by transtympanic injection in one ear. The administered dose of palyloden fumarate was therefore 243 μg per ear per rat.

[0207] At time TO, 30 μL of composition 7X was administered to 15 other rats in one ear by transtympanic injection. The dose of xaliproden hydrochloride administered was therefore 181.2 μg per ear per rat.

[0208] Plasma and inner ear exposures were measured for 15 rats receiving Composition 7P and for 15 rats receiving Composition 7X by sampling blood and cochlear terminals to obtain lithium heparin plasma and inner ear fluid preparations at T+1, T+24, and T+168 hours. Bioanalytical methods were validated in both matrices (lithium heparin plasma and inner ear fluid) with ranges of 0.2-815 ng / mL for pariloden (fumarate) and 0.2-763 ng / mL for xaliproden (hydrochloride).

[0209] result The results are shown in FIG. 2 and in Tables 8 and 9 below.

[0210] [Table 8]

[0211] [Table 9]

[0212] As shown in Tables 8 and 9 and FIG. 2, pariloden and xaliproden, when administered in a lipid-based mucoadhesive solution by transtympanic injection, can cross the round window membrane and rapidly reach high concentrations of approximately 5000 ng / mL and 2500 ng / mL, respectively, in the cochlear fluid (approximately 10 μM and 5 μM in IEF).

[0213] Example 4: Pharmacokinetic profile of palyloden and xaliproden in the cochlear fluid of male Wistar rats after transtympanic injection with a thermoreversible hydrogel composition

[0214] material and method Composition 4P and Composition 4X described in Example 2 were administered to male Wistar rats (5 animals per active agent and time point) as described below.

[0215] At time TO, 15 rats were administered 30 μL of composition 4P by transtympanic injection in one ear. The dose of palilodene fumarate administered was therefore 300 μg per ear per rat.

[0216] At time TO, 15 other rats were administered 30 μL of composition 4X by transtympanic injection in one ear. The dose of xaliproden hydrochloride administered was therefore 150 μg per ear per rat.

[0217] Plasma and inner ear exposures were measured by sampling blood and cochlear terminals to obtain lithium heparin plasma and inner ear fluid preparations at T+1, T+24, and T+168 hours for 15 rats receiving Composition 4P and 15 rats receiving Composition 4X. Bioanalytical methods were validated in both matrices (lithium heparin plasma and inner ear fluid) with ranges of 0.2-815 ng / mL for pariloden (fumarate) and 0.38-763 ng / mL for xaliproden (hydrochloride).

[0218] result The results are shown in FIG. 3 and in Tables 10 and 11 below.

[0219] [Table 10]

[0220] [Table 11]

[0221] As shown in Tables 10 and 11 and FIG. 3, when pariloden and xaliproden were administered as a suspension in a thermoreversible hydrogel composition by transtympanic injection, they could cross the round window membrane and rapidly reach a high concentration of about 5000 ng / mL (about 10 μM in IEF) in the inner ear fluid, which was continuously released for 7 days, and the concentrations in the inner ear fluid on the 7th day after injection were about 600 ng / ml (about 1.2 μM) and 100 ng / ml (about 0.2 μM) for pariloden and xaliproden, respectively.

[0222] Example 5: Transtympanic administration of pariloden or xaliproden (by injection between the tympanic membrane and the round window using a needle through the tympanic membrane) achieves a reduction in hearing thresholds after acoustic trauma in male Wistar rats.

[0223] material and method Forty-three male Wistar rats were selected and distributed into treatment and control groups, each containing 6-9 rats at the start of the study. Randomization was performed using the ABR threshold in the left ear at 16 kHz as the criterium. The "sham" group included 7 rats, which received neither noise exposure nor transtympanic injection. The "non-trauma vehicle" group included 6 rats, which received no noise exposure but received a transtympanic injection of placebo (a composition containing only Cremophor EL®). The "trauma" group included 9 rats, which received only noise exposure and no treatment. The "trauma vehicle" group included 7 rats, which received noise exposure and a transtympanic injection of placebo (a composition containing only Cremophor EL®). The "trauma pariloden" group included 7 rats that received noise exposure and a transtympanic injection of a composition comprising pariloden (fumarate salt) corresponding to composition 7P described in Example 2. The "trauma xaliproden" group included 7 rats that received noise exposure and a transtympanic injection of a composition comprising xaliproden (hydrochloride salt) corresponding to composition 7X described in Example 2.

[0224] All animals (except the sham group) received bilateral noise exposure for a period of 2 hours (from time T0 to time T0+2 hours) in the noise band of 8–16 kHz at 115 dB SPL RMS.

[0225] 30 μL of a composition containing either palyloden or xaliproden as active agent was administered once (30 μL / ear) to each rat of the treatment group in both ears, under isoflurane anesthesia, 4 hours after the start of the noise exposure (i.e. at T0+4 hours, thus 2 hours after the end of the noise exposure), by transtympanic administration by injection between the tympanic membrane and the round window with a needle through the tympanic membrane. The compositions correspond to compositions 7P and 7X, respectively, described in Example 2, i.e. they contain only Cremophor EL® as excipient and either palyloden (fumarate) or xaliproden (hydrochloride) as active agent. The dose of palyloden (fumarate) administered is 240 μg per ear of rats belonging to the "trauma palyloden" group (240 μg in 30 μL, injected by transtympanic route by injection between the tympanic membrane and the round window with a needle through the tympanic membrane). The dose of xaliproden (hydrochloride) administered is 192 μg per ear for rats belonging to the "trauma xaliproden" group (192 μg in 30 μL, injected by the transtympanic route by injection between the tympanic membrane and the fenestra cochlea using a needle through the tympanic membrane).

[0226] In summary, the chronology of the protocol was as follows: -T0-1 days: ABR baseline assessment -T0: Start of noise exposure, beginning of trauma -T0+2 hours: End of noise exposure, end of trauma -T0+4 hours: transtympanic injection in both ears of rats belonging to the treatment group, the composition injected contains either pariloden (fumarate) or xaliproden (hydrochloride) as active agent. 240 μg of pariloden (fumarate) was administered in each ear of rats belonging to the "trauma pariloden" group, and 192 μg of xaliproden (hydrochloride) was administered in each ear of rats belonging to the "trauma xaliproden" group. In the "trauma vehicle" group, animals received an injection of 30 μL of Cremophor EL® between the membrane and the fenestra cochlea using a needle through the tympanic membrane. -T0+1 day: ABR assessment (n=6-14 ears) -T0+7 days: ABR assessment (n=6-14 ears)

[0227] result The results are shown in Figures 4 and 5.

[0228] The protocol used in this study (8-16 kHz tones at 115 dB SPL RMS, delivered in an open field for 2 h) induced hearing loss in Wistar rats after noise exposure, as demonstrated in all trauma groups by a significant elevation of ABR thresholds at T0+1 day (see Figure 4). Hearing impairment was further observed at T0+7 day for traumatized animals, with a threshold shift of more than 20 dB from 8 to 32 kHz (see Figure 4).

[0229] Transtympanic administration of vehicle alone, not combined with noise-trauma, induced an elevation in ABR thresholds compared to control animals (see Figure 4). Therefore, groups treated with parilodene (fumarate) or xaliproden (hydrochloride) were compared to the trauma vehicle group (and the non-trauma untreated group, data not shown) to consider the effect of transtympanic injection of vehicle on ABR thresholds.

[0230] Hearing improvements were observed in both the pariloden and xaliproden treatment groups, as shown in FIGS.

[0231] Paliloden at 240 μg / ear and xaliproden at 192 μg / ear exhibited beneficial effects on auditory function in rats already 1 day after noise exposure, with a reduction in ABR threshold shifts of approximately 10 dB at 25 kHz to 32 kHz compared to the trauma vehicle group (Figure 4).

[0232] This beneficial effect on auditory function in rats was maintained and prolonged at day 7 post-noise. Paliloden at 240 μg / ear and xaliproden at 192 μg / ear achieved a reduction in ABR threshold shifts of approximately 15 dB at 25-32 kHz for xaliproden and approximately 15-20 dB at 16-32 kHz for paliloden treatment compared to the trauma vehicle group (Figure 4).

[0233] Overall, in addition to the hearing improvements observed at day T0+1, pariloden at 240 μg / ear and xaliproden at 192 μg / ear allow for additional hearing recovery of approximately 5–10 dB at 32–25 kHz with xaliproden and 5–20 dB at 32–16 kHz with pariloden treatment compared to the trauma vehicle group between days T0+7 and T0+1 (Figure 5).

[0234] Example 6: Treatment of noise-induced synaptic damage in male Wistar rats with permanent hearing loss by immediate transtympanic administration of palyloden or xaliproden (by injection between the tympanic membrane and the round window using a needle through the tympanic membrane). Fifty male Wistar rats were selected and distributed into treatment groups ("trauma pariloden" and "trauma xaliproden" groups) and control groups ("sham", "trauma", and "trauma vehicle" groups), each of which contained at least 9 rats at the end of the study. Randomization was performed using the ABR threshold in the left ear at 16 kHz as the criterium. The "sham" group consisted of rats that received neither noise exposure nor transtympanic injection (n=11). The "trauma" group consisted of rats that received only noise exposure and no treatment (n=9). The "trauma vehicle" group consisted of rats (n=10) that underwent noise exposure and under isoflurane anesthesia received a transtympanic injection in both ears of 30 μL of placebo (a composition comprising poloxamer 407 (in phosphate buffer pH=7.4, 7.2% w / w), poloxamer 188 (8% w / w) and Cremophor EL® (20% w / w), percentages expressed relative to the total weight of the composition) between the tympanic membrane and the fenestra cochlea, using a needle through the tympanic membrane, 4 hours after the start of the noise exposure (i.e. 2 hours after the injection of placebo at T0+4 hours and therefore the end of the noise exposure) and 8 days after the noise exposure. The "trauma pariloden" group consisted of rats (n=10) that underwent noise exposure and a transtympanic injection of a composition comprising pariloden (fumarate), corresponding to composition 4P described in Example 2. The "trauma xaliproden" group consisted of rats (n=10) that underwent noise exposure and a transtympanic injection of a composition containing xaliproden (hydrochloride) corresponding to composition 4X described in Example 2.

[0235] All animals (except the sham group) received bilateral noise exposure for 2 hours (time T0 to time T0+2 hours) in the noise band 8–16 kHz at 110 dB SPL RMS.

[0236] 30 μL of a composition containing either palyloden or xaliproden as active agent was administered once (30 μL / ear) to each rat in the treatment group in both ears by transtympanic administration by injection between the tympanic membrane and the round window with a needle through the tympanic membrane under isoflurane anesthesia, 4 hours after the start of the noise exposure (i.e. at T0+4 hours, thus 2 hours after the end of the noise exposure) and on the 8th day after the noise exposure. The compositions correspond respectively to compositions 4P and 4X described in Example 2, i.e. they contain a mixture of poloxamer 407, poloxamer 188 and Cremophor EL® (7.2% w / w, 8% w / w and 20% w / w, respectively, percentages expressed relative to the total weight of the composition) and either palyloden (fumarate) or xaliproden (hydrochloride) as active agent. The dose of Pariloden (fumarate) administered is 300 μg per ear for rats belonging to the "Paliloden trauma" group (300 μg in 30 μL, injected by transtympanic route by injection between the tympanic membrane and the cochlear window with a needle through the tympanic membrane). The dose of Xaliproden (hydrochloride) administered is 150 μg per ear for rats belonging to the "Xaliproden trauma" group (150 μg in 30 μL, injected by transtympanic route by injection between the tympanic membrane and the cochlear window with a needle through the tympanic membrane).

[0237] In summary, the chronology of the protocol was as follows: -T0-1 days: ABR / DPOAE baseline assessment -T0: Start of noise exposure, beginning of trauma -T0+2 hours: End of noise exposure, end of trauma -T0+4 hours: transtympanic injection in both ears of rats belonging to the treatment group and the "trauma vehicle" group, the composition injected contains either pariloden (fumarate) or xaliproden (hydrochloride) as active agent (treatment group) or placebo ("trauma vehicle" group). 300 μg of pariloden (fumarate) was administered in each ear of rats belonging to the "trauma pariloden" group, and 150 μg of xaliproden (hydrochloride) was administered in each ear of rats belonging to the "trauma xaliproden" group. In the "trauma vehicle" group, animals received 30 μL of a mixture of poloxamer 407, poloxamer 188, and Cremophor EL® (7.2% w / w; 8% w / w, 20% w / w, respectively, percentages expressed relative to the total weight of the composition) by injection between the tympanic membrane and the round window using a needle through the tympanic membrane. -T0+1 day: ABR / DPOAE assessment (n=18-22 ears / group) -T0+7 days: ABR assessment (n=18-22 ears / group) - T0+8 days: Repeated transtympanic injections in both ears of rats belonging to the treatment and "trauma vehicle" groups of the same composition containing either parilodene (fumarate) or xaliproden (hydrochloride) as active agent and a mixture of poloxamer 407, poloxamer 188 and Cremophor EL® (7.2% w / w, 8% w / w and 20% w / w respectively, percentages expressed relative to the total weight of the composition) as vehicle control (treatment group) or placebo ("trauma vehicle" group). -T0+14 days: ABR / DPOAE assessment (n=18-22 ears / group) -T0+21 days: ABR / DPOAE assessment (n=18-22 ears / group) -T0+28 days: ABR / DPOAE assessment (n=18-22 ears / group)

[0238] On day T+28, after DPOAE / ABR measurements, 10 cochleae / group (all 8 left cochleae and 2 right cochleae taken randomly) were rapidly sampled and immediately fixed by PFA perfusion (a small hole was drilled at the apex followed by PFA 4% through the cochlear window and oval window) for ribbon synapse immunostaining and analysis. Cochleae were fixed in 4% PFA solution for 1 h and decalcified in undiluted RDO (10 mL / cochlea, minimum 2 h). Membranous and sensory spirals including the organ of Corti were dissected as planar preparations under a dissecting microscope and immunolabeled with the appropriate antibodies: -Vglut3 (Vglut3-Guinea Pig IgG; #135204, synaptic system and anti-Guinea Pig IgG (H+L), #A21450; Thermo Fisher Scientific 647nm Far-Red) to stain the inner hair cell bodies (vesicular glutamate transporter). -Homer (Homer-Rabbit IgG; #GTX103278; Genetex and Anti-Rabbit IgG(H+L) #A11008 Thermo Fisher Scientific 568nm Red) to stain dendritic proteins in auditory nerve fibers connecting to the IHC (postsynaptic). - CtBP2 (CtBP2-Mouse-IgG1; #612044; BD Transduction Laboratories and Anti-Mouse IgG1, #A21121, Thermo Fisher Scientific 488 Green) to stain ribeye protein as a presynaptic marker in IHC. - Phalloidin (Alexa Fluor™ Plus 405 Phalloidin; #A30104, Thermo Fisher Scientific 405 Blue).

[0239] Images were acquired with a confocal microscope and slides were analyzed i) to assess the presence of OHCs (outer hair cells) and IHCs (inner hair cells) by visual observation (based on nuclear staining with CtBP2 and staining of HC cell bodies with phalloidin) and ii) to count the number of synaptic ribbons of selected inner hair cells in cochlear regions encoding sounds of selected frequencies (16 kHz, 25 kHz, and 32 kHz).

[0240] The number of presynaptic (CtBP2) and postsynaptic (Homer) labeled spots was counted in three dimensions for each image using Imaris software. Colocalization of presynaptic and postsynaptic elements was defined as a maximum distance of 1 μm between CtBP2- and Homer-labeled spots using our Matlab program to calculate the distance between the CtBP2 and Homer labels from x, y, and z coordinates.

[0241] result The results are shown in Figure 6.

[0242] The protocol used in the present study (8–16 kHz tones at 110 dB SPL RMS, delivered in an open field for 2 h) induced permanent hearing loss in Wistar rats after noise exposure, realized as a residual ABR threshold shift and a reduction in DPOAE amplitude from baseline of approximately 20 dB at T0 + 28 days in all traumatized animals (data not shown).

[0243] Treatment with xaliproden, pariloden and vehicle showed no effect on ABR thresholds, DPOAE amplitudes, or ABR wave I amplitudes at TO+28 days compared to untreated or vehicle-treated traumatized animals.

[0244] ABR wave I amplitude measured at T0+28 days primarily reflects permanent hearing loss and cannot be used to assess treatment of synaptopathy, defined as a reduction in ABR wave I amplitude in animals with normal hearing thresholds comparable to the sham group, following noise exposure that causes a temporary ABR threshold elevation.

[0245] Therefore, synaptic damage was examined by immunohistochemistry in noise-exposed versus sham cochleae, comparing the number of intact synapses (where pre- and postsynaptic elements are colocalized) in traumatized and non-traumatized control animals, with an emphasis on the basal cochlear region that codes for the higher frequencies (16 kHz, 25 kHz, and 32 kHz) most affected by the acoustic trauma noise band (see Figure 6 ).

[0246] Paliloden at 300 μg / ear and xaliproden at 150 μg / ear administered 2 hours and 8 days after noise resulted in an increase in the number of colocalized ribbons per IHC at 25 kHz compared to the trauma vehicle group (Figure 6C). Paliloden at 300 μg / ear was also found to have a similar effect at 32 kHz.

[0247] Furthermore, pariloden at 300 μg / ear and xaliproden at 150 μg / ear administered 2 h and 8 days after noise resulted in an increase in the number of presynaptic elements CtBP2 per IHC at 25 kHz and 32 kHz compared to the trauma vehicle group (Figure 6A).

[0248] Overall, pariloden at 300 μg / ear and xaliproden at 150 μg / ear administered 2 hours and 8 days after noise tend to repair synaptic loss in inner hair cells of rats exposed to noise that causes permanent hearing loss, in areas that code for high-frequency sounds. Translated to humans, this is expected to improve patients' speech coding abilities and address their intelligibility deficits in noisy environments (hidden hearing loss).

[0249] Example 7: Treatment of noise-induced synaptic damage in male Wistar rats with permanent hearing loss by delayed release transtympanic administration of pariloden or xaliproden (by injection between the tympanic membrane and the round window using a needle through the tympanic membrane). Forty male Wistar rats were selected and distributed equally between treatment and control groups, each group containing 8 rats at the end of the study. Randomization was performed using the ABR threshold in the left ear at 16 kHz as the criterium. The "sham" group consisted of rats (n=8) that received neither noise exposure nor transtympanic injection. The "trauma NaCl" group consisted of rats (n=8) that received only noise exposure and transtympanic injection of saline. The "trauma vehicle" group consisted of rats (n=8) that received noise exposure and transtympanic injection of placebo (a composition containing poloxamer 407 (7.2% w / w), poloxamer 188 (8% w / w), and CremophorEL® (20% w / w) in phosphate buffer pH=7.4, percentages expressed relative to the total weight of the composition). The "trauma pariloden" group consisted of rats (n=8) that underwent noise exposure and a transtympanic injection of a composition comprising pariloden (fumarate salt) corresponding to composition 4P described in Example 2. The "trauma xaliproden" group consisted of rats (n=10) that underwent noise exposure and a transtympanic injection of a composition comprising xaliproden (hydrochloride salt) corresponding to composition 4X described in Example 2.

[0250] All animals (except the sham group) received bilateral noise exposure for 2 hours (time T0 to time T0+2 hours) in the noise band 8–16 kHz at 110 dB SPL RMS.

[0251] Thirty microliters of saline (0.9% w / w aqueous NaCl solution) was administered once in both ears of each rat in the “trauma NaCl” group (30 μL / ear) by transtympanic administration via injection between the tympanic membrane and the cochlear window using a needle through the tympanic membrane under isoflurane anesthesia on days 2 and 9 after noise exposure.

[0252] 30 μL of placebo (a composition consisting of poloxamer 407 (7.2% w / w), poloxamer 188 (8% w / w) and Cremophor EL® (20% w / w) in phosphate buffer pH=7.4, percentages expressed relative to the total weight of the composition) was administered once in both ears (30 μL / ear) to each rat in the “trauma vehicle” group by transtympanic administration via injection between the tympanic membrane and the round window using a needle through the tympanic membrane, under isoflurane anesthesia, on days 2 and 9 after noise exposure.

[0253] 30 μL of a composition containing either palyloden or xaliproden as active agent was administered once in both ears of each rat in the treatment group (30 μL / ear) by transtympanic administration by injection between the tympanic membrane and the round window with a needle through the tympanic membrane under isoflurane anesthesia on the second and ninth days after noise exposure. The compositions correspond to compositions 4P and 4X, respectively, described in Example 2, i.e. they contain a mixture of poloxamer 407, poloxamer 188 and Cremophor EL® (7.2% w / w, 8% w / w and 20% w / w, respectively, percentages expressed relative to the total weight of the composition) and either palyloden (fumarate) or xaliproden (hydrochloride) as active agent. The dose of Pariloden (fumarate) administered is 300 μg per ear for rats belonging to the "Paliloden trauma" group (300 μg in 30 μL, injected by transtympanic route by injection between the tympanic membrane and the cochlear window with a needle through the tympanic membrane). The dose of Xaliproden (hydrochloride) administered is 150 μg per ear for rats belonging to the "Xaliproden trauma" group (150 μg in 30 μL, injected by transtympanic route by injection between the tympanic membrane and the cochlear window with a needle through the tympanic membrane).

[0254] In summary, the chronology of the protocol was as follows: -T0-1 days: ABR / DPOAE baseline assessment -T0: Start of noise exposure, beginning of trauma - Day T0+1: Randomization based on ABR / DPOAE assessment (n=16 ears / group) and post-noise hearing at 16 kHz. - Days T0+2 and T+9: transtympanic injections in both ears of rats belonging to the treatment group, the "trauma NaCl" group and the "trauma vehicle" group. The injected compositions contain either pariloden (fumarate) or xaliproden (hydrochloride) as active agent (treatment group), or placebo ("trauma vehicle" group) or saline ("trauma NaCl" group). 300 μg of pariloden (fumarate) was administered in each ear of rats belonging to the "trauma pariloden" group and 150 μg of xaliproden (hydrochloride) was administered in each ear of rats belonging to the "trauma xaliproden" group. In the "Trauma Vehicle" group, animals received 30 μL of a mixture of Poloxamer 407, Poloxamer 188, and Cremophor EL® (7.2% w / w; 8% w / w, 20% w / w, respectively, percentages expressed relative to the total weight of the composition) in both ears by injection between the tympanic membrane and the round window using a needle through the tympanic membrane. In the "Trauma NaCl" group, animals received 30 μL of saline in both ears. -T0+21 days: ABR / DPOAE assessment (n=16 ears / group) -T0+28 days: ABR / DPOAE assessment (n=16 ears / group)

[0255] On day T+28, after DPOAE / ABR measurements, 10 cochleae / group (all 8 left cochleae and 2 right cochleae taken randomly) were rapidly sampled and immediately fixed by PFA perfusion (a small hole was drilled at the apex followed by PFA 4% through the cochlear window and oval window) for ribbon synapse immunostaining and analysis. Cochleae were fixed in 4% PFA solution for 1 h and decalcified in undiluted RDO (10 mL / cochlea, minimum 2 h). Membranous and sensory spirals including the organ of Corti were dissected as planar preparations under a dissecting microscope and immunolabeled with the appropriate antibodies: -Vglut3 (Vglut3-Guinea Pig IgG; #135204, synaptic system and anti-Guinea Pig IgG (H+L), #A21450; Thermo Fisher Scientific 647nm Far-Red) to stain the inner hair cell bodies (vesicular glutamate transporter). -Homer (Homer-Rabbit IgG; #GTX103278; Genetex and Anti-Rabbit IgG(H+L) #A11008 Thermo Fisher Scientific 568nm Red) to stain dendritic proteins in auditory nerve fibers connecting to the IHC (postsynaptic). - CtBP2 (CtBP2-Mouse-IgG1; #612044; BD Transduction Laboratories and Anti-Mouse IgG1, #A21121, Thermo Fisher Scientific 488 Green) to stain ribeye protein as a presynaptic marker in IHC. - Phalloidin (Alexa Fluor™ Plus 405 Phalloidin; #A30104, Thermo Fisher Scientific 405 Blue).

[0256] Images were acquired with a confocal microscope and slides were analyzed i) to assess the presence of OHCs and IHCs by visual observation (based on nuclear staining with CtBP2 and staining of HC cell bodies with phalloidin) and ii) to count the number of synaptic ribbons in selected inner hair cells in cochlear regions encoding sounds of selected frequencies (16 kHz, 25 kHz, and 32 kHz).

[0257] The number of presynaptic (CtBP2) and postsynaptic (Homer) labeled spots was counted in three dimensions for each image using Imaris software. Colocalization of presynaptic and postsynaptic elements was defined as a maximum distance of 1 μm between CtBP2- and Homer-labeled spots using our Matlab program to calculate the distance between the CtBP2 and Homer labels from x, y, and z coordinates.

[0258] result The results are shown in Figures 7 and 8.

[0259] The protocol used in the present study (8 kHz–16 kHz tones at 110 dB SPL RMS, delivered in an open field for 2 h) induced permanent hearing loss in Wistar rats after noise exposure, realized by a residual ABR threshold shift and a reduction in DPOAE amplitude from baseline of approximately 20 dB at T0 + 28 days in all traumatized animals (data not shown).

[0260] Treatment with xaliproden, pariloden and vehicle showed no effect on ABR thresholds, DPOAE amplitudes, or ABR wave I amplitudes at TO+28 days compared to untreated or vehicle-treated traumatized animals.

[0261] ABR wave I amplitude measured at T0+28 days primarily reflects permanent hearing loss and cannot be used to evaluate treatment of synaptopathy, defined as a reduction in ABR wave I amplitude in animals with normal hearing thresholds comparable to the sham group after noise exposure that causes a temporary ABR threshold elevation. Indeed, a reduction in wave I amplitude can be attributed to synaptopathy only in the context of trauma accompanied by temporary severe hearing loss. In the case of permanent severe hearing loss, even with moderate permanent hearing loss, a reduction in wave I amplitude reflects not only synaptic loss but also this permanent hearing loss.

[0262] Therefore, synaptic damage was examined by immunohistochemistry in noise-exposed versus sham cochleae, comparing the number of intact synapses (where pre- and postsynaptic elements are colocalized) in traumatized and non-traumatized control animals, with an emphasis on the basal cochlear region that codes for the higher frequencies (16 kHz, 25 kHz, and 32 kHz) most affected by the acoustic trauma noise band (see Figure 7 ).

[0263] Paliloden at 300 μg / ear and xaliproden at 150 μg / ear administered 2 and 9 days after noise resulted in an increase in the number of colocalized ribbons per IHC at 25 kHz compared to the trauma vehicle and trauma NaCl groups (Figure 7C), which was found to be statistically significant for palinodene at this frequency. Paliloden at 300 μg / ear was also found to have a similar effect at 16 kHz.

[0264] Furthermore, pariloden at 300 μg / ear and xaliproden at 150 μg / ear administered 2 and 9 days after noise resulted in an increase in the number of presynaptic and postsynaptic elements (CtBP2 and Homer, respectively) per IHC at 25 kHz compared to the trauma vehicle and trauma NaCl groups (Figures 7A and 7B).

[0265] As shown in Figure 8, pariloden at 300 μg / ear and xaliproden at 150 μg / ear administered 2 hours and 8 days after noise significantly restore synaptic loss in inner hair cells of rats exposed to noise causing permanent hearing loss in areas coding for high frequency sounds. Significantly more orphan pre- and postsynaptic elements (green and red dots, respectively) are seen in traumatized animals treated with NaCl or vehicle than in animals treated with pariloden. Significantly more co-localized synaptic elements resulting in intact and functional synapses are therefore observed upon treatment with pariloden and xaliproden. Translated to humans, this is expected to improve patients' speech coding abilities and address their intelligibility deficits in noisy environments (hidden hearing loss).

[0266] Example 8: Treatment of noise-induced synaptic damage in male CBA mice with permanent speech coding defects (hidden hearing loss) by immediate transtympanic administration of pariroden (by injection between the tympanic membrane and the round window using a needle through the tympanic membrane). Twelve male CBA / CaJ mice were selected and distributed equally between treatment and control groups, each group containing 4 mice at the end of the study. Randomization was performed using the ABR threshold in the left ear at 16 kHz as the criterium. The "sham" group consisted of mice (n=4) that received neither noise exposure nor transtympanic injection. The "trauma" group consisted of mice (n=4) that received noise exposure only. The "trauma pariloden" group consisted of mice (n=4) that received noise exposure and transtympanic injection of a composition containing pariloden (fumarate) corresponding to composition 4P described in Example 2.

[0267] All animals (except the sham group) received bilateral noise exposure in the 8–16 kHz noise band at 95 dB SPL RMS for 2 h (time T0 to time T0 + 2 h) in the awake state.

[0268] 5 μL of a composition containing palyloden or xaliproden as active agent was administered once in both ears of each mouse of the treatment group (5 μL / ear) under isoflurane anesthesia, 24 hours after noise exposure, by transtympanic administration by injection between the tympanic membrane and the round window with a needle through the tympanic membrane. The composition corresponds to composition 4P described in Example 2, i.e. it contains a mixture of palyloden (fumarate) with poloxamer 407, poloxamer 188 and Cremophor EL® (7.2% w / w, 8% w / w and 20% w / w, respectively, percentages expressed relative to the total weight of the composition). The dose of palyloden (fumarate) administered is 50 μg / ear of mice belonging to the "trauma palyloden" group (50 μg in 5 μL, injected by transtympanic route by injection between the tympanic membrane and the round window with a needle through the tympanic membrane).

[0269] In summary, the chronology of the protocol was as follows: -T0-1 days: ABR / DPOAE baseline assessment -T0: Onset of noise exposure, onset of trauma in awake state -T0+1 days: Randomization based on ABR / DPOAE assessment (n=8 ears / group) and post-noise hearing at 16 kHz. Transtympanic injection in both ears in mice in the pariroden treatment group -T0+35 days: ABR / DPOAE assessment (n=8 ears / group)

[0270] On day T+35, after DPOAE / ABR measurements, all cochleae per group (all 4 left cochleae and 4 right cochleae) were rapidly sampled and immediately fixed by PFA perfusion (a small hole was made at the apex followed by PFA 4% through the cochlear window and oval window) for ribbon synapse immunostaining and analysis. Cochleae were fixed in 4% PFA solution for 1 h and decalcified in undiluted RDO (10 mL / cochlea, minimum 2 h). Membranous and sensory spirals including the organ of Corti were dissected as planar preparations under a dissecting microscope and immunolabeled with the appropriate antibodies: -Vglut3 (Vglut3-Guinea Pig IgG; #135204, synaptic system and anti-Guinea Pig IgG (H+L), #A21450; Thermo Fisher Scientific 647nm Far-Red) to stain the inner hair cell bodies (vesicular glutamate transporter). -Homer (Homer-Rabbit IgG; #GTX103278; Genetex and Anti-Rabbit IgG(H+L) #A11008 Thermo Fisher Scientific 568nm Red) to stain dendritic proteins in auditory nerve fibers connecting to the IHC (postsynaptic). - CtBP2 (CtBP2-Mouse-IgG1; #612044; BD Transduction Laboratories and Anti-Mouse IgG1, #A21121, Thermo Fisher Scientific 488 Green) to stain ribeye protein as a presynaptic marker in IHC. - Phalloidin (Alexa Fluor™ Plus 405 Phalloidin; #A30104, Thermo Fisher Scientific 405 Blue).

[0271] Images were acquired with a confocal microscope and slides were analyzed i) to assess the presence of OHCs and IHCs by visual observation (based on nuclear staining with CtBP2 and staining of HC cell bodies with phalloidin) and ii) to count the number of synaptic ribbons in selected inner hair cells in cochlear regions encoding sounds of selected frequencies (25 kHz, 32 kHz, and 45 kHz).

[0272] The number of presynaptic (CtBP2) and postsynaptic (Homer) labeled spots was counted in three dimensions for each image using Imaris software. Colocalization of presynaptic and postsynaptic elements was defined as a maximum distance of 1 μm between CtBP2- and Homer-labeled spots using our Matlab program to calculate the distance between the CtBP2 and Homer labels from x, y, and z coordinates.

[0273] result The results are shown in Figures 9, 10, 11, 12, and 13.

[0274] The protocol used in this study (awake noise trauma at 8-16 kHz, 95 dB SPL RMS, 2 h, delivered in an open field) induced temporary hearing loss in CBA / CaJ mice after noise exposure, realized by a temporary elevation of ABR thresholds and a decrease in DPOAE amplitudes from baseline of at least 20 dB at day T0+1 (Figures 9A and 10A), with full recovery observed at day T0+35 and ABR thresholds and DPOAE amplitudes returning to normal values ​​(less than 10 dB difference) identical to those observed in the sham group (Figures 9B and 10B).

[0275] In such a temporary hearing loss model, synaptic damage is characterized by a persistent and significant decrease in ABR wave I at T0+35 days observed in the trauma group (group 2) compared to the sham group (group 1), as shown in Figures 11A-11E. At 25, 32, 40, and 45 kHz, untreated traumatized mice show a decrease in the immediate ABR wave I amplitude at 1 day after noise exposure, ranging from 50% to 75% reduction, compared to non-traumatized control mice (sham group). At T0+35 days, these ABR wave I amplitude reductions were found to persist, ranging from 25% to 50%, indicating very limited spontaneous recovery.

[0276] Pariloden treatment immediately following hearing assessment 1 day after noise exposure led to a complete recovery of ABR wave I amplitudes at all frequencies assessed (16 kHz, 25 kHz, 32 kHz, 40 kHz, and 45 kHz) 5 weeks after noise exposure. Indeed, ABR wave I amplitudes in traumatized mice treated with pariloden were found to be comparable to non-traumatized control mice (sham group) at all frequencies.

[0277] In subset analyses (displayed in Figures 12 and 13), corresponding only to animals meeting the noise exposure acceptance criteria (i.e., at least a 20 dB increase in ABR threshold at 1 day after noise exposure) and normal conditions in controls (sham should not exhibit an increase in ABR threshold of more than 20 dB compared to baseline levels), the recovery of ABR wave I amplitude achieved by pariroden treatment was found to be statistically significant (p-value < 0.001) at frequencies of 25 kHz (Figure 12A), 32 kHz (Figure 12B), 40 kHz (Figure 12C), and 45 kHz (Figure 12D) compared to untreated traumatized mice.

[0278] Moreover, in this same subset analysis group, this finding correlated with a significant decrease in the number of presynaptic and postsynaptic elements (CtBP2 and Homer, respectively) per IHC at 32 kHz in traumatized mice compared to control mice (sham) (p-value < 0.01; Figure 13). Paliroden at 50 μg / ear administered 1 day after noise tended to increase the number of presynaptic and postsynaptic elements (CtBP2 and Homer, respectively) per IHC at 32 kHz compared to the untreated traumatized group (Figure 13A and Figure 13B), and also resulted in an increase in colocalized ribbons per IHC representing functional synapses at 32 kHz (Figure 13C). At frequencies ranging from 25 kHz to 40 kHz, the number of colocalized ribbons per IHC obtained in pairoden-treated mice was intermediate between traumatized and control mice and was found to be not statistically different from the values ​​obtained in control mice (sham).

[0279] Example 9: Treatment of noise-induced synaptic damage in male CBA mice with permanent speech coding defects (hidden hearing loss) by immediate transtympanic administration of pariloden or xaliproden (by injection between the tympanic membrane and the round window using a needle through the tympanic membrane). In another ongoing experiment to complete Example 8 above, 17 additional male CBA / CaJ mice are distributed equally between treatment and control groups. Randomization is performed using the ABR threshold in the left ear at 16 kHz as the criterium. The "sham" group consists of mice (n=5) that received neither noise exposure nor transtympanic injection. The "trauma" group consists of mice (n=4) that received noise exposure only. The "trauma pariloden" group consists of mice (n=3) that received noise exposure and transtympanic injection of a composition comprising pariloden (fumarate salt) corresponding to composition 4P described in Example 2. The "trauma xaliproden" group consists of mice (n=5) that received noise exposure and transtympanic injection of a composition comprising xaliproden (hydrochloride salt) corresponding to composition 4X described in Example 2.

[0280] An identical procedure to that of Example 8 is planned for these animals to demonstrate similar findings achieved by xaliproden treatment. The expected outcome is that both pariroden and xaliproden treatments can restore the amplitude of ABR wave I to normal levels (non-traumatized animals) 5 weeks after noise exposure causing temporary hearing loss and persistent sound coding defects due to loss of afferent ribbon synapses at the inner hair cell level. As shown for pariroden, xaliproden is expected to restore ribbon synapses of IHCs in cochlear regions that code for high frequencies (>25 kHz).

[0281] Translated to humans, pariloden and xaliproden treatments are expected to address hidden hearing loss by enhancing speech encoding abilities in patients with normal or near-normal hearing test results, with deficits in intelligibility in noise associated with loss of auditory synapses.

Claims

1. 1. A pharmaceutical composition for use in treating a hearing disorder in a subject, said pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof; wherein formula (I) is 【Chemistry 1】 (I) During the ceremony: R １ is a halogen atom, CF ３ Group, (C １ -C ４ ) alkyl group or (C １ -C ４ ) an alkoxy group; R ２ and R ３ are independently a hydrogen atom or (C １ -C ３ ) alkyl group; A is: a phenyl radical substituted by a substituent X, where X is: (a) (C ３ -C ６ ) cycloalkyl, (C ３ -C ６ ) cycloalkylmethyl, (C ３ -C ６ ) cycloalkoxy, (C ３ -C ６ ) a group selected from cycloalkylamino and cyclohexenyl; or (b) phenyl, phenylmethyl, phenylcarbonyl, phenoxy, phenylamino, N—(C １ -C ３ ) a group selected from alkylphenylamino, phenylthio, phenylsulfinyl, and phenylsulfonyl a phenyl radical which is - unsubstituted or 1 or 2 hydroxyl groups, 1 or 2 (C １ -C ４ ) 1-naphthyl or 2-naphthyl radicals, either substituted in the 5-, 6-, 7- and / or 8-positions by alkoxy or 6,7-methylenedioxy groups; A pharmaceutical composition comprising:

2. R １ But CF ３ The pharmaceutical composition of claim 1 , wherein the compound is a group.

3. R ２ and R ３ The pharmaceutical composition of claim 1 , wherein at least one of is a hydrogen atom.

4. R ２ and R ３ The pharmaceutical composition of claim 1 , wherein each of is a hydrogen atom.

5. 2. The pharmaceutical composition of claim 1, wherein A is a biphenyl radical or an unsubstituted 2-naphthyl radical.

6. 2. The pharmaceutical composition of claim 1, wherein the salt is the hydrochloride or fumarate salt of the compound of formula (I).

7. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is pariloden or a pharmaceutically acceptable salt and / or solvate thereof.

8. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is the fumarate salt of pariloden and / or a solvate thereof.

9. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is xaliproden or a pharmaceutically acceptable salt and / or solvate thereof.

10. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is xaliproden hydrochloride and / or a solvate thereof.

11. The pharmaceutical composition according to any one of claims 1 to 10, which is administered to the subject by oral route or by transtympanic route.

12. The pharmaceutical composition described in claim 11, wherein the administration via the transtympanic route consists of an injection between the tympanic membrane and the cochlear window using a needle that passes through the tympanic membrane.

13. The pharmaceutical composition of claim 11, wherein the compound or its pharmaceutically acceptable salt and / or solvate is administered by transtympanic route at a dose ranging from 10 μg to 400 mg once a month to once every 12 months.

14. The pharmaceutical composition described in claim 13, wherein the administration by the transtympanic route consists of an injection between the tympanic membrane and the cochlear window using a needle that passes through the tympanic membrane.

15. 12. The pharmaceutical composition of claim 11, wherein the hearing disease is selected from the group consisting of unilateral or bilateral hearing loss, unilateral or bilateral tinnitus, unilateral or bilateral hyperacusis, hidden hearing loss such as cochlear synaptopathy with normal thresholds, speech intelligibility deficits, unilateral or bilateral temporary auditory threshold shifts, central auditory processing disorders, unilateral or bilateral auditory recruitment, acoustic neuroma, unilateral severe hearing loss, ototoxicity such as excitotoxicity, drug-induced ototoxicity, and any combination thereof.

16. The pharmaceutical composition described in claim 11, wherein the hearing disease is selected from the group consisting of unilateral and bilateral hearing loss such as unilateral and bilateral sensorineural hearing loss, unilateral or bilateral tinnitus, unilateral or bilateral hyperacusis, hidden hearing loss such as cochlear synaptic damage with normal threshold, and deficits in speech intelligibility.

17. 12. The pharmaceutical composition of claim 11, wherein the hearing disease is unilateral or bilateral sensorineural hearing loss selected from the group consisting of unilateral or bilateral noise-induced sensorineural hearing loss, unilateral or bilateral inflammation-induced sensorineural hearing loss, unilateral or bilateral sudden idiopathic sensorineural hearing loss, unilateral or bilateral ototoxic chemical-induced sensorineural hearing loss, and unilateral or bilateral age-induced sensorineural hearing loss such as presbycusis.

18. The pharmaceutical composition described in claim 11, wherein the hearing disease is unilateral or bilateral sensorineural hearing loss selected from the group consisting of unilateral or bilateral noise-induced sensorineural hearing loss and unilateral or bilateral age-induced sensorineural hearing loss.

19. The pharmaceutical composition according to claim 11, wherein the hearing disease is unilateral or bilateral inflammation-induced sensorineural hearing loss caused by a chronic inflammatory disease.

20. The pharmaceutical composition of claim 19, wherein the chronic inflammatory disease is selected from the group consisting of diabetes, chronic kidney disease, inflammatory bowel disease, and rheumatoid arthritis.

21. 12. The pharmaceutical composition of claim 11, wherein the hearing disorder is unilateral or bilateral hearing loss with tonal hearing thresholds greater than 30 dB at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus.

22. The pharmaceutical composition described in claim 11, wherein the hearing disorder is unilateral or bilateral hearing loss with tonal hearing thresholds of 30 dB to 70 dB at three consecutive frequencies, optionally associated with unilateral or bilateral tinnitus, and the tonal hearing thresholds are measured by auditory brainstem response or pure tone audiometry.

23. The pharmaceutical composition of claim 11 , wherein the subject is wearing at least one hearing device.

24. The pharmaceutical composition of claim 11, administered to the subject during cochlear surgery, such as cochlear implant surgery.

25. The pharmaceutical composition of claim 11 , wherein the subject is a mammal having a tympanic membrane.

26. The pharmaceutical composition described in claim 25, wherein the mammal having a tympanic membrane is selected from the group consisting of humans, cats, dogs and non-human primates.

27. ​​The pharmaceutical composition described in claim 25, wherein the mammal having a tympanic membrane is a dog.

28. 11. A transtympanic pharmaceutical composition comprising a combination of a compound of formula (I) as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt and / or solvate thereof and a mixture of a polyoxyethylated triglyceride and a poloxamer, wherein the transtympanic pharmaceutical composition is a thermoreversible gel.

29. The pharmaceutical composition of any one of claims 1 to 10, further comprising at least one pharmaceutically acceptable excipient.

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