Combination therapy for the treatment of hearing loss

Abstract

Provided herein are methods and compositions for the treatment of hearing impairment by administering a combination of two or more calcium channel blockers.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 478,889, filed January 6, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Hearing impairment is a growing health problem with diverse and complex etiologies. While some forms of hearing impairment are clearly genetic in origin, others are wholly or at least partially environmental in nature. One such common hearing impairment is tinnitus, a debilitating condition that can lead to fatigue, stress, sleep disturbances, concentration problems, memory impairment, depression, anxiety, irritability, and headaches, among other things. Tinnitus affects approximately 20% of the population and is particularly common among older adults or those who are regularly exposed to loud noise as an occupational hazard.

[0003] Meniere's disease is a disorder of the inner ear that can result in tinnitus (ringing in the ears), reduced or lost hearing, dizziness, and a feeling of fullness or congestion in the ears. Attacks of dizziness can occur suddenly or after a short period of tinnitus or muffled hearing. In some cases, a single attack of dizziness may occur separated by a long period of time. In other cases, a person may experience many attacks spaced closely together over several days. Some people with Meniere's disease have such extreme dizziness that they lose their balance and fall. Meniere's disease is often a severe and debilitating condition for those affected.

[0004] Treatment options for hearing disorders, such as tinnitus and Meniere's disease, are very limited, and most available treatments are non-pharmaceutical-based, which do not directly treat the constant tinnitus but rather focus on the patient's subjective management of the condition, e.g., using white noise machines or counseling. There remains a need in the art for pharmaceutical compositions for reducing, ameliorating, and / or counteracting one or more symptoms of hearing disorders. Summary of the Invention

[0005] Disclosed herein are combinations of pharmaceutical compositions for treating hearing disorders, such as tinnitus and Meniere's disease. The disclosure relates to novel combinations of therapeutic agents for the treatment of hearing disorders that exhibit superior efficacy over the individual agents acting alone.

[0006] In one aspect, described herein are methods for treating hearing impairment or symptoms of hearing impairment in a subject in need thereof. In some embodiments, the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a first agent comprising a first calcium channel blocker and a second agent comprising a second calcium channel blocker. In some embodiments, the first agent is nimodipine (NMDP) or a salt thereof, and the second agent is carbamazepine (CBZ) or a salt thereof. In some embodiments, the first agent is amlodipine (AML) or a salt thereof, and the second agent is carbamazepine or a salt thereof. In some embodiments, the first agent is nimodipine or a salt thereof, and the second agent is amlodipine or a salt thereof. In some embodiments, the first agent is tetrandrine (TET) or a salt thereof, and the second agent is nimodipine or a salt thereof. In some embodiments, the first agent is tetrandrine or a salt thereof, and the second agent is carbamazepine or a salt thereof. In some embodiments, the first agent is tetrandrine or a salt thereof, and the second agent is amlodipine or a salt thereof. In some embodiments, the first agent is an L-type calcium channel blocker. In some embodiments, the L-type calcium channel blocker is amlodipine. In some embodiments, the L-type calcium channel blocker is nimodipine. In some embodiments, the second agent is a potassium channel opener (e.g., retigabine). In some embodiments, the second agent is a GABAA receptor positive allosteric modulator (e.g., zolpidem). In some embodiments, the second agent is a dopamine receptor antagonist (e.g., risperidone). In some embodiments, the second agent is a serotonin antagonist and reuptake inhibitor (SARI, e.g., trazadone or nefazodone). In some embodiments, the second agent is a sodium channel blocker (e.g., carbamazepine). In some embodiments, the second agent comprises a SARI or a dopamine receptor antagonist, and the method can further treat anxiety, insomnia, or depression. In some embodiments, the first agent and the second agent are administered sequentially.In some embodiments, the first agent and the second agent are administered simultaneously.

[0007] In another aspect, methods for selecting a subject in need of treatment for hearing impairment or symptoms of hearing impairment are described herein. In some embodiments, the method includes administering a test drug comprising an L-type calcium channel blocker or an N-type calcium channel blocker to the subject. In some embodiments, the method includes evaluating whether the subject has responded to the test drug. In some embodiments, the method includes selecting the subject for administration of a first pharmaceutical composition if the subject has responded to the test drug comprising an L-type calcium channel blocker, or selecting the subject for administration of a second pharmaceutical composition if the subject has responded to the test drug comprising an N-type calcium channel blocker.

[0008] In some embodiments, the method comprises administering a therapeutically effective amount of a first pharmaceutical composition or a therapeutically effective amount of a second pharmaceutical composition. In some embodiments, the first pharmaceutical composition comprises i) a first agent comprising a first L-type calcium channel blocker, and ii) a second agent comprising a second N-type calcium channel blocker, a T-type calcium channel blocker, an L-type calcium channel blocker, or a nonspecific calcium channel blocker. In some embodiments, the second pharmaceutical composition comprises i) a third agent comprising a first N-type calcium channel blocker, and ii) a fourth agent comprising a second N-type calcium channel blocker or an L-type calcium channel blocker. In some embodiments, the test agent is selected from the group consisting of tetrandrine or a salt thereof, nimodipine or a salt thereof, carbamazepine or a salt thereof, and amlodipine or a salt thereof. In some embodiments, the first agent is selected from the group consisting of tetrandrine or a salt thereof, nimodipine or a salt thereof, and amlodipine or a salt thereof. In some embodiments, the first agent comprising an L-type calcium channel blocker comprises NMDP, CBZ, or AML. In some embodiments, the second agent comprising a second N-type calcium channel blocker, T-type calcium channel blocker, L-type calcium channel blocker, or nonspecific calcium channel blocker comprises TET.

[0009] In some embodiments, the second drug is selected from the group consisting of tetrandrine or a salt thereof, nimodipine or a salt thereof, amlodipine or a salt thereof, and carbamazepine or a salt thereof. In some embodiments, the third drug is selected from the group consisting of tetrandrine or a salt thereof, and carbamazepine or a salt thereof. In some embodiments, the fourth drug is selected from the group consisting of tetrandrine or a salt thereof, nimodipine or a salt thereof, amlodipine or a salt thereof, and carbamazepine or a salt thereof. In some embodiments, the method further comprises administering the pharmaceutical composition orally, intratympanically, bucally, intradermally, transdermally, topically, or by inhalation.

[0010] In some embodiments, the method comprises administering the pharmaceutical composition intravenously to a subject in need thereof. In some embodiments, the method comprises administering the pharmaceutical composition orally to a subject in need thereof. In some embodiments, the method comprises administering the pharmaceutical composition to a subject in need thereof by intratympanic injection. In some embodiments, the method comprises administering the pharmaceutical composition by contacting the composition with the crista fenestrae cochleae, round window, tympanic cavity, tympanic membrane, middle ear, or outer ear.

[0011] In some embodiments, the method comprises administering the pharmaceutical composition into the ear canal or into the vestibule of the ear. In some embodiments, the method comprises administering the pharmaceutical composition by a single dose of intratympanic injection. In some embodiments, the method comprises administering the pharmaceutical composition at any time before or after the onset of symptoms of hearing impairment that may be treatable with the pharmaceutical composition. In some embodiments, the method comprises administering the pharmaceutical composition about every 4 hours. In some embodiments, the method comprises administering the pharmaceutical composition about every 2 hours.

[0012] In some embodiments, the method comprises administering the pharmaceutical composition about every 8 hours. In some embodiments, the method comprises administering the pharmaceutical composition at least once daily, twice daily, three times daily, four times daily, five times daily, six times daily, seven times daily, eight times daily, nine times daily, or ten times daily.

[0013] In some embodiments, the method comprises administering the pharmaceutical composition once a week. In some embodiments, the method comprises administering the pharmaceutical composition via low-dose therapy. In some embodiments, the method comprises continuously administering the pharmaceutical composition. In some embodiments, the method comprises titrating the pharmaceutical composition to the vestibular symptoms. In some embodiments, the method comprises administering the pharmaceutical composition for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 6 months, or at least 1 year. In some embodiments, the method comprises administering another active pharmaceutical composition or a salt thereof to the subject. In some embodiments, the method comprises administering the pharmaceutical composition in a unit dosage form.

[0014] In some embodiments, the method comprises administering the pharmaceutical composition to the subject without altering the endocochlear potential. In some embodiments, the method comprises increasing the dose of the pharmaceutical composition to the subject until symptoms of an inner ear disorder are observed in the subject. In some embodiments, the method comprises increasing the dose of the pharmaceutical composition to the subject until the patient reports no instances of dizziness or a decrease in instances of dizziness. In some embodiments, the method comprises administering the pharmaceutical composition via a drug delivery device. In some embodiments, the method comprises delivering the pharmaceutical composition via a dropper bottle, needle, syringe, pump, microinjection device, microcatheter, or combinations thereof. In some embodiments, the method comprises discontinuing administration of the pharmaceutical composition once symptoms of an inner ear disorder are observed in the subject.

[0015] In some embodiments, the symptoms of the inner ear disorder include spontaneous nystagmus observed with Frenzel glasses, imbalance, exercise intolerance, or hearing loss / loss. In some embodiments, the pharmaceutical composition is administered at at least about 1 mg / ml. In some embodiments, the pharmaceutical composition is administered at a unit dose of about 1 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is administered at a unit dose of about 1 mg to about 100 mg. In some embodiments, the hearing impairment in the subject in need thereof is noise-induced hearing loss (NIHL). In some embodiments, the hearing impairment in the subject in need thereof is age-related hearing loss (ARHL) or presbycusis. In some embodiments, the hearing impairment in the subject in need thereof is injury- or drug-induced hearing loss.

[0016] In some embodiments, the hearing disorder in the subject in need thereof is tinnitus or Meniere's disease. In some embodiments, the therapeutically effective amount of NMDP is about 50 mg to about 1000 mg per kg of the subject in need thereof. In some embodiments, the therapeutically effective amount of AML is about 50 mg to about 1000 mg per kg of the subject in need thereof. In some embodiments, the therapeutically effective amount of CBZ is about 50 mg to about 1000 mg per kg of the subject in need thereof. In some embodiments, the therapeutically effective amount of TET is about 50 mg to about 1000 mg per kg of the subject in need thereof. In some embodiments, the effect of the test agent on the subject is measured by an assessment selected from the group consisting of: a) measurement of change in ABR threshold, b) change in auditory speech recognition as measured by a words-in-noise test, c) change in auditory speech recognition as measured by a digits-in-noise test, d) change in low frequency hearing threshold, e) change in incidence of adverse events after administration of said test agent, f) change in tinnitus severity, g) change in tinnitus loudness, h) change in dizziness severity, i) change in ear fullness, j) change in dizziness sensation, and k) change in hair cell function as measured by change in ABR threshold, after administration of a first or second test agent.

[0017] In some embodiments, ABR threshold measurements are performed in the frequency range of 5 kHz to 50 kHz. In some embodiments, the therapeutically effective amount of the first agent and the therapeutically effective amount of the second agent are less than the amount of the first agent or the second agent, when administered individually, required to treat the hearing impairment. In some embodiments, the therapeutically effective amount of the third agent and the therapeutically effective amount of the fourth agent provide a synergistic effect. In some embodiments, the therapeutically effective amount of the third agent and the therapeutically effective amount of the fourth agent are less than the amount of the third agent or the fourth agent, when administered individually, required to treat the hearing impairment. In some embodiments, the therapeutically effective amount of the third agent and the therapeutically effective amount of the fourth agent provide a synergistic effect.

[0018] In another aspect, described herein are pharmaceutical compositions for treating symptoms of hearing impairment in a subject in need thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of tetrandrine (TET) or a salt thereof and a pharmaceutically effective amount of nimodipine or a salt thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of tetrandrine or a salt thereof and a pharmaceutically effective amount of amlodipine or a salt thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of tetrandrine or a salt thereof and a pharmaceutically effective amount of carbamazepine (CBZ) or a salt thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of amlodipine (AML) or a salt thereof and a pharmaceutically effective amount of carbamazepine or a salt thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of nimodipine (NMDP) or a salt thereof and a pharmaceutically effective amount of amlodipine or a salt thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of nimodipine or a salt thereof and a pharmaceutically effective amount of carbamazepine or a salt thereof.

[0019] In some embodiments, the concentration of NMDP in the administered pharmaceutical composition is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 12 2.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350 or 400 mg / ml. In some embodiments, the concentration of TET in the administered pharmaceutical composition is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42 0.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350 or 400 mg / ml. In some embodiments, the concentration of CBZ in the administered pharmaceutical composition is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42 0.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350 or 400 mg / ml.

[0020] In some embodiments, the concentration of AML in the administered pharmaceutical composition is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42 In some embodiments, the volume of the pharmaceutical composition administered is 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.0 ml. In some embodiments, the pharmaceutical composition is released continuously, variably, or pulsatilely, or a combination thereof. In some embodiments, the pharmaceutical composition is in a unit dosage form. In some embodiments, the unit dosage form is a tablet, capsule, caplet, gelcap, powder, or solution dosage form. In some embodiments, the composition is aqueous.

[0021] In some embodiments, the composition is in the form of a gel or film. In some embodiments, the composition comprises micronized particles. In some embodiments, the unit dosage form has a unit weight of about 10 mg to about 10 g. In some embodiments, the pharmaceutical composition comprises NMDP at a concentration of about 0.1% to about 20% w / w of the formulation. In some embodiments, the pharmaceutical composition comprises tetrandrine or a salt thereof at a concentration of about 0.1% to about 20% of the formulation. In some embodiments, the pharmaceutical composition comprises carbamazepine or a salt thereof at a concentration of about 0.1% to about 20% of the formulation. In some embodiments, the pharmaceutical composition comprises amlodipine or a salt thereof at a concentration of about 0.1% to about 20% of the formulation.

[0022] These and other objects and features of the present disclosure will be more fully understood from the following detailed description of the disclosure, taken in conjunction with the accompanying examples and drawings.

[0023] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0024] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0025] [Figure 1A] The results of the go / no-go test of TET administered at doses of 30, 60, and 90 mg / kg are shown. [Figure 1B] The results of the go / no-go test for NMDP administered at doses of 10, 30, and 50 mg / kg are shown. [Figure 1C] The results of a go / no-go study of AML administered at doses of 5 and 8 mg / kg are shown. [Figure 1D] The results of the go / no-go test for CBZ administered at doses of 5 and 8 mg / kg are shown. [Figure 2A] The results of the go / no-go test of TET and NMDP, each administered at a dose of 10 mg / kg, are shown. [Figure 2B] 1 shows the results of a go / no-go test for ESM and GAB administered at 300 mg / kg ESM and 20 mg / kg GAB, and 300 mg / kg ESM and 40 mg / kg GAB. [Figure 3] 1 summarizes the go / no-go test tone based avoidance detection methodology utilized herein. [Figure 4] Shown are the results of no-go trials for TET and NMDP administered at 10 + 10 mg / kg, CBZ administered at 5 and 8 mg / kg, and CBZ and NMDP administered at 5 + 10 mg / kg. DETAILED DESCRIPTION OF THE INVENTION

[0026] In response to the unmet need in the art for pharmaceutical compositions for treating hearing impairment, disclosed herein are pharmaceutical compositions and combination therapies for treating hearing impairment, such as tinnitus or Meniere's disease. The present disclosure relates to novel pharmaceutical formulations and treatment methods for delivering an effective amount of a first therapeutic agent or a first therapeutic agent and a second therapeutic agent for treating hearing impairment (e.g., tinnitus or Meniere's disease). The first agent can include a first calcium channel blocker, and the second agent can include a second calcium channel blocker. The first agent can include a first L-type calcium channel blocker, and the second agent can include a second L-type calcium channel blocker, a T-type calcium channel blocker, an N-type calcium channel blocker, and / or a non-specific calcium channel blocker, a potassium channel opener, a sodium blocker, a GABAA modulator, and / or one or more SARIs. The combined administration of the first and second agents can be either sequential or simultaneous. Co-administration can include administration of a pharmaceutical composition or formulation that includes both a first and second agent described herein.

[0027] The compositions of the present disclosure can be administered by any typical route for administering pharmaceutical compositions, such as intravenous administration, injection, delivery, or oral administration.

[0028] The present researchers have developed a method of treatment that includes the use of a composition and a first and / or second agent to alleviate the symptoms of tinnitus or Meniere's disease after administration of one or more doses of the composition.

[0029] I. Definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms having commonly understood meanings are defined herein for clarity and / or quick reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0030] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0031] It should be noted that as used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "sample" includes multiple samples, including mixtures thereof.

[0032] The terms "determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present (e.g., detecting). These terms can include quantitative determination, qualitative determination, or quantitative and qualitative determination. Evaluation can be relative or absolute. "Detecting the presence of" can include determining the amount of something present in addition to determining whether it is present, as the case may be.

[0033] The terms "subject," "individual," or "patient" are often used interchangeably herein. A "subject" can be a biological entity containing expressed genetic material. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject can be tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro. A subject can be a mammal. A mammal can be a human. A subject may be diagnosed or suspected of being at high risk for a disease. In some cases, a subject is not necessarily diagnosed or suspected of being at high risk for a disease.

[0034] The term "in vivo" is used to describe events that take place inside a subject's body.

[0035] The term "ex vivo" is used to describe events that occur outside of a subject's body. An ex vivo assay is not performed on a subject. Rather, it is performed on a sample isolated from a subject. An example of an ex vivo assay performed on a sample is an "in vitro" assay.

[0036] The term "in vitro" is used to describe events that occur in a container that holds experimental reagents separate from the biological source from which the materials are obtained. In vitro assays can include cell-based assays in which live or dead cells are used. In vitro assays can also include cell-free assays in which intact cells are not used.

[0037] As used herein, the term "about" a number refers to ±10% of that number. The term "about" a range refers to a range spanning 10% of its lowest value minus 10% of its highest value.

[0038] As used herein, the terms "treatment" or "treating" refer to a pharmaceutical or other intervention regimen to achieve a beneficial or desired result in a recipient. Beneficial or desired results include, but are not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit can refer to the eradication or amelioration of the condition or underlying disease being treated. Furthermore, therapeutic benefit can be achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the subject, even though the subject may still be suffering from the underlying disease. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, delaying, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, subjects at risk of developing a particular disease or who report one or more physiological symptoms of a disease can receive treatment, even if a diagnosis of the disease cannot be made.

[0039] The term "nimodipine" is intended to relate to nimodipine or a pharmaceutically acceptable salt thereof. The term "equivalent to about ... nimodipine" is intended to relate to a specified volume, concentration, or amount of nimodipine free base provided by a certain volume, concentration, or amount of a salt of nimodipine (NMDP). Thus, the specified amount relates to the amount of nimodipine (NMDP) free base, not the amount of a nimodipine (NMDP) salt, despite the use of a salt in the composition. In one embodiment, the compositions, methods, and uses of the present disclosure include the use of nimodipine (NMDP) citrate salt.

[0040] The term "tetrandrine" is intended to refer to tetrandrine or a pharmaceutically acceptable salt thereof. The term "equivalent to about ... tetrandrine" is intended to refer to a specified volume, concentration, or amount of tetrandrine free base provided by a certain volume, concentration, or amount of tetrandrine (TET) salt. Thus, the specified amount relates to the amount of tetrandrine (TET) free base, not the amount of tetrandrine (TET) salt, despite the use of a salt in the composition. In one embodiment, the compositions, methods, and uses of the present disclosure include the use of tetrandrine (TET) citrate.

[0041] The term "carbamazepine" is intended to refer to tetrandrine or a pharmaceutically acceptable salt thereof. The term "equivalent to about ... carbamazepine" is intended to refer to a specified volume, concentration, or amount of carbamazepine free base provided by a certain volume, concentration, or amount of tetrandrine (CBZ) salt. Thus, the specified amount relates to the amount of carbamazepine (CBZ) free base, not the amount of carbamazepine (CBZ) salt, despite the use of a salt in the composition. In one embodiment, the compositions, methods, and uses of the present disclosure include the use of carbamazepine (CBZ) citrate salt.

[0042] The term "amlodipine" is intended to refer to tetrandrine or a pharmaceutically acceptable salt thereof. The term "equivalent to about ... amlodipine" is intended to refer to a specified volume, concentration, or amount of amlodipine free base provided by a certain volume, concentration, or amount of an amlodipine (AML) salt. Thus, the specified amount relates to the amount of amlodipine (AML) free base, not the amount of an amlodipine (AML) salt, despite the use of a salt in the composition. In one embodiment, the compositions, methods, and uses of the present disclosure include the use of amlodipine (AML) citrate salt.

[0043] The terms "ethosuximide" and "ESM" are intended to relate to ethosuximide or a pharmaceutically acceptable salt thereof.

[0044] The terms "gabapentin" and "GAB" are intended to refer to gabapentin or a pharmaceutically acceptable salt thereof.

[0045] The term "zolpidem" is intended to relate to zolpidem or a pharmaceutically acceptable salt thereof.

[0046] The term "retigabine" is intended to relate to zolpidem or a pharmaceutically acceptable salt thereof.

[0047] The terms "SARI" and "SARIs" generally refer to serotonin antagonists and reuptake inhibitors and their pharmaceutically acceptable salts. Examples of SARIs are trazodone, nefazodone, mCPP, hydroxynefazodone, etoperidone, triazolediones, combinations thereof, and / or pharmaceutically acceptable salts thereof.

[0048] The term "formulated" is intended to relate to the selection of excipients, carriers, vehicles, preservatives, stabilizers, etc. in the preparation of a medicament using said composition. The term "formulated" is further intended to relate to the selection of a device for delivery of the composition or the selection of a storage device for administration or storage of the composition.

[0049] The term "dosage unit" refers to a composition administered in one administration by one delivery act. A delivery act is the act of delivering a dosage unit. Treatment refers to administering the composition during one episode of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, said episode lasting until the tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease are alleviated.

[0050] The term "onset of action" is generally intended to mean the moment at which a patient begins to experience relief of tinnitus or Meniere's disease or the symptoms of tinnitus or Meniere's disease as a result of sufficient plasma concentrations of a first drug, typically comprising a first L-type calcium channel blocker, in combination with a second drug, typically comprising either a second L-type calcium channel blocker and / or an N-type calcium channel blocker. Plasma concentrations sufficient to achieve this all vary among patients, their grade and type, and the nature of tinnitus or Meniere's disease, or the symptoms of tinnitus or Meniere's disease experienced. The "action" in "onset of action" is relief of tinnitus or Meniere's disease, or the symptoms of tinnitus or Meniere's disease.

[0051] The term "duration of action" relates to the time that relief of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease is felt by the patient consistently.

[0052] By "long-term" is intended a period of more than about 4 months, preferably more than about 6 months.

[0053] The phrase "an amount effective to suppress one or more symptoms of tinnitus or Meniere's disease" refers to an amount of a therapeutic compound that reduces one or more symptoms of tinnitus or Meniere's disease in a subject following delivery of the pharmaceutical composition.

[0054] The terms used herein are merely for the purpose of describing particular embodiments and are not intended to limit the present disclosure. The terms "comprising" and "comprises" used in the claims should not be construed as being limited to the subsequently listed elements and steps. They do not exclude other elements or steps. They should be construed as specifying the presence of the stated features, integers, steps, and / or elements as recited, but do not exclude the presence and / or addition of one or more other features, integers, steps, or elements, or groups thereof. Thus, the scope of the expression "a composition comprising A and B" is not intended to be limited to a composition consisting solely of elements A and B. Similarly, the scope of the expression "a method comprising steps X and Z" is not intended to be limited to a method consisting solely of those steps.

[0055] As used herein, the term "about" a number refers to ±10% of that number. The term "about" a range refers to a range spanning 10% minus its lowest value plus 10% of its highest value. For example, the term "about" can be readily understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. By way of illustration, a numerical range of "about 1 to about 5" is intended to encompass not only the explicitly recited values ​​of about 1 to about 5, but also individual values ​​and subranges within the stated range. This includes, at least, the degree of experimental, technical, and instrumental error expected for a given experiment, technique, or device used to measure the value.

[0056] As used herein, the term "and / or" includes any combination of one or more of the associated listed items. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Terms, for example, those defined in commonly used dictionaries, should be interpreted to have a meaning consistent with their meaning in the context of this specification and the related art, and it will be further understood that they should not be interpreted in an idealized or overly formal sense unless explicitly defined as such herein. Well-known functions or configurations may not be described in detail for the sake of brevity and / or clarity.

[0057] When an element is referred to as "on," "attached," "connected," "coupled," "in contact with," etc., another element, it is understood that it can be directly on, attached to, connected to, coupled to, or in contact with the other element, or that intervening elements may also be present. In contrast, when an element is referred to as, for example, "directly on," "directly attached," "directly connected," "directly coupled," or "in direct contact with" another element, there are no intervening elements present. Those skilled in the art will also understand that references to structures or features disposed "adjacent" to another feature can have portions that overlap or underlie the adjacent feature.

[0058] The terms "active agent", "pharmaceutical active agent", "active", "API", "active pharmaceutical ingredient", "active substance", "active molecule", "active compound" or "drug" are used interchangeably with L-type calcium channel blockers and / or N-type calcium channel blockers and / or their salts.

[0059] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Terms, for example, those defined in commonly used dictionaries, should be interpreted to have a meaning consistent with their meaning in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless explicitly defined as such in this specification. Well-known functions or configurations may not be described in detail for the sake of brevity and / or clarity.

[0060] The disintegrant included in the disclosed composition is an inert carrier, as described in detail below. Note that the terms "disintegrant," "carrier," "diluent," and "disaggregating agent" are used interchangeably herein and refer to inactive ingredients added to the pharmaceutical composition, including the second type of particles.

[0061] "Non-infusion administration" means any delivery method that does not involve direct injection into an artery or vein, particularly a method of forcing or driving something (typically a fluid) into a body part by needle, syringe, or other invasive method. Non-infusion administration includes subcutaneous injection, intramuscular injection, intraperitoneal injection, and non-infusion methods of delivery to mucosal membranes.

[0062] A "subject" according to some embodiments is a subject whose symptoms, physical examination results, and / or psychological examination results are assessed and recorded in relation to the individual's condition (i.e., disease or disorder status). As used herein, the disease or disorder is hearing impairment. As used herein, the disease or disorder is tinnitus or Meniere's disease. As used herein, "subject" is intended to refer to, but is not necessarily limited to, a human subject. The subject may be male or female and may be of any race or ethnicity, including, but not limited to, Caucasian, African American, African, Asian, Hispanic, Native American, etc. As used herein, a subject is an animal, particularly a mammal that may be treated according to the methods of the present disclosure or screened for veterinary and pharmaceutical or pharmaceutical drug development purposes, such as a dog, cat, cow, goat, horse, sheep, or both, pig, rodent (e.g., rat and mouse), rabbit, primate (including non-human primate), etc. A subject according to some embodiments of the present disclosure includes a patient or human in need of therapeutic treatment for a disorder treatable by the compositions disclosed herein.

[0063] Methods and Compositions The disclosed method includes the combined administration of therapeutic doses of a first therapeutic agent and a second therapeutic agent to treat hearing disorders (e.g., tinnitus or Meniere's disease). The first agent can include a first L-type calcium channel blocker, and the second agent can include a second L-type calcium channel blocker or an N-type calcium channel blocker. The combined administration of the first and second agents can be sequential or simultaneous. The combined administration can include the administration of a pharmaceutical composition or formulation containing both the first and second agents described herein.

[0064] L-type calcium channel blockers may include, but are not limited to, nimodipine, tetrandrine, carbamazepine, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, efonidipine, and / or nicardipine, and pharmaceutically acceptable salts, solvates, and excipients thereof. N-type calcium channel blockers may include, but are not limited to, ω-conotoxin, cadmium, caroverine, cilnidipine, desipramine, gabapentin, levetiracetam, lamotrigine, nicardipine, piracetam, pregabalin, Trox-1, and / or ziconotide, and pharmaceutically acceptable salts, solvates, and excipients thereof. T-type calcium channel blockers may include, but are not limited to, tetrandrine, amlodipine, nimodipine, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, efonidipine, and / or nicardipine, as well as pharmaceutically acceptable salts, solvates, and excipients thereof. Non-specific calcium channel blockers may include, but are not limited to, tetrandrine, tetrandrine, amlodipine, nimodipine, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, efonidipine, and / or nicardipine, as well as pharmaceutically acceptable salts, solvates, and excipients thereof.

[0065] The compositions of the present disclosure can be administered by any typical route for administering pharmaceutical compositions, such as intravenous administration, injection, delivery, or oral administration. The first agent and the second agent can be administered sequentially (e.g., in two or more dosage forms) or simultaneously (e.g., in a single dosage form).

[0066] In some embodiments, the pharmaceutical composition is administered at a dose of about 1 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is administered at a dose of about 1 mg to about 2 mg, about 1 mg to about 3 mg, about 1 mg to about 4 mg, about 1 mg to about 5 mg, about 1 mg to about 6 mg, about 1 mg to about 7 mg, about 1 mg to about 8 mg, about 1 mg to about 9 mg, about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 50 mg, about 2 mg to about 3 mg, about 2 mg to about 4 mg, about 2 mg to about 5 mg, about 2 mg to about 6 mg, or about 2 mg to about 7 mg. , about 2 mg to about 8 mg, about 2 mg to about 9 mg, about 2 mg to about 10 mg, about 2 mg to about 20 mg, about 2 mg to about 50 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3 mg to about 6 mg, about 3 mg to about 7mg, about 3mg to about 8mg, about 3mg to about 9mg, about 3mg to about 10mg, about 3mg to about 20mg, about 3mg to about 50mg, about 4mg to about 5mg, about 4mg to about 6mg, about 4mg to about 7mg, about 4mg ~ about 8mg, ~ about 4mg to about 9mg, ~ about 4mg to about 10mg, ~ about 4mg to about 20mg, ~ about 4mg to about 50mg, ~ about 5mg to about 6mg, ~ about 5mg to about 7mg, ~ about 5mg to about 8mg, ~ about 5mg to about 9mg, ~ about 5mg to about 10mg, ~ about 5mg to about 20mg, ~ about 5mg to about 50mg, ~ about 6mg to about 7mg, ~ about 6mg to about 8mg, ~ about 6mg to about 9mg, ~ about 6mg to about 10mg, ~ about 6mg to about 20mg, ~ about 6mg to about 5 In some embodiments, the pharmaceutical composition is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg to about 8 mg, about 7 mg to about 9 mg, about 7 mg to about 10 mg, about 7 mg to about 20 mg, about 7 mg to about 50 mg, about 8 mg to about 9 mg, about 8 mg to about 10 mg, about 8 mg to about 20 mg, about 8 mg to about 50 mg, about 9 mg to about 10 mg, about 9 mg to about 20 mg, about 9 mg to about 50 mg, about 10 mg to about 20 mg, about 10 mg to about 50 mg, or about 20 mg to about 50 mg. In some embodiments, the pharmaceutical composition is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, or about 50 mg. In some embodiments, the pharmaceutical composition is administered at a dose of at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 20 mg. In some embodiments, the pharmaceutical composition is administered at a dose of at most about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 20 mg.The pharmaceutical composition is administered at a dose of about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, or about 50 mg. In some embodiments, the pharmaceutical composition is administered at a dose of about 20 mg to about 30 mg, about 20 mg to about 40 mg, about 20 mg to about 50 mg, about 20 mg to about 60 mg, about 20 mg to about 70 mg, about 20 mg to about 80 mg, about 20 mg to about 90 mg, about 20 mg to about 100 mg, about 20 mg to about 150 mg, about 20 mg to about 200 mg, about 20 mg to about 250 mg, about 30 mg to about 40 mg, about 30 mg to about 50 mg, about 30 mg to about 60 mg, about 30 mg to about 70 mg, about 30 mg to about 80 mg, or about 30mg to about 90mg, about 30mg to about 100mg, about 30mg to about 150mg, about 30mg to about 200mg, about 30mg to about 250mg, about 40mg to about 50mg, about 40mg to about 60mg, about 40mg to about 70mg, about 40mg to about 80 mg, approx. 40 mg to approx. 90 mg, approx. 40 mg to approx. 100 mg, approx. 40 mg to approx. 150 mg, approx. 40 mg to approx. 200 mg, approx. 40 mg to approx. 250 mg, approx. Approximately 90mg, approximately 50mg to approximately 100mg, approximately 50mg to approximately 150mg, approximately 50mg to approximately 200mg, approximately 50mg to approximately 250mg, approximately 60mg to approximately 70mg, approximately 60mg to approximately 80mg, approximately 60mg to approximately 90mg, approximately 60mg to approximately 100mg, approximately 60mg to about 150mg, about 60mg to about 200mg, about 60mg to about 250mg, about 70mg to about 80mg, about 70mg to about 90mg, about 70mg to about 100mg, about 70mg to about 150mg, about 70mg to about 200mg, about 70mg to about 2 In some embodiments, the pharmaceutical composition is administered at a dose of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg to about 90 mg, about 80 mg to about 100 mg, about 80 mg to about 150 mg, about 80 mg to about 200 mg, about 80 mg to about 250 mg, about 90 mg to about 100 mg, about 90 mg to about 150 mg, about 90 mg to about 200 mg, about 90 mg to about 250 mg, about 100 mg to about 150 mg, about 100 mg to about 200 mg, about 100 mg to about 250 mg, about 150 mg to about 200 mg, about 150 mg to about 250 mg, or about 200 mg to about 250 mg.or about 250 mg. In some embodiments, the pharmaceutical composition is administered at a dose of at least about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the pharmaceutical composition is administered at a dose of up to about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg. In some embodiments, the pharmaceutical composition contains about 100 mg to about 200 mg, about 100 mg to about 250 mg, about 100 mg to about 300 mg, about 100 mg to about 350 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 100 mg to about 600 mg, about 100 mg to about 700 mg, about 100 mg to about 800 mg, about 100 mg to about 900 mg, about 100 mg to about 1,000 mg, about 200 mg to about 250 mg, about 200 mg to about 300 mg, about 350 mg, ...400 mg, about 500 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 100 mg to about 1,000 mg, about 200 mg to about 350 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 100 mg to about 1,000 mg, about 200 mg to about 350 mg, about 400 mg, about 500 mg, about 600 mg ~ about 300mg, about 200mg - about 350mg, about 200mg - about 400mg, about 200mg - about 500mg, about 200mg - about 600mg, about 200mg - about 700mg, about 200mg - about 800mg, about 2 00mg to about 900mg, about 200mg to about 1,000mg, about 250mg to about 300mg, about 250mg to about 350mg, about 250mg to about 400mg, about 250mg to about 500mg, about 250mg to about 600mg , about 250 mg to about 700 mg, about 250 mg to about 800 mg, about 250 mg to about 900 mg, about 250 mg to about 1,000 mg, about 300 mg to about 350 mg, about 300 mg to about 400 mg, about 300 mg to about 5 00mg, about 300mg to about 600mg, about 300mg to about 700mg, about 300mg to about 800mg, about 300mg to about 900mg, about 300mg to about 1,000mg, about 350mg to about 400mg, about 350mg ~500mg, 350mg~600mg, 350mg~700mg, 350mg~800mg, 350mg~900mg, 350mg~1,000mg, 400mg~500mg, 40 0mg to about 600mg, about 400mg to about 700mg, about 400mg to about 800mg, about 400mg to about 900mg, about 400mg to about 1,000mg, about 500mg to about 600mg, about 500mg to about 700mg,It is administered at a dose of about 500 mg to about 800 mg, about 500 mg to about 900 mg, about 500 mg to about 1,000 mg, about 600 mg to about 700 mg, about 600 mg to about 800 mg, about 600 mg to about 900 mg, about 600 mg to about 1,000 mg, about 700 mg to about 800 mg, about 700 mg to about 900 mg, about 700 mg to about 1,000 mg, about 800 mg to about 900 mg, about 800 mg to about 1,000 mg, or about 900 mg to about 1,000 mg. In some embodiments, the pharmaceutical composition is administered at a dose of about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the pharmaceutical composition is administered at a dose of at least about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg. In some embodiments, the pharmaceutical composition is administered at a dose of up to about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the pharmaceutical composition is administered at a dose of about 1 mg to about 2,000 mg. In some embodiments, the pharmaceutical composition is administered at a dose of about 1 mg to about 50 mg, about 1 mg to about 100 mg, about 1 mg to about 200 mg, about 1 mg to about 300 mg, about 1 mg to about 500 mg, about 1 mg to about 750 mg, about 1 mg to about 1,000 mg, about 1 mg to about 1,250 mg, about 1 mg to about 1,500 mg, about 1 mg to about 1,750 mg, about 1 mg to about 2,000 mg, about 50 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 300 mg, about 50 mg ~ approx. 500 mg, approx. 50 mg ~ approx. 750 mg, approx. 50 mg ~ approx. 1,000 mg, approx. 50 mg ~ approx. 1,250 mg, approx. 0mg to about 200mg, about 100mg to about 300mg, about 100mg to about 500mg, about 100mg to about 750mg, about 100mg to about 1,000mg, about 100mg to about 1,250mg, about 100mg to about 1,500mg,Approximately 100mg to approximately 1,750mg, approximately 100mg to approximately 2,000mg, approximately 200mg to approximately 300mg, approximately 200mg to approximately 500mg, approximately 200mg to approximately 750mg, approximately 200mg ~1,000mg, 200mg~1,250mg, 200mg~1,500mg, 200mg~1,750mg, 200mg~2,000mg, 300mg~ Approximately 500mg, approximately 300mg to approximately 750mg, approximately 300mg to approximately 1,000mg, approximately 300mg to approximately 1,250mg, approximately 300mg to approximately 1,500mg, approximately 300mg to approximately 1,75 0mg, about 300mg to about 2,000mg, about 500mg to about 750mg, about 500mg to about 1,000mg, about 500mg to about 1,250mg, about 500mg to about 1,500mg , about 500mg to about 1,750mg, about 500mg to about 2,000mg, about 750mg to about 1,000mg, about 750mg to about 1,250mg, about 750mg to about 1,500mg , about 750mg to about 1,750mg, about 750mg to about 2,000mg, about 1,000mg to about 1,250mg, about 1,000mg to about 1,500mg, about 1,000mg to about 1, In some embodiments, the pharmaceutical composition is administered at a dose of about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 500 mg, about 750 mg, about 1,000 mg to about 2,000 mg, about 1,250 mg to about 1,500 mg, about 1,250 mg to about 1,750 mg, about 1,250 mg to about 2,000 mg, about 1,500 mg to about 1,750 mg, or about 1,750 mg to about 2,000 mg (including increments therein). In some embodiments, the pharmaceutical composition is administered at a dose of at least about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, or about 1,750 mg. In some embodiments, the pharmaceutical composition is administered at a dose of at most about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, or about 1,750 mg.The pharmaceutical composition is administered in a dose of about 1,750 mg or about 2,000 mg. In some embodiments, the pharmaceutical composition is administered in a therapeutically effective dose.

[0067] The first and / or second therapeutically effective amount can depend on the body weight of the subject. In some cases, the first and / or second therapeutically effective amount is at least about 1 mg of the first and / or second per kg of subject, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg of the first and / or second per kg of subject.

[0068] In some embodiments, the pharmaceutical composition is administered in about 1 dose per day to about 12 doses per day.In some embodiments, the pharmaceutical composition comprises from about 1 dose / day to about 2 doses / day, from about 1 dose / day to about 3 doses / day, from about 1 dose / day to about 4 doses / day, from about 1 dose / day to about 5 doses / day, from about 1 dose / day to about 6 doses / day, from about 1 dose / day to about 7 doses / day, from about 1 dose / day to about 8 doses / day, from about 1 dose / day to about 9 doses / day, from about 1 dose / day to about 10 doses / day, from about 1 dose / day to about 11 doses / day, from about 1 dose / day to about 12 doses / day, from about 2 doses / day to about 3 doses / day, from about 2 doses / day to about 4 doses / day, from about 2 doses / day to about 5 doses / day, from about 2 doses / day to about 6 doses / day, from about 2 doses / day to about 7 doses / day, About 2 doses / day to about 8 doses / day, about 2 doses / day to about 9 doses / day, about 2 doses / day to about 10 doses / day, about 2 doses / day to about 11 doses / day, about 2 doses / day to about 12 doses / day, about 3 doses / day to about 4 doses / day, about 3 doses / day to about 5 doses / day, about 3 doses / day to about 6 doses / day, about 3 doses / day to about 7 doses / day, about 3 doses / day to about 8 doses / day, about 3 doses / day to about 9 doses / day, about 3 doses / day to about 10 doses / day, about 3 doses / day to about 11 doses / day, about 3 doses / day to about 12 doses / day, about 4 doses / day to about 5 doses / day, about 4 doses / day to about 6 doses / day, about 4 doses / day to about 7 doses / day, about 4 doses / day Dosage / day ~ 8 doses / day, 4 doses / day ~ 9 doses / day, 4 doses / day ~ 10 doses / day, 4 doses / day ~ 11 doses / day, 4 doses / day ~ 12 doses / day, 5 doses / day ~ 6 doses / day, 5 doses / day ~ 7 doses / day, 5 doses / day ~ 8 doses / day, 5 doses / day ~ 9 doses / day Amount / day, about 5 doses / day to about 10 doses / day, about 5 doses / day to about 11 doses / day, about 5 doses / day to about 12 doses / day, about 6 doses / day to about 7 doses / day, about 6 doses / day to about 8 doses / day, about 6 doses / day to about 9 doses / day, about 6 doses / day to about 10 doses / day, about 6 doses / day to about 11 doses / day, about 6 doses / day doses / day to about 12 doses / day, about 7 doses / day to about 8 doses / day, about 7 doses / day to about 9 doses / day, about 7 doses / day to about 10 doses / day, about 7 doses / day to about 11 doses / day, about 7 doses / day to about 12 doses / day, about 8 doses / day to about 9 doses / day, about 8 doses / day to about 10 doses / day, about 8 doses / day to about 11 doses / day, about 8 doses / day to about 12 doses / day, about 9 doses / day to about 10 doses / day, about 9 doses / day to about 11 doses / day, about 9 doses / day to about 12 doses / day, about 10 doses / day to about 11 doses / day, about 10 doses / day to about 12 doses / day, or about 11 doses / day to about 12 doses / day.In some embodiments, the pharmaceutical composition is administered at about 1 dose / day, about 2 doses / day, about 3 doses / day, about 4 doses / day, about 5 doses / day, about 6 doses / day, about 7 doses / day, about 8 doses / day, about 9 doses / day, about 10 doses / day, about 11 doses / day, or about 12 doses / day. In some embodiments, the pharmaceutical composition is administered at least about 1 dose / day, about 2 doses / day, about 3 doses / day, about 4 doses / day, about 5 doses / day, about 6 doses / day, about 7 doses / day, about 8 doses / day, about 9 doses / day, about 10 doses / day, or about 11 doses / day. In some embodiments, the pharmaceutical composition is administered at a maximum of about 2 doses / day, about 3 doses / day, about 4 doses / day, about 5 doses / day, about 6 doses / day, about 7 doses / day, about 8 doses / day, about 9 doses / day, about 10 doses / day, about 11 doses / day, or about 12 doses / day.

[0069] In some embodiments, the first drug is administered at a dose of about 1 mg to about 1,000 mg. In some embodiments, the first drug is administered at a dose of about 1 mg to about 2 mg, about 1 mg to about 3 mg, about 1 mg to about 4 mg, about 1 mg to about 5 mg, about 1 mg to about 6 mg, about 1 mg to about 7 mg, about 1 mg to about 8 mg, about 1 mg to about 9 mg, about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 50 mg, about 2 mg to about 3 mg, about 2 mg to about 4 mg, about 2 mg to about 5 mg, about 2 mg to about 6 mg, or about 2 mg to about 7 mg. , about 2 mg to about 8 mg, about 2 mg to about 9 mg, about 2 mg to about 10 mg, about 2 mg to about 20 mg, about 2 mg to about 50 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3 mg to about 6 mg, about 3 mg to about 7mg, about 3mg to about 8mg, about 3mg to about 9mg, about 3mg to about 10mg, about 3mg to about 20mg, about 3mg to about 50mg, about 4mg to about 5mg, about 4mg to about 6mg, about 4mg to about 7mg, about 4mg ~ about 8mg, ~ about 4mg to about 9mg, ~ about 4mg to about 10mg, ~ about 4mg to about 20mg, ~ about 4mg to about 50mg, ~ about 5mg to about 6mg, ~ about 5mg to about 7mg, ~ about 5mg to about 8mg, ~ about 5mg to about 9mg, ~ about 5mg to about 10mg, ~ about 5mg to about 20mg, ~ about 5mg to about 50mg, ~ about 6mg to about 7mg, ~ about 6mg to about 8mg, ~ about 6mg to about 9mg, ~ about 6mg to about 10mg, ~ about 6mg to about 20mg, ~ about 6mg to about 5 In some embodiments, the first agent is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg to about 8 mg, about 7 mg to about 9 mg, about 7 mg to about 10 mg, about 7 mg to about 20 mg, about 7 mg to about 50 mg, about 8 mg to about 9 mg, about 8 mg to about 10 mg, about 8 mg to about 20 mg, about 8 mg to about 50 mg, about 9 mg to about 10 mg, about 9 mg to about 20 mg, about 9 mg to about 50 mg, about 10 mg to about 20 mg, about 10 mg to about 50 mg, or about 20 mg to about 50 mg. In some embodiments, the first agent is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, or about 50 mg. In some embodiments, the first agent is administered in a dose of at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 20 mg.In some embodiments, the first agent is administered at a dose of up to about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, or about 50 mg. In some embodiments, the first agent is administered at a dose of about 20 mg to about 250 mg. In some embodiments, the first drug is about 20 mg to about 30 mg, about 20 mg to about 40 mg, about 20 mg to about 50 mg, about 20 mg to about 60 mg, about 20 mg to about 70 mg, about 20 mg to about 80 mg, about 20 mg to about 90 mg, about 20 mg to about 100 mg, about 20 mg to about 150 mg, about 20 mg to about 200 mg, about 20 mg to about 250 mg, about 30 mg to about 40 mg, about 30 mg to about 50 mg, about 30 mg to about 60 mg, about 30 mg to about 70 mg, about 30 mg to about 80 mg, or about 30mg to about 90mg, about 30mg to about 100mg, about 30mg to about 150mg, about 30mg to about 200mg, about 30mg to about 250mg, about 40mg to about 50mg, about 40mg to about 60mg, about 40mg to about 70mg, about 40mg to about 80 mg, approx. 40 mg to approx. 90 mg, approx. 40 mg to approx. 100 mg, approx. 40 mg to approx. 150 mg, approx. 40 mg to approx. 200 mg, approx. 40 mg to approx. 250 mg, approx. Approximately 90mg, approximately 50mg to approximately 100mg, approximately 50mg to approximately 150mg, approximately 50mg to approximately 200mg, approximately 50mg to approximately 250mg, approximately 60mg to approximately 70mg, approximately 60mg to approximately 80mg, approximately 60mg to approximately 90mg, approximately 60mg to approximately 100mg, approximately 60mg to about 150mg, about 60mg to about 200mg, about 60mg to about 250mg, about 70mg to about 80mg, about 70mg to about 90mg, about 70mg to about 100mg, about 70mg to about 150mg, about 70mg to about 200mg, about 70mg to about 2 It is administered at a dose of 50 mg, about 80 mg to about 90 mg, about 80 mg to about 100 mg, about 80 mg to about 150 mg, about 80 mg to about 200 mg, about 80 mg to about 250 mg, about 90 mg to about 100 mg, about 90 mg to about 150 mg, about 90 mg to about 200 mg, about 90 mg to about 250 mg, about 100 mg to about 150 mg, about 100 mg to about 200 mg, about 100 mg to about 250 mg, about 150 mg to about 200 mg, about 150 mg to about 250 mg, or about 200 mg to about 250 mg.In some embodiments, the first agent is administered at a dose of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg. In some embodiments, the first agent is administered at a dose of at least about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the first agent is administered at a dose of up to about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg. In some embodiments, the first agent is administered at a dose of about 100 mg to about 1,000 mg.In some embodiments, the first drug is about 100 mg to about 200 mg, about 100 mg to about 250 mg, about 100 mg to about 300 mg, about 100 mg to about 350 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 100 mg to about 600 mg, about 100 mg to about 700 mg, about 100 mg to about 800 mg, about 100 mg to about 900 mg, about 100 mg to about 1,000 mg, about 200 mg to about 250 mg, about 200 mg to about 300 mg, about 200 mg to about 350 mg, about 200 mg to about 400 mg, or about 200 mg to about 500 mg , approx. 200 mg ~ approx. 600 mg, approx. 200 mg ~ approx. 700 mg, approx. 200 mg ~ approx. 800 mg, approx. 200 mg ~ approx. 900 mg, approx. 200 mg ~ approx. 1,000 mg, approx. About 500mg, about 250mg to about 600mg, about 250mg to about 700mg, about 250mg to about 800mg, about 250mg to about 900mg, about 250mg to about 1,000mg, about 300mg to about 350mg, about 300mg to about 400mg, about 300mg to about 500mg, about 300mg to about 600mg, about 300mg to about 700mg, about 300mg to about 800mg, about 300mg to about 900mg, about 300mg to about 1,000mg, about 350mg to about 400mg, about 350mg to about 500mg, about 350mg to about 600mg, about 350mg to about 7 00mg, about 350mg to about 800mg, about 350mg to about 900mg, about 350mg to about 1,000mg, about 400mg to about 500mg, about 400mg to about 600mg, about 400mg to about 700mg, about 400mg to about 800mg, about 400mg to about 900mg, about 40 The dose is administered at a range of 0 mg to about 1,000 mg, about 500 mg to about 600 mg, about 500 mg to about 700 mg, about 500 mg to about 800 mg, about 500 mg to about 900 mg, about 500 mg to about 1,000 mg, about 600 mg to about 700 mg, about 600 mg to about 800 mg, about 600 mg to about 900 mg, about 600 mg to about 1,000 mg, about 700 mg to about 800 mg, about 700 mg to about 900 mg, about 700 mg to about 1,000 mg, about 800 mg to about 900 mg, about 800 mg to about 1,000 mg, or about 900 mg to about 1,000 mg.In some embodiments, the first agent is administered at a dose of about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the first agent is administered at a dose of at least about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg. In some embodiments, the first agent is administered at a dose of up to about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the dose of the first agent is a therapeutically effective dose.

[0070] In some embodiments, the second agent is administered at a dose of about 1 mg to about 1000 mg. In some embodiments, the second agent is administered at a dose of about 1 mg to about 2 mg, about 1 mg to about 3 mg, about 1 mg to about 4 mg, about 1 mg to about 5 mg, about 1 mg to about 6 mg, about 1 mg to about 7 mg, about 1 mg to about 8 mg, about 1 mg to about 9 mg, about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 50 mg, about 2 mg to about 3 mg, about 2 mg to about 4 mg, about 2 mg to about 5 mg, about 2 mg to about 6 mg, or about 2 mg to about 7 mg. , about 2 mg to about 8 mg, about 2 mg to about 9 mg, about 2 mg to about 10 mg, about 2 mg to about 20 mg, about 2 mg to about 50 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3 mg to about 6 mg, about 3 mg to about 7mg, about 3mg to about 8mg, about 3mg to about 9mg, about 3mg to about 10mg, about 3mg to about 20mg, about 3mg to about 50mg, about 4mg to about 5mg, about 4mg to about 6mg, about 4mg to about 7mg, about 4mg ~ about 8mg, ~ about 4mg to about 9mg, ~ about 4mg to about 10mg, ~ about 4mg to about 20mg, ~ about 4mg to about 50mg, ~ about 5mg to about 6mg, ~ about 5mg to about 7mg, ~ about 5mg to about 8mg, ~ about 5mg to about 9mg, ~ about 5mg to about 10mg, ~ about 5mg to about 20mg, ~ about 5mg to about 50mg, ~ about 6mg to about 7mg, ~ about 6mg to about 8mg, ~ about 6mg to about 9mg, ~ about 6mg to about 10mg, ~ about 6mg to about 20mg, ~ about 6mg to about 5 In some embodiments, the second agent is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg to about 8 mg, about 7 mg to about 9 mg, about 7 mg to about 10 mg, about 7 mg to about 20 mg, about 7 mg to about 50 mg, about 8 mg to about 9 mg, about 8 mg to about 10 mg, about 8 mg to about 20 mg, about 8 mg to about 50 mg, about 9 mg to about 10 mg, about 9 mg to about 20 mg, about 9 mg to about 50 mg, about 10 mg to about 20 mg, about 10 mg to about 50 mg, or about 20 mg to about 50 mg. In some embodiments, the second agent is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, or about 50 mg. In some embodiments, the second agent is administered in a dose of at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 20 mg.In some embodiments, the second agent is administered at a dose of up to about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, or about 50 mg. In some embodiments, the second agent is administered at a dose of about 20 mg to about 250 mg. In some embodiments, the second agent is about 20 mg to about 30 mg, about 20 mg to about 40 mg, about 20 mg to about 50 mg, about 20 mg to about 60 mg, about 20 mg to about 70 mg, about 20 mg to about 80 mg, about 20 mg to about 90 mg, about 20 mg to about 100 mg, about 20 mg to about 150 mg, about 20 mg to about 200 mg, about 20 mg to about 250 mg, about 30 mg to about 40 mg, about 30 mg to about 50 mg, about 30 mg to about 60 mg, about 30 mg to about 70 mg, about 30 mg to about 80 mg, or about 30mg to about 90mg, about 30mg to about 100mg, about 30mg to about 150mg, about 30mg to about 200mg, about 30mg to about 250mg, about 40mg to about 50mg, about 40mg to about 60mg, about 40mg to about 70mg, about 40mg to about 80 mg, approx. 40 mg to approx. 90 mg, approx. 40 mg to approx. 100 mg, approx. 40 mg to approx. 150 mg, approx. 40 mg to approx. 200 mg, approx. 40 mg to approx. 250 mg, approx. Approximately 90mg, approximately 50mg to approximately 100mg, approximately 50mg to approximately 150mg, approximately 50mg to approximately 200mg, approximately 50mg to approximately 250mg, approximately 60mg to approximately 70mg, approximately 60mg to approximately 80mg, approximately 60mg to approximately 90mg, approximately 60mg to approximately 100mg, approximately 60mg to about 150mg, about 60mg to about 200mg, about 60mg to about 250mg, about 70mg to about 80mg, about 70mg to about 90mg, about 70mg to about 100mg, about 70mg to about 150mg, about 70mg to about 200mg, about 70mg to about 2 It is administered at a dose of 50 mg, about 80 mg to about 90 mg, about 80 mg to about 100 mg, about 80 mg to about 150 mg, about 80 mg to about 200 mg, about 80 mg to about 250 mg, about 90 mg to about 100 mg, about 90 mg to about 150 mg, about 90 mg to about 200 mg, about 90 mg to about 250 mg, about 100 mg to about 150 mg, about 100 mg to about 200 mg, about 100 mg to about 250 mg, about 150 mg to about 200 mg, about 150 mg to about 250 mg, or about 200 mg to about 250 mg.In some embodiments, the second agent is administered at a dose of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg. In some embodiments, the second agent is administered at a dose of at least about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the second agent is administered at a dose of up to about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg. In some embodiments, the second agent is administered in a dose of about 100 mg to about 1,000 mg.In some embodiments, the second drug is about 100 mg to about 200 mg, about 100 mg to about 250 mg, about 100 mg to about 300 mg, about 100 mg to about 350 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 100 mg to about 600 mg, about 100 mg to about 700 mg, about 100 mg to about 800 mg, about 100 mg to about 900 mg, about 100 mg to about 1,000 mg, about 200 mg to about 250 mg, about 200 mg to about 300 mg, about 200 mg to about 350 mg, about 200 mg to about 400 mg, or about 200 mg to about 500 mg , approx. 200 mg ~ approx. 600 mg, approx. 200 mg ~ approx. 700 mg, approx. 200 mg ~ approx. 800 mg, approx. 200 mg ~ approx. 900 mg, approx. 200 mg ~ approx. 1,000 mg, approx. About 500mg, about 250mg to about 600mg, about 250mg to about 700mg, about 250mg to about 800mg, about 250mg to about 900mg, about 250mg to about 1,000mg, about 300mg to about 350mg, about 300mg to about 400mg, about 300mg to about 500mg, about 300mg to about 600mg, about 300mg to about 700mg, about 300mg to about 800mg, about 300mg to about 900mg, about 300mg to about 1,000mg, about 350mg to about 400mg, about 350mg to about 500mg, about 350mg to about 600mg, about 350mg to about 7 00mg, about 350mg to about 800mg, about 350mg to about 900mg, about 350mg to about 1,000mg, about 400mg to about 500mg, about 400mg to about 600mg, about 400mg to about 700mg, about 400mg to about 800mg, about 400mg to about 900mg, about 40 The dose is administered at a range of 0 mg to about 1,000 mg, about 500 mg to about 600 mg, about 500 mg to about 700 mg, about 500 mg to about 800 mg, about 500 mg to about 900 mg, about 500 mg to about 1,000 mg, about 600 mg to about 700 mg, about 600 mg to about 800 mg, about 600 mg to about 900 mg, about 600 mg to about 1,000 mg, about 700 mg to about 800 mg, about 700 mg to about 900 mg, about 700 mg to about 1,000 mg, about 800 mg to about 900 mg, about 800 mg to about 1,000 mg, or about 900 mg to about 1,000 mg.In some embodiments, the second agent is administered at a dose of about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the second agent is administered at a dose of at least about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg. In some embodiments, the second agent is administered at a dose of up to about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the dose of the second agent is a therapeutically effective dose.

[0071] In some embodiments, the ratio of the first drug to the second drug is about 0.01 to about 1. In some embodiments, the ratio of the first drug to the second drug is about 0.01 to about 0.05, about 0.01 to about 0.1, about 0.01 to about 0.2, about 0.01 to about 0.3, about 0.01 to about 0.4, about 0.01 to about 0.5, about 0.01 to about 0.6, about 0.01 to about 0.7, about 0.01 to about 0.8, about 0.01 to about 0.9, about 0.01 to about 1, about 0.05 to about 0.1, about 0.05 to about 0.2, about 0.0 0.5 to about 0.3, about 0.05 to about 0.4, about 0.05 to about 0.5, about 0.05 to about 0.6, about 0.05 to about 0.7, about 0.05 to about 0.8, about 0.05 to about 0.9, about 0.05 to about 1, about 0.1 to about 0.2, about 0.1 to about 0.3, about 0.1 to about 0.4, about 0.1 to about 0.5, about 0.1 to about 0.6, about 0.1 to about 0.7, about 0.1 to about 0.8, about 0.1 to about 0.9, about 0.1 to about 1, about 0. 2 to about 0.3, about 0.2 to about 0.4, about 0.2 to about 0.5, about 0.2 to about 0.6, about 0.2 to about 0.7, about 0.2 to about 0.8, about 0.2 to about 0.9, about 0.2 to about 1, about 0.3 to about 0.4, about 0.3 to about 0.5, about 0.3 to about 0.6, about 0.3 to about 0.7, about 0.3 to about 0.8, about 0.3 to about 0.9, about 0.3 to about 1, about 0.4 to about 0.5, about 0.4 to about 0.6, about 0.4 to about 0.7, about 0.4 to about 0.8, about 0.4 to about 0.9, about 0.4 to about 1, about 0.5 to about 0.6, about 0.5 to about 0.7, about 0.5 to about 0.8, about 0.5 to about 0.9, about 0.5 to about 1, about 0.6 to about 0.7, about 0.6 to about 0.8, about 0.6 to about 0.9, about 0.6 to about 1, about 0.7 to about 0.8, about 0.7 to about 0.9, about 0.7 to about 1, about 0.8 to about 0.9, about 0.8 to about 1, or about 0.9 to about 1. In some embodiments, the ratio of the first agent to the second agent is about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1. In some embodiments, the ratio of the first agent to the second agent is at least about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9.In some embodiments, the ratio of the first agent to the second agent is at most about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.

[0072] In some embodiments, the ratio of the second drug to the first drug is about 0.01 to about 1. In some embodiments, the ratio of the second drug to the first drug is about 0.01 to about 0.05, about 0.01 to about 0.1, about 0.01 to about 0.2, about 0.01 to about 0.3, about 0.01 to about 0.4, about 0.01 to about 0.5, about 0.01 to about 0.6, about 0.01 to about 0.7, about 0.01 to about 0.8, about 0.01 to about 0.9, about 0.01 to about 1, about 0.05 to about 0.1, about 0.05 to about 0.2, about 0.0 0.5 to about 0.3, about 0.05 to about 0.4, about 0.05 to about 0.5, about 0.05 to about 0.6, about 0.05 to about 0.7, about 0.05 to about 0.8, about 0.05 to about 0.9, about 0.05 to about 1, about 0.1 to about 0.2, about 0.1 to about 0.3, about 0.1 to about 0.4, about 0.1 to about 0.5, about 0.1 to about 0.6, about 0.1 to about 0.7, about 0.1 to about 0.8, about 0.1 to about 0.9, about 0.1 to about 1, about 0. 2 to about 0.3, about 0.2 to about 0.4, about 0.2 to about 0.5, about 0.2 to about 0.6, about 0.2 to about 0.7, about 0.2 to about 0.8, about 0.2 to about 0.9, about 0.2 to about 1, about 0.3 to about 0.4, about 0.3 to about 0.5, about 0.3 to about 0.6, about 0.3 to about 0.7, about 0.3 to about 0.8, about 0.3 to about 0.9, about 0.3 to about 1, about 0.4 to about 0.5, about 0.4 to about 0.6, about 0.4 to about 0.7, about 0.4 to about 0.8, about 0.4 to about 0.9, about 0.4 to about 1, about 0.5 to about 0.6, about 0.5 to about 0.7, about 0.5 to about 0.8, about 0.5 to about 0.9, about 0.5 to about 1, about 0.6 to about 0.7, about 0.6 to about 0.8, about 0.6 to about 0.9, about 0.6 to about 1, about 0.7 to about 0.8, about 0.7 to about 0.9, about 0.7 to about 1, about 0.8 to about 0.9, about 0.8 to about 1, or about 0.9 to about 1. In some embodiments, the ratio of the second agent to the first agent is about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1. In some embodiments, the ratio of the second agent to the first agent is at least about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9.In some embodiments, the ratio of the second agent to the first agent is at most about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.

[0073] In some embodiments, the minimum therapeutically effective dose of the first agent is reduced by about 5% when co-administered with the second agent compared to when administered alone, to about 80% when co-administered with the second agent compared to when administered alone. In some embodiments, the minimum therapeutically effective dose of the first agent is reduced by about 5% when co-administered with the second agent compared to when administered alone, to about 10% when co-administered with the second agent compared to when administered alone, to about 5% when co-administered with the second agent compared to when administered alone, to about 15% when co-administered with the second agent compared to when administered alone, to about 5% when co-administered with the second agent compared to when administered alone, to about 10% when co-administered with the second agent compared to when administered alone, to about 1 ... about 20% when co-administered with a second drug compared to when administered alone, about 5% when co-administered with a second drug compared to when administered alone, about 25% when co-administered with a second drug compared to when administered alone, about 5% when co-administered with a second drug compared to when administered alone, about 30% when co-administered with a second drug compared to when administered alone, about 5% when co-administered with a second drug compared to when administered alone, about 35% when co-administered with a second drug compared to when administered alone, When administered in combination with a second drug, the reduction in vasopressin levels ranged from about 5% compared to when administered alone, to about 40% when administered in combination with a second drug compared to when administered alone, from about 5% compared to when administered alone, to about 45% when administered in combination with a second drug compared to when administered alone, from about 5% compared to when administered alone, to about 50% when administered in combination with a second drug compared to when administered alone, and from about 5% when administered in combination with a second drug compared to when administered alone. to about 65% when co-administered with the second drug compared to when administered alone, from about 5% when co-administered with the second drug compared to when administered alone, to about 80% when co-administered with the second drug compared to when administered alone, from about 10% when co-administered with the second drug compared to when administered alone, to about 15% when co-administered with the second drug compared to when administered alone, from about 10% when co-administered with the second drug compared to when administered alone, to about 15% when co-administered with the second drug compared to when administered alone,about 20% compared to when administered alone, about 10% to about 25% when administered in combination with a second drug compared to when administered alone, about 10% to about 30% when administered in combination with a second drug compared to when administered alone, about 10% to about 35% when administered in combination with a second drug compared to when administered alone, and about 10% to about 35% when administered in combination with a second drug compared to when administered alone. from about 10% compared to when administered alone to about 40% when administered in combination with the second agent compared to when administered alone; from about 10% compared to when administered alone to about 45% when administered in combination with the second agent compared to when administered alone; from about 10% compared to when administered alone to about 50% when administered in combination with the second agent compared to when administered alone; from about 10% compared to when administered alone to about 65% when administered in combination with the second agent compared to when administered alone. , when administered in combination with a second drug, from about 10% compared to when administered alone, to about 80% when administered in combination with a second drug, from about 15% compared to when administered alone, to about 20% when administered in combination with a second drug, from about 15% compared to when administered alone, to about 25% when administered in combination with a second drug, from about 15% compared to when administered alone, to about 25% when administered in combination with a second drug, from about 15% compared to when administered alone, to about 25% when administered in combination with a second drug. When administered in combination with a second drug, the reduction in serum serotonin levels is about 30% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 15% to about 35% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 15% to about 40% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 15% to about 45% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 20% to about 30% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 20% to about 35% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 20% to about 35% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 20% to about 40% compared to when administered alone; when administered in combination with a second drug, the reduction in serum serotonin levels is about 20% to about 4 ...45% compared to when administered alone.from about 15% compared to when administered alone to about 50% when administered in combination with a second drug compared to when administered alone; from about 15% compared to when administered alone to about 65% when administered in combination with a second drug compared to when administered alone; from about 15% compared to when administered alone to about 80% when administered in combination with a second drug compared to when administered alone; from about 20% compared to when administered alone to about 50% when administered in combination with a second drug compared to when administered alone. about 25% compared to when administered in combination with a second drug, about 20% to about 30% compared to when administered in combination with a second drug, about 20% to about 35% compared to when administered in combination with a second drug, about 20% to about 40% compared to when administered in combination with a second drug, about 20% to about 40% compared to when administered in combination with a second drug When administered in combination with a second drug, the reduction was about 45% compared to when administered alone; when administered in combination with a second drug, the reduction was about 20% to about 50% compared to when administered alone; when administered in combination with a second drug, the reduction was about 20% to about 65% compared to when administered alone; when administered in combination with a second drug, the reduction was about 20% to about 80% compared to when administered alone; when administered in combination with a second drug, the reduction was about 45% compared to when administered alone; when administered in combination with a second drug, the reduction was about 20% to about 50% compared to when administered alone; when administered in combination with a second drug, the reduction was about 20% to about 65% compared to when administered alone; when administered in combination with a second drug, the reduction was about 20% to about 80% compared to when administered alone; when administered in combination with a second drug, the reduction was about 45% compared to when administered alone; when administered in combination with a second drug, the reduction was about 40 ... When administered alone, the reduction in vasopressin levels is about 25% to about 30% when administered in combination with a second drug compared to when administered alone; when administered in combination with a second drug, the reduction in vasopressin levels is about 25% to about 35% when administered in combination with a second drug compared to when administered alone; when administered in combination with a second drug, the reduction in vasopressin levels is about 25% to about 40% when administered in combination with a second drug compared to when administered alone; when administered in combination with a second drug, the reduction in vasopressin levels is about 25% to about 40% when administered in combination with a second drug compared to when administered alone; when administered in combination with a second drug, the reduction in vasopressin levels is about 25% to about 40% when administered in combination with a second drug compared to when administered alone;Approximately 45% compared to monotherapy, When administered in combination with the second drug, the reduction in efficacy is from about 25% compared to when administered alone, to about 50% when administered in combination with the second drug compared to when administered alone, from about 25% when administered in combination with the second drug compared to when administered alone, to about 65% when administered in combination with the second drug compared to when administered alone, from about 25% when administered in combination with the second drug compared to when administered alone, to about 80% when administered in combination with the second drug compared to when administered alone, from about 30% when administered in combination with the second drug .... When administered in combination with a second drug, the reduction was about 35% compared to when administered alone; when administered in combination with a second drug, the reduction was about 30% compared to when administered alone to about 40% compared to when administered alone; when administered in combination with a second drug, the reduction was about 30% compared to when administered alone to about 45% compared to when administered alone; when administered in combination with a second drug, the reduction was about 30% compared to when administered alone to about 50% compared to when administered alone; when administered in combination with a second drug, the reduction was about 10% compared to when administered alone. from about 30% compared to when administered alone to about 65% when administered in combination with a second drug compared to when administered alone; from about 30% compared to when administered alone to about 80% when administered in combination with a second drug compared to when administered alone; from about 35% compared to when administered alone to about 40% when administered in combination with a second drug compared to when administered alone; from about 35% compared to when administered alone to about 40% when administered in combination with a second drug compared to when administered alone. from about 45% when co-administered with a second drug compared to when administered alone, from about 35% when co-administered with a second drug compared to when administered alone, from about 50% when co-administered with a second drug compared to when administered alone, from about 35% when co-administered with a second drug compared to when administered alone, from about 65% when co-administered with a second drug compared to when administered alone, from about 35% when co-administered with a second drug compared to when administered alone, from about 80% when co-administered with a second drug compared to when administered alone, from about 40% when co-administered with a second drug compared to when administered alone,When administered in combination with the second drug, the effect is about 45% compared to when administered alone; when administered in combination with the second drug, the effect is about 40% to about 50% compared to when administered alone; when administered in combination with the second drug, the effect is about 40% to about 65% compared to when administered alone; when administered in combination with the second drug, the effect is about 40% to about 80% compared to when administered alone; when administered in combination with the second drug, the effect is about 45% to about 50% compared to when administered alone; when administered in combination with the second drug, the effect is about 50% compared to when administered alone; when administered in combination with the second drug, the effect is about 50% to about 65% compared to when administered alone. from about 45% compared to when administered alone, to about 65% when administered in combination with the second agent compared to when administered alone; from about 45% compared to when administered alone, to about 80% when administered in combination with the second agent compared to when administered alone; from about 50% compared to when administered alone, to about 65% when administered in combination with the second agent compared to when administered alone; from about 50% compared to when administered alone, to about 80% when administered in combination with the second agent compared to when administered alone; or from about 65% compared to when administered alone, to about 80% when administered in combination with the second agent compared to when administered alone. In some embodiments, the reduction in the minimum therapeutically effective dose of the first agent is about 5% when co-administered with the second agent compared to when administered alone, about 10% when co-administered with the second agent compared to when administered alone, about 15% when co-administered with the second agent compared to when administered alone, about 20% when co-administered with the second agent compared to when administered alone, about 25% when co-administered with the second agent compared to when administered alone, about 30% when co-administered with the second agent compared to when administered alone, about 35% when co-administered with the second agent compared to when administered alone, about 40% when co-administered with the second agent compared to when administered alone, about 45% when co-administered with the second agent compared to when administered alone, about 50% when co-administered with the second agent compared to when administered alone, about 65% when co-administered with the second agent compared to when administered alone, or about 80% when co-administered with the second agent compared to when administered alone. In some embodiments, the reduction in the minimum therapeutically effective dose of the first agent is at least about 5% when co-administered with the second agent compared to when administered alone, about 10% when co-administered with the second agent compared to when administered alone, about 15% when co-administered with the second agent compared to when administered alone, about 20% when co-administered with the second agent compared to when administered alone, about 25% when co-administered with the second agent compared to when administered alone, about 30% when co-administered with the second agent compared to when administered alone, about 35% when co-administered with the second agent compared to when administered alone, about 40% when co-administered with the second agent compared to when administered alone, about 45% when co-administered with the second agent compared to when administered alone, about 50% when co-administered with the second agent compared to when administered alone, or about 65% when co-administered with the second agent compared to when administered alone.In some embodiments, the minimum therapeutically effective dose of the first agent is reduced by at most about 10% when co-administered with the second agent compared to when administered alone, about 15% when co-administered with the second agent compared to when administered alone, about 20% when co-administered with the second agent compared to when administered alone, about 25% when co-administered with the second agent compared to when administered alone, about 30% when co-administered with the second agent compared to when administered alone, about 35% when co-administered with the second agent compared to when administered alone, about 40% when co-administered with the second agent compared to when administered alone, about 45% when co-administered with the second agent compared to when administered alone, about 50% when co-administered with the second agent compared to when administered alone, about 65% when co-administered with the second agent compared to when administered alone, or about 80% when co-administered with the second agent compared to when administered alone.

[0074] In some embodiments, the minimum therapeutically effective dose of the second agent is reduced by about 5% when co-administered with the first agent compared to when administered alone, to about 80% when co-administered with the first agent compared to when administered alone. In some embodiments, the minimum therapeutically effective dose of the second agent is reduced by about 5% when co-administered with the first agent compared to when administered alone, to about 10% when co-administered with the first agent compared to when administered alone, to about 5% when co-administered with the first agent compared to when administered alone, to about 15% when co-administered with the first agent compared to when administered alone, to about 5% when co-administered with the first agent compared to when administered alone. about 20% when co-administered with the first drug compared to when administered alone, about 5% when co-administered with the first drug compared to when administered alone, about 25% when co-administered with the first drug compared to when administered alone, about 5% when co-administered with the first drug compared to when administered alone, about 30% when co-administered with the first drug compared to when administered alone, about 5% when co-administered with the first drug compared to when administered alone, about 35% when co-administered with the first drug compared to when administered alone, When administered in combination with the first agent, from about 5% compared to when administered alone, when administered in combination with the first agent, to about 40% compared to when administered alone, when administered in combination with the first agent, from about 5% compared to when administered alone, to about 45% when administered in combination with the first agent, when administered in combination with the first agent, from about 5% compared to when administered alone, to about 50% when administered in combination with the first agent, when administered in combination with the first agent, to about 65% when administered in combination with the first drug compared to when administered alone, from about 5% when administered in combination with the first drug compared to when administered alone, to about 80% when administered in combination with the first drug compared to when administered alone, from about 10% when administered in combination with the first drug compared to when administered alone, to about 15% when administered in combination with the first drug compared to when administered alone, from about 10% when administered in combination with the first drug compared to when administered alone, to about 15% when administered in combination with the first drug compared to when administered alone,about 20% compared to when administered alone, about 10% to about 25% when administered in combination with the first drug compared to when administered alone, about 10% to about 30% when administered in combination with the first drug compared to when administered alone, about 10% to about 35% when administered in combination with the first drug compared to when administered alone, about 10% to about 35% when administered in combination with the first drug compared to when administered alone, about 10% to about 35% when administered in combination with the first drug compared to when administered alone from about 10% compared to when administered alone to about 40% when administered in combination with the first agent compared to when administered alone; from about 10% compared to when administered alone to about 45% when administered in combination with the first agent compared to when administered alone; from about 10% compared to when administered alone to about 50% when administered in combination with the first agent compared to when administered alone; from about 10% compared to when administered alone to about 65% when administered in combination with the first agent compared to when administered alone. , when administered in combination with the first drug, from about 10% compared to when administered alone, to about 80% when administered in combination with the first drug, from about 15% compared to when administered alone, to about 20% when administered in combination with the first drug, from about 15% compared to when administered alone, to about 25% when administered in combination with the first drug, from about 15% compared to when administered alone, to about 25% when administered in combination with the first drug, from about 15% compared to when administered alone, to about 25% when administered in combination with the first drug. When co-administered with the first drug, the reduction in serum saturation is about 30% compared to when administered alone, when co-administered with the first drug, from about 15% compared to when administered alone to about 35% when co-administered with the first drug, from about 15% compared to when administered alone to about 40% when co-administered with the first drug, from about 15% compared to when administered alone to about 45% when co-administered with the first drug, when co-administered with the first drug,from about 15% compared to when administered alone, to about 50% when administered in combination with the first drug compared to when administered alone; from about 15% compared to when administered alone, to about 65% when administered in combination with the first drug compared to when administered alone; from about 15% compared to when administered alone, to about 80% when administered in combination with the first drug compared to when administered alone; 20% to about 25% when co-administered with the first drug compared to when administered alone; about 20% to about 30% when co-administered with the first drug compared to when administered alone; about 20% to about 35% when co-administered with the first drug compared to when administered alone; about 20% to about 35% when co-administered with the first drug compared to when administered alone; When administered in combination with the first drug, the reduction in efficacy is about 40% compared to when administered alone; when administered in combination with the first drug, the reduction in efficacy is about 20% to about 45% compared to when administered alone; when administered in combination with the first drug, the reduction in efficacy is about 20% to about 50% compared to when administered alone; when administered in combination with the first drug, the reduction in efficacy is about 20% to about 50% compared to when administered alone; when administered in combination with the first drug, the reduction in efficacy is about 20% to about 50% compared to when administered alone. about 65% compared to when administered in combination with the first drug, about 20% to about 80% compared to when administered in combination with the first drug, about 25% to about 30% compared to when administered in combination with the first drug, about 25% to about 35% compared to when administered in combination with the first drug, When co-administered with the first drug, the reduction in serum serotonin levels is from about 25% compared to when administered alone, to about 40% when co-administered with the first drug, from about 25% compared to when administered alone, to about 45% when co-administered with the first drug, from about 25% compared to when administered alone, to about 50% when co-administered with the first drug, from about 25% compared to when administered alone, to about 50% when co-administered with the first drug, from about 25% compared to when administered alone, to about 50% when co-administered with the first drug. When administered in combination with the first drug, the reduction was about 65% compared to when administered alone; when administered in combination with the first drug, the reduction was about 25% compared to when administered alone, to about 80% compared to when administered alone; when administered in combination with the first drug, the reduction was about 30% compared to when administered alone, to about 35% compared to when administered alone; when administered in combination with the first drug, the reduction was about 30% compared to when administered alone, to about 40% compared to when administered alone; when administered in combination with the first drug, the reduction was about 40% compared to when administered alone. from about 30% compared to administration alone to about 45% when co-administered with the first drug compared to administration alone; from about 30% compared to administration alone to about 50% when co-administered with the first drug compared to administration alone; from about 30% compared to administration alone to about 65% when co-administered with the first drug compared to administration alone; from about 30% compared to administration alone to about 50% when co-administered with the first drug compared to administration alone; about 80% when co-administered with the first drug compared to when administered alone, about 35% when co-administered with the first drug compared to when administered alone, about 40% when co-administered with the first drug compared to when administered alone, about 35% when co-administered with the first drug compared to when administered alone, about 45% when co-administered with the first drug compared to when administered alone, about 35% when co-administered with the first drug compared to when administered alone, about 50% when co-administered with the first drug compared to when administered alone,When administered in combination with the first drug, the efficacy is about 65% compared to when administered alone; when administered in combination with the first drug, the efficacy is about 35% to about 80% compared to when administered alone; when administered in combination with the first drug, the efficacy is about 40% to about 45% compared to when administered alone; when administered in combination with the first drug, the efficacy is about 40% to about 50% compared to when administered alone; when administered in combination with the first drug, the efficacy is about 40% to about 65% compared to when administered alone; when administered in combination with the first drug, the efficacy is about 40% to about 80% compared to when administered alone; when administered in combination with the first drug, the efficacy is about from about 45% when administered in combination with the first agent compared to when administered alone, to about 50% when administered in combination with the first agent compared to when administered alone, from about 45% when administered in combination with the first agent compared to when administered alone, to about 65% when administered in combination with the first agent compared to when administered alone, from about 45% when administered in combination with the first agent compared to when administered alone, to about 80% when administered in combination with the first agent compared to when administered alone, from about 50% when administered in combination with the first agent compared to when administered alone, to about 65% when administered in combination with the first agent compared to when administered alone, from about 50% when administered in combination with the first agent compared to when administered alone, to about 80% when administered in combination with the first agent compared to when administered alone, or from about 65% when administered in combination with the first agent compared to when administered alone, to about 80% when administered in combination with the first agent compared to when administered alone. In some embodiments, the reduction in the minimum therapeutically effective dose of the second agent is about 5% when co-administered with the first agent compared to when administered alone, about 10% when co-administered with the first agent compared to when administered alone, about 15% when co-administered with the first agent compared to when administered alone, about 20% when co-administered with the first agent compared to when administered alone, about 25% when co-administered with the first agent compared to when administered alone, about 30% when co-administered with the first agent compared to when administered alone, about 35% when co-administered with the first agent compared to when administered alone, about 40% when co-administered with the first agent compared to when administered alone, about 45% when co-administered with the first agent compared to when administered alone, about 50% when co-administered with the first agent compared to when administered alone, about 65% when co-administered with the first agent compared to when administered alone, or about 80% when co-administered with the first agent compared to when administered alone. In some embodiments, the reduction in the minimum therapeutically effective dose of the second agent is at least about 5% when co-administered with the first agent compared to when administered alone, about 10% when co-administered with the first agent compared to when administered alone, about 15% when co-administered with the first agent compared to when administered alone, about 20% when co-administered with the first agent compared to when administered alone, about 25% when co-administered with the first agent compared to when administered alone, about 30% when co-administered with the first agent compared to when administered alone, about 35% when co-administered with the first agent compared to when administered alone, about 40% when co-administered with the first agent compared to when administered alone, about 45% when co-administered with the first agent compared to when administered alone, about 50% when co-administered with the first agent compared to when administered alone, or about 65% when co-administered with the first agent compared to when administered alone.In some embodiments, the minimum therapeutically effective dose of the second agent is reduced by at most about 10% when co-administered with the first agent compared to when administered alone, about 15% when co-administered with the first agent compared to when administered alone, about 20% when co-administered with the first agent compared to when administered alone, about 25% when co-administered with the first agent compared to when administered alone, about 30% when co-administered with the first agent compared to when administered alone, about 35% when co-administered with the first agent compared to when administered alone, about 40% when co-administered with the first agent compared to when administered alone, about 45% when co-administered with the first agent compared to when administered alone, about 50% when co-administered with the first agent compared to when administered alone, about 65% when co-administered with the first agent compared to when administered alone, or about 80% when co-administered with the first agent compared to when administered alone.

[0075] The pharmaceutical composition of the present disclosure can be formulated to contain either or both of the first and second drugs necessary to treat a subject by combination therapy according to the methods described herein.In some embodiments, the pharmaceutical compositions can be administered simultaneously or sequentially.In some embodiments, the pharmaceutical compositions can be administered in separate formulations.

[0076] A therapeutically effective amount of the first or second agent or its salt can be administered before the onset of hearing impairment, such as tinnitus or Meniere's disease. A therapeutically effective amount of the first or second agent or its salt can be administered at least about 1 hour before the onset of hearing impairment, for example, at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours before the onset of hearing impairment. A therapeutically effective amount of the first or second agent or its salt can be administered less than about 1 month before the onset of hearing loss, for example, at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours before the onset of hearing impairment. In some cases, a therapeutically effective amount of the first or second agent or its salt can be administered at least 6 hours before the onset of hearing impairment.

[0077] The therapeutically effective amount of the first and / or second agent or its salt can be administered after or simultaneously with the onset of hearing impairment, such as tinnitus or Meniere's disease. The therapeutically effective amount of the first and / or second agent or its salt can be administered at least about 1 minute after the onset of hearing impairment, for example, at least about 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 54, or 60 minutes after the onset of hearing impairment. The therapeutically effective amount of the first and / or second agent or its salt can be administered at least about 1 hour after the onset of hearing impairment, for example, at least about 1, 2, 3, 4, 5, or 6 hours after the onset of hearing impairment. The therapeutically effective amount of the first and / or second agent or salt thereof can be administered less than about 1 month after the onset of hearing loss, for example, at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after the onset of hearing impairment. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is administered at least 12 hours after the onset of hearing impairment.

[0078] In some embodiments, the first drug is nimodipine (NMDP) or a salt thereof, and the second drug is tetrandrine (TET) or a salt thereof. In some embodiments, the first drug is nimodipine (NMDP) or a salt thereof, and the second drug is carbamazepine (CBZ) or a salt thereof. In some embodiments, the first drug is amlodipine (AML) or a salt thereof, and the second drug is carbamazepine or a salt thereof. In some embodiments, the first drug is nimodipine or a salt thereof, and the second drug is amlodipine or a salt thereof. In some embodiments, the first drug is tetrandrine (TET) or a salt thereof, and the second drug is nimodipine or a salt thereof. In some embodiments, the first drug is tetrandrine or a salt thereof, and the second drug is carbamazepine or a salt thereof. In some embodiments, the first drug is tetrandrine or a salt thereof, and the second drug is amlodipine or a salt thereof.

[0079] It may be a solution dosage form. The solution dosage form may have a unit volume of at least about 1 mL, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, or 900 mL. The solution dosage form may have a unit volume of less than about 1000 mL, for example, less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, or 900 mL. The solution dosage form may have a unit volume range of about 1 to 500 mL, for example, 1 to 500, 1 to 300, 1 to 100, 1 to 80, 1 to 60, 1 to 40, 1 to 20, 1 to 10, 1 to 5, 10 to 500, 10 to 300, 10 to 100, 10 to 80, 10 to 60, 10 to 40, 10 to 20, 20 to 500, 20 to 300, 20 to 100, 2 It can have a range of 0-80, 20-60, 20-40, 40-500, 40-300, 40-100, 40-80, 40-60, 60-500, 60-300, 60-100, 60-80, 80-500, 80-300, 80-100, 100-500, 100-300 or 300-500 mL.

[0080] Combination treatment The therapeutically effective amount of the first and / or second agent or salt thereof can be the only active pharmaceutical ingredient (API). Alternatively, the therapeutically effective amount of the first and / or second agent or salt thereof can be used in combination with one or more additional APIs. In some embodiments, the first and / or second agent and the additional API can be administered simultaneously or sequentially. In some embodiments, the first and / or second agent and the additional API can be administered in separate formulations. Disclosed herein are pharmaceuticals, compositions, kits, and methods for preventing or treating hearing loss by administering a first and / or second agent or salt thereof, e.g., a therapeutically effective amount of the first and / or second agent or salt thereof, and one or more active pharmaceutical ingredients (APIs), e.g., a therapeutically effective amount of an API.

[0081] The one or more APIs can include one or more antioxidants, spin traps, N-methyl-D-aspartate (NMDA) antagonists, selective serotonin reuptake inhibitor (SSRI) antagonists, dopamine releasing agents (DRAs), acetylcholine release inducers, norepinephrine reuptake inhibitors (NERIs), monoamine oxidase-A inhibitors (MAIs), serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine selective reuptake inhibitors (NSRIs), 5HT serotonin reuptake inhibitors (5TH SRIs), zonisamide, gabapentin, cannabinoids, or any combination thereof.

[0082] Also disclosed herein are pharmaceutical agents, compositions, kits, and methods for treating or preventing hearing loss in a subject in need thereof by administering therapeutically effective amounts of a first and / or second agent or salt thereof, and one or more active pharmaceutical ingredients (APIs), which can be administered in therapeutically effective amounts. The one or more APIs can include one or more antioxidants, spin traps, N-methyl-D-aspartate (NMDA) antagonists, selective serotonin reuptake inhibitor (SSRI) antagonists, dopamine releasing agents (DRAs), acetylcholine release inducers, norepinephrine reuptake inhibitors (NERIs), monoamine oxidase-A inhibitors (MAIs), serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine selective reuptake inhibitors (NSRIs), 5HT serotonin reuptake inhibitors (5TH SRIs), zonisamide, gabapentin, cannabinoids, or any combination thereof.

[0083] One or more APIs may include one or more antioxidants or spin trapping agents. For example, the one or more antioxidants or spin trapping agents may include allopurinol, glutathione, L-carnitine, methionine, or any combination thereof. One or more APIs may include one or more NMDA antagonists. For example, the one or more NMDA antagonists may include riluzole, caroverine, memantine, magnesium, or any combination thereof. One or more APIs may include one or more SSRI antagonists. For example, the one or more SSRI antagonists may include fluoxetine, sertraline, S-citalopram, alaprolclate, or any combination thereof. One or more APIs may include one or more DRAs. For example, the one or more DRAs may include amantadine. One or more APIs may include one or more acetylcholine release inducers or NERIs. For example, the one or more acetylcholine release inducers or NERIs may include bifemelane. One or more APIs may include one or more MAIs or SRIs. For example, one or more MAIs or SRIs can include pirlindole. One or more APIs can include one or more SNRIs. For example, one or more SNRIs can include milnacipran, bicifadine, or both. One or more APIs can include one or more CCBs. For example, one or more CCBs can include the first and / or second drug, verapamil, or both. One or more APIs can include one or more NSRIs. For example, one or more NSRIs can include atomoxetine. One or more APIs can include one or more 5-th SRIs. For example, one or more 5-th SRIs can include indeloxazine. One or more APIs can include zonisamide.

[0084] The one or more APIs can include one or more drugs, such as gabapentin. Other drugs that can be used are anticonvulsants. Other drugs that can be used are drugs that stimulate gamma-aminobutyric acid (GABA) receptors. The one or more APIs can include cannabinoids. For example, the cannabinoid can be marijuana or any extract or synthetic composition of marijuana that can stimulate cannabinoid receptors, CB1 receptors, CB2 receptors, or G-coupled receptors. These drugs can be used in combination with nimodipine or a salt thereof.

[0085] kit Disclosed herein is a kit for treating or preventing hearing loss in a subject in need thereof, comprising a first and / or second agent or a salt thereof and written instructions for using the first and / or second agent or a salt thereof to treat or prevent hearing loss. The first and / or second agent or a salt thereof may be a therapeutically effective amount of the first and / or second agent or a salt thereof. The therapeutically effective amount of the first and / or second agent or a salt thereof may be in the form of a tablet, capsule, caplet, spray, powder, gelcap, powder, or solution. For example, the therapeutically effective amount of the first and / or second agent or a salt thereof may be in powder form. The kit may further comprise a sterile solution. The kit may further comprise a sterile solution to be mixed with the powder dosage form of the therapeutically effective amount of the first and / or second agent or a salt thereof prior to administration. The kit may further comprise one or more active pharmaceutical ingredients (APIs). The one or more APIs can include one or more antioxidants, spin traps, N-methyl-D-aspartate (NMDA) antagonists, selective serotonin reuptake inhibitor (SSRI) antagonists, dopamine releasing agents (DRAs), acetylcholine release inducers, norepinephrine reuptake inhibitors (NERIs), monoamine oxidase-A inhibitors (MAIs), serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine selective reuptake inhibitors (NSRIs), 5HT serotonin reuptake inhibitors (5TH SRIs), zonisamide, gabapentin, cannabinoids, or any combination thereof.

[0086] Patient Selection

[0009] In one aspect, a method is provided for selecting a subject in need thereof for treatment of hearing impairment or symptoms of hearing impairment, the method comprising administering an L-type calcium channel blocker to the subject; if the subject responds to the L-type calcium channel blocker, selecting the patient for treatment of hearing impairment or symptoms of hearing impairment; and if the subject responds to the L-type calcium channel blocker, administering a therapeutically effective amount of a first and / or second agent or a salt thereof to the subject. In some cases, the L-type calcium channel blocker comprises carbamazepine. In some cases, the patient exhibits hearing loss. In some cases, patients exhibit one or more of the following symptoms: a) hearing loss, b) change in auditory speech recognition as measured by a words-in-noise test, c) change in auditory speech recognition as measured by a digits-in-noise test, d) change in low-frequency hearing thresholds, e) change in tinnitus severity, g) change in tinnitus volume, h) change in vertigo severity, i) change in ear fullness, j) change in vertigo sensation, and k) change in hair cell function as measured by change in ABR thresholds.

[0087] In one aspect, provided is a method of selecting a subject in need thereof for treatment of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, the method comprising administering an L-type calcium channel blocker to the subject; if the subject responds to the L-type calcium channel blocker, selecting the subject for treatment of tinnitus or symptoms of tinnitus; and if the subject responds to the L-type calcium channel blocker, administering a therapeutically effective amount of a first and / or second agent or salt thereof to the subject. In some cases, the L-type calcium channel blocker comprises carbamazepine.

[0088] Condition being treated The hearing impairment in a subject in need thereof may be NIHL, ARHL, drug- or injury-induced hearing loss, or tinnitus. The hearing impairment in a subject may also include a combination of two or all four of the listed diseases. For example, both tinnitus or Meniere's disease and drug-induced hearing loss may be caused by ototoxic drugs. Ototoxic drugs may include chemotherapeutic agents, antineoplastic agents, antibiotics, loop diuretics, quinine or quinine-like compounds, or salicylates or salicylate-like compounds. In some cases, the ototoxic drug is not streptomycin. In some cases, the antibiotic is not streptomycin. In some cases, the hearing impairment is not caused by streptomycin.

[0089] Disclosed herein are pharmaceuticals, compositions, kits, and methods for preventing and / or treating hearing impairment, including various conditions such as, but not limited to, noise-induced hearing loss (NIHL), age-related hearing loss (ARHL or presbycusis), drug- or trauma-induced hearing loss, central auditory dysfunction (CAPD), tinnitus, or Meniere's disease.

[0090] NIHL - Noise-Induced Hearing Loss NIHL is one of the most significant health hazards resulting from occupational and recreational environments. However, there are currently no FDA-approved drugs for the relief of NIHL, and the development of effective treatments is hindered by the diverse cellular and molecular pathways involved in NIHL. NIHL can cause damage ranging from attrition to loss of hair cells in the ear. Therefore, NIHL can be the result of overstimulation of hair cells and supporting structures. Structural damage to hair cells (primarily outer hair cells) can result in hearing loss, which can be characterized by attenuation and distortion of incoming auditory stimuli.

[0091] NIHL can be caused by a single exposure to excessive noise. For example, exposure to sounds exceeding 80 dB, 90 dB, 100 dB, 110 dB, 120 dB, 130 dB, 140 dB, or 150 dB over a short period of time can cause NIHL. Alternatively, NIHL can be caused by repeated exposure to noise over a period of time. For example, exposure to sounds exceeding 60 dB, 65 dB, 70 dB, 75 dB, 80 dB, 85 dB, 90 dB, 95 dB, or 100 dB for more than 8 hours per day can cause NIHL. Symptoms of NIHL can include tinnitus, ear pain, hyperacusis, dizziness, vertigo, and / or vestibular damage to the inner ear.

[0092] Disclosed herein are pharmaceuticals, compositions, kits, and methods for treating or preventing hearing loss (e.g., NIHL) in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a first and / or second agent or a salt thereof. In some cases, the therapeutically effective amount of the first and / or second agent or a salt thereof is an amount sufficient to reduce or eliminate NIHL. In some cases, the therapeutically effective amount of the first and / or second agent or a salt thereof is an amount sufficient to stop or prevent NIHL. In some cases, the therapeutically effective amount of the first and / or second agent or a salt thereof is an amount sufficient to reverse NIHL or at least partially restore hearing. The subject may be at risk of developing hearing loss (e.g., NIHL). Alternatively, the subject may be suffering from hearing loss (e.g., NIHL).

[0093] ARHL or presbycusis ARHL or presbycusis is a major health problem for which there is currently no cure or preventive medicine. Age-related hearing loss develops gradually over time, and its early stages are virtually imperceptible to affected individuals. The cause of ARHL or presbycusis is generally believed to be the degeneration of the auditory nervous system, particularly the auditory nerve in the ear. This is the most common form of hearing loss in people over the age of 55.

[0094] Early noise injury can cause ARHL or presbycusis.The subject can be suffering from or at risk of developing hearing loss (e.g., ARHL or presbycusis).For example, the subject can be at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 years old and suffering from or at risk of developing hearing loss (e.g., ARHL or presbycusis).In some cases, the subject can be 50 years old.

[0095] Disclosed herein are pharmaceuticals, compositions, kits, and methods for treating or preventing hearing loss (e.g., ARHL or presbycusis) in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a first and / or second agent or a salt thereof. In some cases, the therapeutically effective amount of the first and / or second agent or a salt thereof is sufficient to reduce or eliminate ARHL or presbycusis. In some cases, the therapeutically effective amount of the first and / or second agent or a salt thereof is sufficient to stop or prevent ARHL or presbycusis. In some cases, the therapeutically effective amount of the first and / or second agent or a salt thereof is sufficient to reverse ARHL or presbycusis or at least partially restore hearing. The subject may be at risk of developing hearing loss (e.g., ARHL or presbycusis). Alternatively, the subject may be suffering from hearing loss (e.g., ARHL or presbycusis).

[0096] Traumatic or drug-induced hearing loss Ototoxic drugs, such as chemotherapeutic agents, antineoplastic agents, antibiotics, loop diuretics, quinine or quinine-like compounds, and salicylates or salicylate-like compounds, can cause drug-induced hearing loss. For example, aminoglycosides are antibiotics used to treat gram-negative bacterial infections and some aerobic gram-positive bacterial infections. However, despite their usefulness, they have serious side effects, including ototoxicity associated with the destruction of sensory hair cells in the organ of Corti of the cochlea of ​​the inner ear. Furthermore, surgery near or on the auditory nerve can cause hearing loss, which subsequently leads to tinnitus.

[0097] Disclosed herein are pharmaceuticals, compositions, kits, and methods for treating or preventing hearing loss (e.g., traumatic or drug-induced hearing loss) in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a first and / or second agent or salt thereof. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to reduce or eliminate this type of hearing loss. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to stop or prevent this type of hearing loss. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient not only to prevent drug-induced hearing loss but also to at least partially restore hearing. The subject may be at risk of developing hearing loss (e.g., drug-induced hearing loss). Alternatively, the subject may be suffering from hearing loss (e.g., drug-induced hearing loss). In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient not only to prevent drug-induced hearing loss but also to act synergistically with a cancer drug to kill cancer cells.

[0098] A therapeutically effective amount of the first and / or second agent or salt thereof can prevent the onset of traumatic or drug-induced hearing loss. For example, disclosed herein is a method for preventing drug-induced hearing loss, comprising administering a therapeutically effective amount of the first and / or second agent or salt thereof to a subject in need thereof before administering to the subject one or more ototoxic drugs for treating a condition other than hearing loss. Administration of the therapeutically effective amount of the first and / or second agent or salt thereof can begin up to about 12 months (e.g., 1 day to 60 days) before administration of the one or more ototoxic drugs. Administration of the therapeutically effective amount of the first and / or second agent or salt thereof can also begin on the same day as administration of the one or more ototoxic drugs. In some cases, administration of a therapeutically effective amount of the first and / or second agent or salt thereof can be initiated up to about 12 months, e.g., 1 hour, 6 hours, 12 hours, 24 hours, 2 days, 4 days, 6 days, 8 days, 10 days, 20 days, 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, or 12 months, before administration of the one or more ototoxic drugs. In some cases, administration of a therapeutically effective amount of the first and / or second agent or salt thereof can be initiated 1 day to 12 months, e.g., 1 day to 2 days, 2 days to 10 days, 10 days to 1 month, 1 month to 3 months, 3 months to 6 months, or 6 months to 12 months, before administration of the one or more ototoxic drugs.

[0099] A therapeutically effective amount of the first and / or second drug or salt thereof can treat or prevent drug-induced hearing loss, for example, improve drug-induced hearing loss, reduce or eliminate tinnitus or Meniere's disease, partially or completely restore hearing, or prevent further hearing loss due to the ototoxic effects of one or more ototoxic drugs. The methods disclosed herein provide for the administration of a pharmaceutical composition in response to a significant decrease in hearing function resulting from or occurring during the administration of one or more ototoxic drugs.

[0100] The administration of the therapeutically effective amount of the first and / or second agent or salt thereof can be continued for the duration of the one or more ototoxic drugs. The administration of the therapeutically effective amount of the first and / or second agent or salt thereof can be discontinued on the same day as the discontinuation of the one or more ototoxic drugs. The administration of the therapeutically effective amount of the first and / or second agent or salt thereof can be continued for at least about 1 day, e.g., at least about 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 20 days, 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, or 12 months, after the discontinuation of the one or more ototoxic drugs. In some cases, the administration of the therapeutically effective amount of the first and / or second agent or salt thereof can be continued for at least about 1 day to 12 months, e.g., 1 day to 2 days, 2 days to 10 days, 10 days to 1 month, 1 month to 3 months, 3 months to 6 months, or 6 months to 12 months, after the discontinuation of the one or more ototoxic drugs.

[0101] Some examples of ototoxic drugs include certain antibacterial agents and antineoplastic drugs. For example, some ototoxic drugs are chemotherapeutic agents, such as antineoplastic agents and antibiotics. Other potential candidates include loop diuretics, quinine or quinine-like compounds, and salicylates or salicylate-like compounds. Thus, disclosed herein are pharmaceuticals, compositions, kits, and methods for treating or preventing hearing loss caused by ototoxic drugs, where the ototoxic drug can be an antineoplastic agent (e.g., an ototoxic aminoglycoside antibiotic), such as cisplatin, an antibiotic, such as an aminoglycoside, a loop diuretic, quinine, a quinine-like compound, a salicylate, or a salicylate-like compound.

[0102] Ototoxic aminoglycoside antibiotics include, but are not limited to, neomycin, paromomycin, ribostamycin, lividomycin, kanamycin, amikacin, tobramycin, viomycin, gentamicin, sisomicin, netilmicin, streptomycin, dibekacin, fortimycin, and dihydrostreptomycin, or combinations thereof. Specific antibiotics include neomycin B, kanamycin A, kanamycin B, gentamicin C1, gentamicin C1a, and gentamicin C2. Thus, disclosed herein are pharmaceuticals, compositions, kits, and methods for treating or preventing drug-induced hearing loss, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to a subject who has been treated, is being treated, or will be treated with one or more aminoglycosides. In some cases, the ototoxic aminoglycoside antibiotic is not streptomycin. In some cases, the hearing loss is not caused by the ototoxic aminoglycoside antibiotic. In some cases, the hearing loss is not caused by streptomycin.

[0103] Aminoglycoside-induced hearing loss can be prevented or alleviated by the medicaments, compositions, kits, and methods disclosed herein. Aminoglycosides are particularly useful due to their rapid bactericidal activity against infections caused by aminoglycoside-susceptible organisms; however, their use has been limited to more severe and complicated infections due to ototoxic and nephrotoxic side effects. For this reason, aminoglycosides have been considered to have a lower treatment-to-risk ratio compared to other systemically administered antibiotics. Accordingly, also disclosed herein is an improved method for treating aminoglycoside-susceptible infections, comprising administering to a subject an antibacterial-effective amount of an aminoglycoside and a pharmaceutical composition disclosed herein. It should be recognized that recommended aminoglycoside dosages have been established. The methods disclosed herein are effective when aminoglycosides are administered at doses ranging from about 100% to about 500%, particularly about 100% to about 250%, and more particularly about 100% to about 150% of the currently recommended dosage (generally available on the product label and package insert of commercially available aminoglycoside drug products). The improved method provides prophylaxis against aminoglycoside-induced hearing loss and / or tinnitus, thereby extending the therapeutic index of aminoglycoside drugs.

[0104] The disclosed pharmaceutical composition can be co-administered with one or more ototoxic drugs in the same dosage form.For example, an improved method is provided for treating infection in a subject by administering an aminoglycoside antibiotic and a therapeutically effective amount of the pharmaceutical composition disclosed herein.Alternatively, the aminoglycoside antibiotic and the pharmaceutical composition disclosed herein can be administered to a subject in separate dosage forms.

[0105] The one or more ototoxic drugs can also be a chemotherapy drug for the treatment of cancer in a subject. For example, improved methods are provided for the treatment of cancer in a subject by administering a chemotherapy drug (e.g., an anti-neoplastic chemotherapy agent) and a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0106] Ototoxic antineoplastic chemotherapeutic agents include cisplatin or cisplatin-like compounds, taxol or taxol-like compounds, and other chemotherapeutic agents believed to cause ototoxin-induced hearing loss, such as vincristine, antineoplastic drugs used to treat hematologic malignancies and sarcomas. Thus, the methods disclosed herein can be used to treat ototoxicity (e.g., drug-induced hearing loss) in a subject who is being treated with, is being treated with, or has been treated with an antineoplastic agent, such as cisplatin or cisplatin-like compounds, taxol or taxol-like compounds, and other chemotherapeutic agents believed to cause ototoxin-induced hearing loss, such as vincristine, antineoplastic drugs used to treat hematologic malignancies and sarcomas.

[0107] Central Auditory Processing Disorder (CAPD) Central auditory processing disorder (CAPD) is associated with difficulties in the perceptual processing of auditory information in the central nervous system (CNS). CAPD tests include auditory discrimination tests, auditory temporal processing and patterning tests, dichotic speech tests, monaural low redundancy speech tests, binaural interaction tests, electroacoustic measurements, and electrophysiological measurements.

[0108] Disclosed herein are pharmaceuticals, compositions, kits, and methods for treating or preventing hearing loss (e.g., CAPD) in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a first and / or second agent or salt thereof. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to reduce or eliminate CAPD. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to terminate or prevent CAPD. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to reverse CAPD or at least partially restore hearing. The subject may be at risk of developing hearing loss (e.g., CAPD). Alternatively, the subject may be suffering from hearing loss (e.g., CAPD).

[0109] tinnitus Tinnitus is the perception of sound in the ears without any external sound stimulus. The most frequent symptom of tinnitus is ringing in the ears, but tinnitus can also present as crickets, roaring, pulsating, ocean waves, buzzing, or even music. Tinnitus can be temporary, intermittent, or even permanent, and its severity can range from a quiet background ringing to an overwhelming auditory sensation that drowns out external sound sources.

[0110] Tinnitus can be caused by one or more factors, such as administration of or exposure to an ototoxic substance (e.g., an aspirin overdose), exposure to short bursts of extreme noise (e.g., a gunshot or explosion), or prolonged exposure to high-decibel noise (e.g., aircraft engine noise, a high-decibel music concert, or the use of high-decibel headphones), or a central auditory processing disorder as discussed herein.

[0111] Disclosed herein are pharmaceuticals, compositions, kits, and methods for treating or preventing hearing impairment (e.g., tinnitus) in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a first and / or second agent or salt thereof. In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to reduce or eliminate the hearing impairment (e.g., tinnitus). In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to stop or prevent the progression of or treat the symptoms of the hearing impairment (e.g., tinnitus). In some cases, the therapeutically effective amount of the first and / or second agent or salt thereof is sufficient to reverse the hearing impairment (e.g., tinnitus) or at least partially restore hearing. The subject may be at risk of developing a hearing impairment (e.g., tinnitus). Alternatively, the subject may be suffering from a hearing impairment (e.g., tinnitus).

[0112] Meniere's disease Meniere's disease is a disorder of the inner ear that can result in tinnitus (ringing in the ears), reduced or lost hearing, dizziness, and a feeling of fullness or congestion in the ears. Attacks of dizziness can occur suddenly or after a short period of tinnitus or muffled hearing. In some cases, a single attack of dizziness may occur separated by a long period of time. In other cases, a person may experience many attacks spaced closely together over several days. Some people with Meniere's disease have such extreme dizziness that they lose their balance and fall. Meniere's disease is often a severe and debilitating condition for those affected.

[0113] Meniere's disease can occur at any age, but is more likely to occur in adults between the ages of 40 and 60. The National Institute on Deafness and Communication Disorders (NIDCD) estimates that approximately 615,000 individuals in the United States are currently diagnosed with Meniere's disease, with 45,500 new cases diagnosed each year. Meniere's disease usually affects only one ear. Without being bound by any particular theory, the symptoms of Meniere's disease may be caused by the accumulation of fluid within the inner ear compartment. There is no known cure for Meniere's disease. There remains a significant need for improved pharmaceutical compositions and methods of use for the treatment of Meniere's disease.

[0114] Salts, stereoisomers and derivatives Although the above-mentioned references to specific compounds, stereoisomers, metabolites, derivatives and / or salts of the active compounds can also be utilized.Examples of therapeutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids.Therapeutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, tolnesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. Therapeutically acceptable salts can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in a non-aqueous medium such as water or an organic solvent, or a mixture thereof, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985, p. 1418).

[0115] Stereoisomers are compounds composed of the same atoms with the same bond orders but with different three-dimensional arrangements of atoms that are not interchangeable. The three-dimensional structure is called a configuration. Two types of stereoisomers include enantiomers and diastereomers. Enantiomers are two stereoisomers that are non-superimposable mirror images of each other. This property of enantiomers is known as chirality. The terms "racemate," "racemic mixture," or "racemic modification" refer to a mixture of equal amounts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. The selection of appropriate chiral columns, eluents, and conditions necessary to achieve separation of enantiomeric pairs is well known to those skilled in the art using standard techniques (see, for example, Jacques, J. et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc. 1981). Diastereomers are two stereoisomers that are not mirror images but are also non-superimposable. Diastereoisomers have distinct physical properties and can be readily separated from one another by taking advantage of these dissimilarities.

[0116] Metabolites of the above compounds result from biochemical processes in living cells that interact with the active parent drug or other agents or compounds in vivo. Metabolites include products or intermediates from any metabolic pathway.

[0117] Measuring the effects of pharmaceutical compositions The compositions are intended to treat, alleviate, or reduce acute or breakthrough tinnitus or the symptoms of tinnitus based on assessments including, after administration of the pharmaceutical composition, a) measurement of change in auditory brainstem response (ABR) threshold, b) change in auditory speech recognition as measured by a words-in-noise test, c) change in auditory speech recognition as measured by a digits-in-noise test, d) change in low frequency hearing threshold, e) change in incidence of adverse events after administration of the pharmaceutical composition, f) change in tinnitus severity, g) change in tinnitus loudness, h) change in dizziness severity, i) change in ear fullness, j) change in dizziness sensation, and k) change in hair cell function as measured by change in ABR threshold.

[0118] In further embodiments, the compositions, dosage units, uses, and methods of the present disclosure are characterized by the effectiveness of treatment on acute tinnitus or tinnitus symptoms, measured as described herein. One method of recording tinnitus or tinnitus symptoms according to the present disclosure involves measuring the onset of tinnitus or the reduction of tinnitus symptoms. Time is measured immediately before administration of the treatment, e.g., by starting a stopwatch. When the subject experiences a significant reduction in tinnitus or tinnitus symptoms, time is recorded, e.g., by stopping the stopwatch. Upon administration, the compositions of the present disclosure have a tinnitus or tinnitus symptom reduction score in the range of 2 to 7, e.g., 2, 3, 4, 5, 6, and 7, preferably 3, 4, 5, and 6, as measured by PID, preferably after delivery of one dosage unit, in response to delivery of two or less dosage units.

[0119] A treatment is considered successful if at least 50% of subjects experience onset within 15 minutes of administration. Similarly, duration of effect can be measured as the difference between the onset of effect and the time the subject declares cessation of effect or the time the subject takes rescue medication, whichever occurs first. A treatment is considered successful if at least 50% of subjects experience relief from tinnitus or tinnitus symptoms lasting at least 30 minutes.

[0120] Another measure is tinnitus or ringing in the ears symptom intensity (TI) on an 11-point numeric rating scale (0 = no tinnitus or ringing in the ears symptoms, 10 = intolerable tinnitus or ringing in the ears symptoms). i is at time T i TI is the intensity of tinnitus or ringing in the ears. i is the time (T i ), measured at one or more of the following times: before treatment (baseline), at the time of significant relief of tinnitus or tinnitus symptoms, every 15 minutes for the first 2 hours after administration of treatment, and every 30 minutes for the next 2 hours. A 40% reduction in mean TI within 15 minutes of treatment can be considered successful. Of course, other time points and intervals may be selected.

[0121] TI0 is the baseline tinnitus or tinnitus symptom intensity (assessed on a scale as disclosed above) before administration of treatment (at time TO). Tinnitus or tinnitus symptom intensity difference (TID) is the difference between the baseline tinnitus or tinnitus symptom intensity (assessed on a scale as disclosed above) at a time point after administration of treatment (TI i ) is the TI0 compared to the symptom intensity of tinnitus or ringing in the ears at 15 minutes after administration. A mean TID of 2 obtained within 15 minutes after administration is considered successful.

[0122] An additional measurement is the area under the Tinnitus or Tinnitus Symptom Intensity Difference curve (STID), where TI is measured at the time points disclosed above. A 4-hour STID average of 3 is considered a success.

[0123] One method involves the use of the tinnitus or tinnitus symptom intensity measures disclosed herein, where the reduction in tinnitus or tinnitus symptoms is determined by comparing the tinnitus or tinnitus symptom score measured near the time of administration, TI0, and the reduction in ... iThe tinnitus or tinnitus symptom intensity difference (TID) is measured as a tinnitus or tinnitus symptom intensity difference (TID) of at least 30%, for example at least 40%, based on the tinnitus or tinnitus symptom score measured at 1000 Hz. The post-administration time can be selected from one or more of 3 minutes, 5 minutes, 7 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutes after administration. These times are used when the purpose of measurement is to evaluate the immediate effect of administration. If it is desired to measure the duration of treatment, the reduction in tinnitus or tinnitus symptoms can be measured by the time interval immediately before administration (TI0) and the time interval after administration (TI0). i The effect is measured as tinnitus or tinnitus symptom intensity difference (TID) based on scores measured at 45, 60, 75, 90, and 120 minutes after administration, with post-administration times selected from 45, 60, 75, 90, and 120 minutes after administration. One alternative is to measure the effect from a given post-administration time to a later time, in which case the desired time range is selected individually.

[0124] The tinnitus or ringing in the ears symptom relief score can be measured according to the methods disclosed herein or on a scale of 1 to 100%, where 100% is tinnitus or ringing in the ears symptom described by the patient as intolerable and 0% is complete absence of tinnitus or ringing in the ears symptom. Preferably, the score is at least 30% from onset until maximum relief is achieved.

[0125] Further measurements were taken as described above, i.e., immediately before administration PI0 and time after administration PI i The tinnitus or tinnitus symptom intensity difference (STID) is based on the score measured at a time after administration, where the time after administration can be selected from any time period as desired, including the times disclosed herein. In one embodiment, the tinnitus or tinnitus symptom intensity difference is measured from at least two values ​​measured over a period of at least 30 minutes, preferably at least 45 minutes, preferably at least 60 minutes, e.g., 90 minutes. Furthermore, the tinnitus or tinnitus symptom intensity difference can be measured from at least five values, e.g., at least seven values, preferably at least 10 values, e.g., 11, 12, or 13 values.

[0126] Exemplary Formulations formulation The compound or its therapeutically acceptable salt, or its polymorphic variant, can be formulated as a pharmaceutical composition. Such compositions can be administered orally, auricularly, e.g., intratympanic, buccal, intravenously, parenterally, by inhalation spray, rectally, intradermally, transdermally, pulmonary, nasally, or topically, optionally in a dosage unit formulation containing conventional non-toxic therapeutically acceptable carriers, adjuvants, and vehicles. Topical administration can also include the use of transdermal administration, such as transdermal patches or iontophoresis devices. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, or interstitial injection or infusion techniques. In one embodiment, the composition is administered orally. In one embodiment, the composition is administered auricularly, e.g., intratympanic.

[0127] Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980).

[0128] Active compound (or its therapeutically acceptable salt) can be administered by itself or in the form of pharmaceutical composition, in which active compound is mixed or mixed with one or more therapeutically acceptable carriers, excipients or diluents.Pharmaceutical composition can be formulated in a conventional manner using one or more therapeutically acceptable carriers, including excipients and adjuvants that facilitate the processing of active compound into preparations that can be used therapeutically.Suitable formulation depends on the selected route of administration.

[0129] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

[0130] Additionally, the coating material may include conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers, and surfactants.

[0131] Therapeutically acceptable excipients present in drug-containing tablets, beads, granules, or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also known as "fillers," are typically needed to increase the bulk of solid dosage forms so that they provide a practical size for tablet compression or bead and granule formation. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate, and powdered sugar.

[0132] Binders are used to impart cohesion to solid dosage forms, thus ensuring that tablets or beads or granules remain intact after the dosage form is formed. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, celluloses such as hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone.

[0133] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0134] Disintegrants are used to facilitate the disintegration or "break-up" of the dosage form after administration and may generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, arginine, gums, or cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

[0135] Stabilizers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.

[0136] The surfactant may be anionic, cationic, amphoteric, or nonionic. Suitable anionic surfactants include, but are not limited to, those containing carboxylate ions, sulfonate ions, and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium salts of long-chain alkyl sulfonates and alkylaryl sulfonates, such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinates, such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinates, such as sodium bis-(2-ethylthiol)sulfosuccinate; and alkyl sulfonates, such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4 oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0137] If desired, the tablets, beads, granules, or particles may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.

[0138] The compound can be complexed with other drugs as part of a therapeutic formulation. Pharmaceutical compositions can be, for example, in the form of tablets or capsules prepared by conventional means using therapeutically acceptable excipients, such as binders (e.g., acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch, and ethylcellulose); fillers (e.g., corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid); lubricants (e.g., magnesium stearate, stearic acid, silicone fluid, talc, wax, oil, and colloidal silica); and disintegrants (e.g., microcrystalline cellulose, corn starch, sodium starch glycolate, and alginic acid). If water-soluble, such formulated complexes can be formulated into suitable buffer solutions, such as phosphate-buffered saline, or other physiologically compatible solutions. Alternatively, if the resulting complex has low solubility in aqueous solvents, it can be formulated with a non-ionic surfactant such as TWEEN™ or polyethylene glycol. In this way, the compounds and their physiologically acceptable solvates can be formulated for administration.

[0139] The liquid preparation for oral administration prepared in water or other aqueous vehicle can contain various suspending agents, such as methylcellulose, alginate, tragacanth, pectin, kerullin, carrageenan, acacia, polyvinylpyrrolidone and polyvinyl alcohol.Liquid preparations can also contain the solution, emulsion, syrup and elixir that contains active compound together with wetting agent, sweetener, coloring agent and flavoring agent.Various liquid preparations and powder preparations for patient inhalation can be prepared by conventional methods.

[0140] Delayed-release and sustained-release compositions can be prepared. Delayed-release / sustained-release pharmaceutical compositions can be obtained by forming a complex between a drug and a therapeutically acceptable ion exchange resin and coating the complex. The formulation is coated with a material that acts as a barrier to control the diffusion of the drug from the core complex into the gastrointestinal fluid. Optionally, the formulation is coated with a polymer film that is insoluble in the acidic environment of the stomach and soluble in the basic environment of the lower GI tract to obtain a final dosage form that releases less than 10% of the drug dose in the stomach.

[0141] Additionally, combinations of immediate release and delayed / sustained release compositions can be formulated together.

[0142] In some cases, the first agent and / or the second agent or its salt is formulated into a dosage form as the sole active pharmaceutical ingredient (API). Such first agent and / or the second agent or its salt dosage form can be used alone or in combination therapy with one or more additional dosages containing one or more active pharmaceutical ingredients for preventing or treating hearing loss. In such cases, the daily dosage of the first agent and / or the second agent TET or its salt can be conveniently provided in a single dosage form as described herein or divided into two, three, four, or more dosages.

[0143] PEGylation In an alternative embodiment, salts of the first and / or second agents, along with other biologically active peptides and proteins, are conjugated to polyalkylene oxide polymers, particularly polyethylene glycol (PEG).

[0144] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [Example]

[0145] II. Working Examples The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0146] Example 1 Monotherapy for tinnitus Single drug treatments for tinnitus are evaluated using the go / no-go methodology further detailed in Example 4 with reference to Figures 1A-1D.

[0147] Figure 1A shows the results of the go / no-go test in tinnitus-positive mice treated with intraperitoneal TET at doses of 30, 60, and 90 mg / kg. All mice showed nearly 100% success in the go test when untreated and when administered 30, 60, and 90 mg / kg of TET, indicating that they were properly trained and performed the experiment. No change in the success rate was observed in the no-go test at a dose of 30 mg / kg TET. At a dose of 60 mg / kg TET, a success rate of approximately 90% was observed, indicating that 60 mg / kg TET has a positive effect on treating tinnitus in animals. Similarly, at a dose of 90 mg / kg, a success rate of approximately 95% was observed, indicating that 60 mg / kg TET has a positive effect on treating tinnitus in animals.

[0148] Figure 1B shows the results of the go / no-go test in tinnitus-positive mice treated with NMDP at doses of 10, 30, and 50 mg / kg via intraperitoneal injection. All mice demonstrated nearly 100% accuracy in the go test, both in the untreated and 10, 30, and 50 mg / kg NMDP-treated groups, indicating that they were properly trained and performed the experiment. At a dose of 10 mg / kg NMDP, only slight changes in the accuracy rate were observed in the no-go test, within the margin of error. At a dose of 30 mg / kg NMDP, approximately 95% accuracy was observed, indicating that 30 mg / kg NMDP has a positive effect on treating tinnitus in animals. Similarly, at a dose of 50 mg / kg, approximately 95% accuracy was observed, indicating that 50 mg / kg NMDP has a positive effect on treating tinnitus in animals.

[0149] Figure 1C shows the results of the go / no-go test in tinnitus-positive mice treated with AML via intraperitoneal injection at doses of 5 and 8 mg / kg. All mice showed nearly 100% success rates in the Go test, both in the untreated and 5 and 8 mg / kg AML groups, indicating that they were properly trained and performed the experiment. At a dose of 5 mg / kg AML, approximately 90% success rates were observed, indicating that 5 mg / kg AML has a positive effect on treating tinnitus in animals. Similarly, at a dose of 8 mg / kg, approximately 95% success rates were observed, indicating that 8 mg / kg AML has a positive effect on treating tinnitus in animals.

[0150] Figure 1D shows the results of the go / no-go test for tinnitus-positive mice treated with CBZ at doses of 5 and 8 mg / kg via intraperitoneal injection. All mice demonstrated nearly 100% accuracy in the Go test, both in the untreated and 5 and 8 mg / kg CBZ groups, indicating that they were properly trained and performed the experiment. At the 5 mg / kg dose of CBZ, a success rate of less than 70% (within the margin of error for saline-treated mice) was observed, indicating that 5 mg / kg CBZ has minimal effect in treating tinnitus in animals. Similarly, at the 8 mg / kg dose, a success rate of less than 80% was observed, indicating that 8 mg / kg CBZ has minimal effect in treating tinnitus in animals.

[0151] Example 2 Combination therapy for the treatment of tinnitus Multi-drug treatments for tinnitus are evaluated using the go / no-go methodology further detailed in Example 4 with reference to Figures 2A-2B.

[0152] Figure 2A shows the results of the go / no-go test in tinnitus-positive mice treated with TET and NMDP by intraperitoneal injection at a dose of 10 mg / kg. All mice demonstrated nearly 100% accuracy in the go test, both in the untreated and 10 mg / kg doses, indicating that they were properly trained and performed the experiment. Approximately 95% accuracy was observed in the no-go test at a dose of 10 mg / kg, indicating that 60 mg / kg of TET had a positive effect on treating tinnitus in animals. Compared to the results of TET alone (Figure 1A) or NMDP alone (Figure 1B), neither was effective in treating tinnitus in animals until a dose of approximately 30 mg / kg was reached. The combination of TET and NMDP at a dose of 10 mg / kg exhibited a synergistic effect greater than either agent acting alone or simply additively. The results in FIG. 2A may indicate that the effect of TET shown in FIG. 2A may be due to blocking L-type calcium channels rather than T-type calcium channels.

[0153] Figure 2B shows the results of the go / no-go test for tinnitus-positive mice treated by intraperitoneal injection with 300 mg / kg ESM, 300 mg / kg ESM and 20 mg / kg GAB, and 300 mg / kg ESM and 40 mg / kg GAB. All mice demonstrated nearly 100% success in the go test when untreated, as well as when treated with 300 mg / kg ESM, 300 mg / kg ESM and 20 mg / kg GAB, and 300 mg / kg ESM and 40 mg / kg GAB, indicating that the mice were properly trained and performed the experiment. At a dose of 300 mg / kg ESM, approximately 70% success was observed, indicating that 300 mg / kg ESM has minimal effect in treating tinnitus in animals. At a dose of 300 mg / kg ESM and 20 mg / kg GAB, a slight increase in the correct answer score up to approximately 80% was observed, indicating that 300 mg / kg ESM and 20 mg / kg GAB had only a modest effect in treating the animals' tinnitus. At a dose of 300 mg / kg ESM and 40 mg / kg GAB, a decrease in the correct answer score to approximately 55% was observed, indicating that 300 mg / kg ESM and 40 mg / kg GAB were ineffective in treating the animals' tinnitus or worsened the animals' tinnitus. Figure 2B illustrates the unpredictable behavior of calcium channel blockers when acting in combination, further demonstrating that such combinations can have negative or adverse effects.

[0154] Example 3 Treatment of induced tinnitus in mice In this example, mice suffering from noise-induced tinnitus are treated with intranasal delivery formulations of a first and / or second agent, such as the formulation of Example 2.

[0155] As shown in Figure 3, a sound-based avoidance detection (SBAD) method was used to detect tinnitus and test animal responses to different pharmacological doses of the first and / or second drugs. Using a shuttle box divided into two compartments, mice were trained for 15 days to cross from one end to the other in response to a sound cue during "Go" trials and to remain motionless in silence during "No-Go" trials. Animals underwent a 5-minute acclimation period in the shuttle box, after which they were randomly assigned to 100 trials per day, lasting approximately 30–40 minutes. The sound cue was played as white noise or narrowband noise at random frequencies of 8, 10, 12.5, 16, and 29 kHz, and at random intensities of 75, 80, or 85 dB. To reinforce the training session, mice were shocked if they failed to cross from one compartment to the other during Go trials and if they moved between compartments in silence during No-Go trials. Further training was strengthened by adding hurdles to training 11. After training day 15, mice were tested for 3 days to obtain baseline scores that were compared after noise exposure, as well as after 3 days of retraining.

[0156] After completing the training and achieving a high success rate on the test, the mice were exposed to noise trauma for tinnitus for two days. To ensure that the mice still had hearing, one ear was protected with earplugs while the other ear was exposed to the noise. Mice were placed in a sound booth where they were exposed to 120 dB broadband noise at 4–25 kHz for two hours. After the noise exposure, the mice were housed for one month and then tested to determine whether they had developed tinnitus. During these testing periods, mice were tested in a shuttle box for three days, where Go and No-Go trials were conducted. However, during the No-Go trials, mice were not shocked, as it was expected that mice with tinnitus would cross the compartment without the sound cue. To ensure that they maintained their hearing and were able to hear the sound cue, mice continued to receive shocks during the Go trials. Examination of the results of the post-noise test showed that tinnitus-positive mice made higher average errors during the No-Go trials compared to the training trials. A chi-square test was completed comparing the post-noise test with the baseline test to ensure there was a significant difference in the No-Go test scores. However, if the mouse did not have tinnitus, the test was performed after waiting an additional month, and if necessary, another month.

[0157] Mice received the first and / or second drug at doses of 50, 30, and 10 mg / kg. Go and No-Go scores for the tests were compared using a chi-square test from Social Science Statistics and JASP. A chi-square test was first used to determine whether the mice were tinnitus-positive by comparing the pre-noise No-Go baseline score with the post-noise No-Go score (a significant difference (p-value < 0.05) in at least two tests indicates a tinnitus-positive mouse). Following this conclusion, the mice were appropriately tested to determine whether their No-Go scores could be improved with different drug doses and combinations. For the Go score, the first and / or second drug did not affect the mice's ability to hear the presented sound. For the No-Go test, the first and / or second drug did not affect the mice's scores, indicating that the concentrations did not cause any behavioral changes and should be appropriate doses for testing.

[0158] Tinnitus was assessed by comparing the No-Go scores after 3 months of noise exposure with baseline scores. The mice had a significant decrease on all three days of testing, indicating that these mice had tinnitus. One or more mice served as control animals. When examining the Go scores of tinnitus animals tested with specific drugs, the mice experienced a significant decrease in their scores. Mice administered the first and / or second drug showed a significant increase in No-Go scores. These results indicate that the first and / or second drug was effective in treating the tinnitus in these mice. In contrast, no change in the No-Go scores indicates that the first and / or second drug was not effective in treating the animal's tinnitus, and a decrease in the score may indicate that the animal's tinnitus had worsened.

[0159] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It is understood that various alternatives to the embodiments of the present disclosure described herein may be used in practicing the present disclosure. It is intended that the following claims define the scope of the disclosure, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A method for treating hearing impairment or symptoms of hearing impairment in a subject in need thereof, comprising: i) a first agent comprising a first L-type calcium channel blocker; and ii) a second agent comprising a calcium channel blocker, a potassium channel opener, a sodium channel blocker, a GABAA receptor positive allosteric modulator, a dopamine receptor antagonist, or one or more SARIs; Administering a therapeutically effective amount of a pharmaceutical composition comprising:

2. 2. The method of claim 1, wherein the first drug comprises nimodipine (NMDP) or a salt thereof and the second drug comprises carbamazepine (CBZ) or a salt thereof.

3. 10. The method of claim 1, wherein the first drug comprises amlodipine (AML) or a salt thereof and the second drug comprises carbamazepine or a salt thereof.

4. 10. The method of claim 1, wherein the first drug comprises nimodipine or a salt thereof and the second drug comprises amlodipine or a salt thereof.

5. 2. The method of claim 1, wherein the first drug comprises tetrandrine (TET) or a salt thereof and the second drug comprises nimodipine or a salt thereof.

6. 2. The method of claim 1, wherein the first drug comprises tetrandrine or a salt thereof and the second drug comprises carbamazepine or a salt thereof.

7. 2. The method of claim 1, wherein the first drug comprises tetrandrine or a salt thereof and the second drug comprises amlodipine or a salt thereof.

8. 10. The method of claim 1, wherein the first agent comprises amlodipine or nimodipine.

9. 9. The method of claim 8, wherein the second agent comprises gabapentin.

10. 9. The method of claim 8, wherein the second agent comprises a GABAA receptor positive allosteric modulator (e.g., zolpidem).

11. 9. The method of claim 8, wherein the second agent comprises a dopamine receptor antagonist (e.g., retigabine).

12. 9. The method of claim 8, wherein the second drug comprises carbamazepine.

13. 9. The method of claim 8, wherein the second agent comprises one or more SARIs.

14. 14. The method of claim 13, wherein the one or more SARIs comprises trazadone or nefazodone.

15. 1. A method of selecting a subject in need thereof for treatment of a hearing impairment or a symptom of hearing impairment in said subject, comprising: a. administering to the subject a test drug comprising an L-type calcium channel blocker; b. assessing whether the subject responded to the study drug; and c. If the subject responds to a test drug comprising an L-type calcium channel blocker, selecting the subject for administration of a first pharmaceutical composition; and d. A method comprising administering therapeutically effective amounts of i) a first agent comprising a first L-type calcium channel blocker, and ii) a second agent comprising a calcium channel blocker, a potassium channel opener, a sodium channel blocker, a GABAA receptor positive allosteric modulator, a dopamine receptor antagonist, or one or more SARIs.

16. 16. The method of claim 15, wherein in step (a), the test drug is selected from the group consisting of tetrandrine or a salt thereof, nimodipine or a salt thereof, carbamazepine or a salt thereof, and amlodipine or a salt thereof.

17. 16. The method of claim 15, wherein the first drug is selected from the group consisting of tetrandrine or a salt thereof, nimodipine or a salt thereof, and amlodipine or a salt thereof.

18. 16. The method of claim 15, wherein the first agent comprises amlodipine or nimodipine.

19. 19. The method of claim 18, wherein the second agent comprises gabapentin.

20. 19. The method of claim 18, wherein the second agent comprises a GABAA receptor positive allosteric modulator (e.g., zolpidem).

21. 19. The method of claim 18, wherein the second agent comprises a dopamine receptor antagonist (e.g., retigabine).

22. 19. The method of claim 18, wherein the second agent comprises carbamazepine.

23. 20. The method of claim 18, wherein the second agent comprises one or more SARIs.

24. 24. The method of claim 23, wherein the one or more SARIs comprises trazadone or nefazodone.

25. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition orally, nasally, intratympanically, bucally, intradermally, transdermally, topically, or by inhalation.

26. 25. The method of any one of claims 1 to 24, further comprising intravenously administering said pharmaceutical composition to said subject in need thereof.

27. The method of any one of claims 1 to 24, further comprising orally administering the pharmaceutical composition to the subject in need thereof.

28. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition to the subject in need thereof by intratympanic injection.

29. 29. The method of claim 28, further comprising administering the pharmaceutical composition by contacting the composition with the crista fenestrae cochleae, round window, tympanic cavity, tympanic membrane, middle ear, or outer ear.

30. 30. The method of claim 29, further comprising administering the pharmaceutical composition into the ear canal or into the vestibule of the ear.

31. 29. The method of claim 28, further comprising administering the pharmaceutical composition by a single dose of intratympanic injection.

32. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition at any time before or after the onset of symptoms of the hearing impairment that may be treatable with the pharmaceutical composition.

33. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition about every 4 hours.

34. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition about every 2 hours.

35. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition about every 8 hours.

36. 25. The method of any one of claims 1-24, further comprising administering the pharmaceutical composition at least once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.

37. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition once a week.

38. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition by low-dose therapy.

39. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition continuously.

40. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition by titration for vestibular symptoms.

41. 25. The method of any one of claims 1-24, further comprising administering the pharmaceutical composition for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 6 months, or at least 1 year.

42. 25. The method of any one of claims 1 to 24, further comprising administering to the subject another active pharmaceutical composition or salt thereof.

43. 25. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition in a unit dosage form.

44. 25. The method of any one of claims 1 to 24, further comprising administering said pharmaceutical composition so as not to alter the endocochlear potential.

45. 25. The method of any one of claims 1 to 24, further comprising increasing the dose of the pharmaceutical composition in the subject until symptoms of an inner ear disorder are observed in the subject.

46. 25. The method of any one of claims 1-24, further comprising increasing the dose of the pharmaceutical composition in the subject until the patient reports no or reduced instances of dizziness.

47. The method of any one of claims 1 to 24, further comprising administering the pharmaceutical composition by a drug delivery device.

48. 48. The method of claim 47, further comprising delivering the pharmaceutical composition by a dropper bottle, a needle, a syringe, a pump, a microinjection device, a microcatheter, or a combination thereof.

49. 25. The method of any one of claims 1 to 24, further comprising discontinuing administration of the pharmaceutical composition if symptoms of an inner ear disorder are observed in the subject.

50. 46. ​​The method of claim 45, wherein the symptoms of the inner ear disorder include spontaneous nystagmus observed with Frenzel glasses, imbalance, exercise intolerance, or hearing loss / loss.

51. 25. The method of any one of claims 1 to 24, wherein the pharmaceutical composition is administered at at least about 1 mg / ml.

52. 25. The method of any one of claims 1 to 24, wherein the pharmaceutical composition is administered in a unit dose of about 1 mg to about 1000 mg.

53. 25. The method of any one of claims 1 to 24, wherein the pharmaceutical composition is administered in a unit dose of about 1 mg to about 100 mg.

54. The method of any one of claims 1 to 24, wherein the hearing impairment in the subject in need thereof is noise-induced hearing loss (NIHL).

55. 25. The method of any one of claims 1 to 24, wherein the hearing impairment in the subject in need thereof is age-related hearing loss (ARHL) or presbycusis.

56. The method of any one of claims 1 to 24, wherein the hearing impairment in the subject in need thereof is traumatic or drug-induced hearing loss.

57. 25. The method of any one of claims 1 to 24, wherein the hearing impairment in the subject in need thereof is tinnitus or Meniere's disease.

58. 58. The method of any one of claims 15-57, wherein the therapeutically effective amount of the pharmaceutical composition comprises a dose of NMDP from about 0.2 mg / kg to about 10 mg / kg of the subject in need thereof.

59. 59. The method of any one of claims 15-58, wherein the therapeutically effective amount of the pharmaceutical composition comprises a dose of AML of about 0.2 mg to about 10 mg / kg of the subject in need thereof.

60. 60. The method of any one of claims 15-59, wherein the therapeutically effective amount of the pharmaceutical composition comprises a dose of CBZ from about 0.1 mg / kg to about 5 mg / kg of the subject in need thereof.

61. 61. The method of any one of claims 15-60, wherein the therapeutically effective amount of the pharmaceutical composition comprises a dose of TET of about 0.2 mg / kg to about 10 mg / kg of the subject in need thereof.

62. 25. The method of any one of claims 15-24, wherein the effect of the test agent on the subject is measured by an assessment selected from the group consisting of: a) measurement of change in ABR threshold, b) change in auditory speech recognition as measured by a words-in-noise test, c) change in auditory speech recognition as measured by a digits-in-noise test, d) change in low frequency hearing threshold, e) change in incidence of adverse events after administration of the test agent, f) change in tinnitus severity, g) change in tinnitus loudness, h) change in dizziness severity, i) change in ear fullness, j) change in dizziness sensation, and k) change in hair cell function as measured by change in ABR threshold, after administration of the first or second test agent.

63. 63. The method of claim 62, wherein the ABR threshold measurement is performed in the frequency range of 5 kHz to 50 kHz.

64. 10. The method of any one of the preceding claims, wherein the therapeutically effective amount of the first agent and the therapeutically effective amount of the second agent are less than the amount of the first agent or the second agent, when administered individually, required to treat a hearing impairment.

65. 10. The method of any one of the preceding claims, wherein the first and second agents provide a synergistic therapeutic effect when administered together.

66. 1. A pharmaceutical composition for treating symptoms of hearing impairment in a subject in need thereof, comprising: a first agent comprising a pharmaceutically effective amount of an L-type calcium channel blocker; and a second agent comprising a calcium channel blocker, a potassium channel opener, a sodium channel blocker, a GABAA receptor positive allosteric modulator, a dopamine receptor antagonist, or one or more SARIs.

67. 67. The pharmaceutical composition of claim 66, wherein the first drug comprises a pharmaceutically effective amount of tetrandrine or a salt thereof and the second drug comprises a pharmaceutically effective amount of amlodipine or a salt thereof.

68. 67. The pharmaceutical composition of claim 66, wherein the first drug comprises a pharmaceutically effective amount of tetrandrine or a salt thereof and the second drug comprises a pharmaceutically effective amount of carbamazepine (CBZ) or a salt thereof.

69. 67. The pharmaceutical composition of claim 66, wherein the first agent comprises a pharmaceutically effective amount of amlodipine (AML) or a salt thereof, and the second agent comprises a pharmaceutically effective amount of carbamazepine or a salt thereof.

70. 67. The pharmaceutical composition of claim 66, wherein the first agent comprises a pharmaceutically effective amount of nimodipine (NMDP) or a salt thereof and the second agent comprises a pharmaceutically effective amount of amlodipine or a salt thereof.

71. 67. The pharmaceutical composition of claim 66, wherein the first agent comprises a pharmaceutically effective amount of nimodipine or a salt thereof and the second agent comprises a pharmaceutically effective amount of carbamazepine or a salt thereof.

72. 72. The pharmaceutical composition of any one of claims 66, 70, or 71, wherein the dose of NMDP in the pharmaceutical composition administered is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, or 60 mg, and administration is every 4 hours.

73. The concentration of TET in the pharmaceutical composition to be administered is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 69. The pharmaceutical composition of any one of claims 66 to 68, wherein the concentration is 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, or 400 mg / ml.

74. The dose of CBZ in the pharmaceutical composition to be administered is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75 72. The pharmaceutical composition of any one of claims 68-69 or 71, wherein the dosage is 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400 or 600 mg, and is administered up to twice per day.

75. 71. The pharmaceutical composition of any one of claims 67, 69, or 70, wherein the concentration of AML in the administered pharmaceutical composition is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg and is administered a maximum of once per day.

76. 67. The pharmaceutical composition of claim 66, wherein the first agent comprises amlodipine or nimodipine.

77. 77. The pharmaceutical composition of claim 76, wherein the second agent comprises gabapentin.

78. 77. The pharmaceutical composition of claim 76, wherein the second agent comprises a GABAA receptor positive allosteric modulator (e.g., zolpidem).

79. 77. The pharmaceutical composition of claim 76, wherein the second agent comprises a dopamine receptor antagonist (e.g., retigabine).

80. 77. The pharmaceutical composition of claim 76, wherein the second agent comprises carbamazepine.

81. 77. The pharmaceutical composition of claim 76, wherein the second agent comprises one or more SARIs.

82. 82. The pharmaceutical composition of claim 81, wherein the one or more SARIs comprises trazadone or nefazodone.

83. 83. The pharmaceutical composition of any of claims 76 to 82, comprising amlodipine in a dose of 0.1 to 10 mg / day.

84. 83. The pharmaceutical composition of any of claims 76 to 82, comprising nimodipine at a dose of about 0.1 to 60 mg per 4 hours.

85. 78. The pharmaceutical composition of claim 77, comprising gabapentin at a dose of about 1 to 600 mg per 8 hours.

86. 79. The pharmaceutical composition of claim 78, comprising zolpidem in a dose of 0.1 to 10 mg / day.

87. 80. The pharmaceutical composition of claim 79, comprising retigabine at a dose of about 1 to 400 mg per 8 hours.

88. 81. The pharmaceutical composition of claim 80, comprising carbamazepine at a dose of about 1 to 600 mg per 12 hours.

89. 83. A pharmaceutical composition according to claim 81 or 82, comprising trazadone in a dose of 1 to 400 mg / day.

90. 83. The pharmaceutical composition of claim 81 or 82, comprising nefazodone in a dose of 1 to 600 mg / day.

91. 10. The pharmaceutical composition of any one of the preceding claims, wherein the volume of the pharmaceutical composition administered is 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95 or 1.0 ml.

92. 10. A pharmaceutical composition according to any one of the preceding claims, which is released continuously, variably or in a pulsatile manner, or a combination thereof.

93. 10. A pharmaceutical composition according to any one of the preceding claims in unit dosage form.

94. 90. The pharmaceutical composition of claim 89, wherein the unit dosage form is a tablet, capsule, caplet, gelcap, powder, or solution dosage form.

95. 10. The pharmaceutical composition of any one of the preceding claims, wherein the composition is aqueous.

96. 10. The pharmaceutical composition of any one of the preceding claims, wherein the composition is in the form of a gel or a film.

97. 10. The pharmaceutical composition of any one of the preceding claims, wherein the composition comprises micronized particles.

98. 70. The pharmaceutical composition of claim 69, wherein the unit dosage form has a unit weight of about 10 mg to about 10 g.

99. 63. The pharmaceutical composition of any one of claims 57, 61 or 62, comprising NMDP in a concentration of about 0.1% to about 20% w / w of the formulation.

100. 60. The pharmaceutical composition of any one of claims 57 to 59, comprising tetrandrine or a salt thereof in a concentration of about 0.1% to about 20% of the formulation.

101. 63. The pharmaceutical composition of any one of claims 59-60, or 62, comprising carbamazepine or a salt thereof in a concentration of about 0.1% to about 20% of the formulation.

102. 62. The pharmaceutical composition of any one of claims 58, 60 or 61, comprising amlodipine or a salt thereof in a concentration of about 0.1% to about 20% of the formulation.

103. 10. The method of any one of the preceding claims, wherein the L-type calcium channel blocker comprises NMDP, CBZ or AML.

104. 10. The method of any one of the preceding claims, wherein the T-type calcium channel blocker, the N-type calcium channel blocker or the non-selective calcium channel blocker comprises TET.

105. 10. The method of any one of the preceding claims, wherein the first agent and the second agent are administered sequentially.

106. 10. The method of any one of the preceding claims, wherein the first agent and the second agent are administered simultaneously.

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