Use of gaboxadol in treatment of tinnitus

Abstract

To provide a novel treatment method for severe tinnitus.SOLUTION: Methods of treating tinnitus with gaboxadol or a pharmaceutically acceptable salt thereof are provided. Also provided are therapeutic compositions that may be used to improve one or more symptoms of tinnitus. Methods of treating acute sensorineural hearing loss or Meniere's disease with gaboxadol or a pharmaceutically acceptable salt thereof are provided. Also provided are therapeutic compositions that may be used to improve one or more symptoms of acute sensorineural hearing loss or Meniere's disease.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 454,280, filed February 3, 2017; U.S. Provisional Application No. 62 / 530,528, filed July 10, 2017; and U.S. Provisional Application No. 62 / 536,669, filed July 25, 2017, each of which is incorporated by reference in its entirety.

[0002] Technical Field A method for treating acute sensorineural hearing loss, Meniere's disease or tinnitus. [Background technology]

[0003] Tinnitus is characterized by hearing in the absence of external sound. In many cases, tinnitus is perceived subjectively, i.e., only the subject can perceive the symptoms. Tinnitus symptoms include ringing, rolling, static, buzzing, hissing, and whistling in one or both ears. The noise can be intermittent or continuous. According to the National Institute of Deafness and Communication Disorders (NIDCD), approximately 10 percent of the adult population of the United States, or 25 million Americans, experience some degree of tinnitus. According to the American Tinnitus Association, 20 million of these patients suffer from severe, chronic tinnitus, and 2 million have extreme and debilitating cases. Severe tinnitus can lead to depression and other mental health problems that have serious effects on the patient and the patient's family. Treatments such as masking, sound therapy, electrical stimulation, and medications have shown some benefit. Unfortunately, these treatments can be insufficient and many patients continue to suffer from tinnitus. Thus, there remains a great need for treatments for tinnitus.

[0004] Acute sensorineural hearing loss (ASNHL) is also known as sudden sensorineural hearing loss (SSNHL), sudden deafness, and acute sensorineural hearing loss. Idiopathic acute sensorineural hearing loss is a form of acute sensorineural hearing loss with no clear cause. The term "acute sensorineural hearing loss" or "ASNHL" is used herein for convenience and includes SSNHL, sudden deafness, acute sensorineural hearing loss, and idiopathic acute sensorineural hearing loss. In certain instances, acute sensorineural hearing loss can be defined as the onset of unilateral sensorineural hearing loss within 72 hours. It affects an estimated 5-20 / 100,000 people per year. In some instances, ASNHL can occur after various inner ear injuries. In certain instances, ASNHL can be induced by excessive noise (acute or other acoustic trauma), viral or bacterial infection in the inner ear, disturbance of the inner ear blood supply, middle and inner ear surgery, exposure to ototoxic drugs, head trauma, tumors in the nerves connecting the ear to the brain, and various other events. In certain instances, ASNHL can be associated with surgically induced acoustic trauma. The most common symptom in ASNHL is a feeling of fullness in the ear (sometimes described as a feeling of pressure in the ear), followed by symptoms of hearing loss and tinnitus. The feeling of fullness in the ear is a non-specific symptom. The most common treatment for ASNHL is corticosteroids, especially when the cause is unknown. Corticosteroids can be associated with a decreased immune response and can be harmful when ASNHL is caused by bacterial or viral infection.

[0005] Meniere's disease is an inner ear disorder that causes progressive, eventually permanent loss of hearing, vertigo and fluctuating hearing loss accompanied by ringing in the ears (tinnitus) and an occasional feeling of fullness or pressure in the affected ear. A common symptom of Meniere's disease is hypersensitivity to sound. Often, Meniere's disease affects only one ear, at least initially; however, over time both ears may become involved. The cause of Meniere's disease is unknown, but genetic and environmental factors may play a role. Meniere's disease involves an abnormal amount of fluid (endolymph) in the inner ear. There is no cure for Meniere's disease, but medications that reduce nausea, such as dimenhydrinate, meclizine, or prochlorperazine, can be administered. Anti-inflammatory medications, such as NSAIDS or corticosteroids, can also be administered.

[0006] Gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) (THIP)) is described in European Patent Nos. 0000338 and 0840601, U.S. Patent Nos. 4,278,676, 4,362,731, 4,353,910, and WO 2005 / 094820. Gaboxadol is a δ-subunit-containing GABA receptor antagonist. A Selective GABA receptor preference A It is a receptor agonist. In the early 1980s, gaboxadol was the subject of a series of pilot studies testing its efficacy as an analgesic and anxiolytic, as well as a treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease, and convulsions. In the 1990s, gaboxadol moved into late-stage development for the treatment of insomnia. Development was discontinued after the compound showed no significant effect on sleep initiation and maintenance in a three-month efficacy study. Furthermore, patients with a history of drug abuse who were given gaboxadol experienced a sharp increase in psychiatric adverse events.

[0007] Gaboxadol has been suggested for the treatment of tinnitus, but recent studies have demonstrated that gaboxadol GABA receptors in the auditory thalamus / medial geniculate body (MGB) are downregulated by gaboxadol. AWe show that mediated tonic inhibition induces a significant increase in tinnitus contralateral to sound exposure, see e.g., Sametsky et al., Journal of Neuroscience, (June 24, 2015) 35(25): 9369-9380.

[0008] Benzodiazepines are a class of drugs with widespread clinical use as anxiolytics, hypnotics, anticonvulsants and muscle relaxants. They act by inhibiting GABA receptors in the central nervous system. A It works by enhancing receptor function. GABA A The receptor complex consists of five glycoprotein subunits, each of which has multiple isoforms. A The receptor contains two α subunits, two β subunits and one γ subunit. Each receptor complex has two GABA binding sites but only one benzodiazepine (BZD) binding site. BZD receptors are classified into several types based on the α subunit isoform and the clinical effects associated with each type. See Griffin III et al., Benzodiazepine Pharmacology and Central Nervous System-Mediated Effects. The Ochsner Journal: Summer 2013, Vol. 13, No. 2, pp. 214-223. Benzodiazepines have been suggested for use in the management of tinnitus. See Jufas and Wood, Journal of Laryngology & Otology (2015) 129 (Suppl. S3) S14-S22. However, the use of benzodiazepines in the medical management of subjective tinnitus does not have a solid evidence base. Ibid. Clonazepam has been shown to be effective in treating tinnitus in three trials, two alprazolam trials showed conflicting results, diazepam has been shown to be ineffective in two trials, and oxazepam has been shown to be effective in one trial. Summary of the Invention

[0009] The method for treating tinnitus described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in tinnitus. The method for treating tinnitus described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in one or more symptoms of tinnitus. The method for treating tinnitus described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in tinnitus the next day. The method for treating tinnitus described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in the patient for more than 6 hours after administration to the patient. 1. A method for treating tinnitus comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of such treatment, wherein said method provides a C of less than about 400 ng / ml. max and wherein the method provides an improvement in the patient for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. 6-12 and wherein the method provides an improvement in the patient for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. Described herein is a method for treating a patient comprising administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC at least 20% lower than the first pharmaceutical composition. 0-∞Described herein is a method for treating tinnitus, the method providing an in vivo plasma profile comprising: a) administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with a benzodiazepine, wherein the method provides for improvement of the tinnitus; b) administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam, wherein the method provides for improvement of the tinnitus; c) administering to a patient in need of treatment about 10 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with 10 mg of clobazam, wherein the method provides for improvement of the tinnitus.

[0010] A method for treating acute sensorineural hearing loss described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides for improvement of acute sensorineural hearing loss. A method for treating acute sensorineural hearing loss described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with a benzodiazepine, wherein the method provides for improvement of acute sensorineural hearing loss. A method for treating acute sensorineural hearing loss described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam, wherein the method provides for improvement of acute sensorineural hearing loss. Described herein is a method for treating acute sensorineural hearing loss comprising administering to a patient in need of treatment about 10 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with 10 mg of clobazam, wherein said method provides improvement in acute sensorineural hearing loss.

[0011] A method for treating Meniere's disease as described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein said method provides for an improvement of Meniere's disease. A method for treating Meniere's disease as described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with a benzodiazepine, wherein said method provides for an improvement of Meniere's disease. A method for treating Meniere's disease as described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam, wherein said method provides for an improvement of Meniere's disease. A method for treating Meniere's disease as described herein comprises administering to a patient in need of treatment about 10 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with 10 mg of clobazam, wherein said method provides for an improvement of Meniere's disease. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the mean arithmetic plasma concentration-time profiles of gaboxadol after single oral doses (2.5 mg, 5 mg, 10 mg, 15 mg and 20 mg) as described in Example 1, with the horizontal line Δ indicating the change between 6 and 12 hours. [Diagram 2] 1 shows the mean arithmetic plasma concentration-time profiles of gaboxadol after single oral doses (2.5 mg, 5 mg, 10 mg, 15 mg and 20 mg) as described in Example 1. [Diagram 3] Schematic representation of the three proposed arms of gaboxadol treatment for 12 weeks: 1) a single evening dose, 2) morning and evening doses, and 3) placebo. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description Described herein is a method for treating tinnitus with gaboxadol or a pharma- ceutically acceptable salt thereof. Also described herein is a method for treating acute sensorineural hearing loss with gaboxadol or a pharma- ceutically acceptable salt thereof. Also described herein is a method for treating Meniere's disease with gaboxadol or a pharma- ceutically acceptable salt thereof.

[0014] Many pharmaceutical products are administered as fixed doses at regular intervals to achieve therapeutic efficacy. Their duration of action is reflected by their plasma half-life. Gaboxadol is a selective GABAergic receptor antagonist with a relatively short half-life (t1 / 2 = 1.5 hours). A These are receptor agonists. Because efficacy often depends on sufficient exposure within the central nervous system, administration of CNS drugs with short half-lives may require frequent maintenance doses.

[0015] Advantageously disclosed herein is a method for treating tinnitus by administering gaboxadol or a pharma- ceutically acceptable salt thereof.For example, in one embodiment, a method for treating tinnitus is provided, comprising administering to a patient in need of treatment 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides improvement for more than 6 hours after administration to the patient.

[0016] Advantageously disclosed herein is a method for treating acute sensorineural hearing loss by administering gaboxadol or a pharmaceutically acceptable salt thereof.For example, in one embodiment, a method for treating acute sensorineural hearing loss is provided, comprising administering to a patient in need of treatment a pharmaceutical composition comprising about 0.05 mg to about 30 mg of gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement for more than 6 hours after administration to the patient.

[0017] Advantageously disclosed herein is a method for treating Meniere's disease by administering gaboxadol or a pharmaceutically acceptable salt thereof.For example, in one embodiment, a method for treating Meniere's disease is provided, which comprises administering to a patient in need of treatment a pharmaceutical composition comprising about 0.05 mg to about 30 mg of gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement for more than 6 hours after administration to the patient.

[0018] A method for treating tinnitus as described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in one or more symptoms of tinnitus. A method for treating tinnitus as described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in tinnitus the next day. A method for treating tinnitus as described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in the patient for more than 6 hours after administration to the patient ... max and providing patient improvement for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. Described herein is a method for treating tinnitus comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of treatment, wherein the method provides an AUC of less than about 900 ng·hr / ml. 6-12and wherein the method provides an improvement in the patient for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. Described herein is a method for treating a patient comprising administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC at least 20% lower than the first pharmaceutical composition. 0-∞ Described herein is a method for treating tinnitus, which provides an in vivo plasma profile comprising:

[0019] The method for treating acute sensorineural hearing loss described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in one or more symptoms of acute sensorineural hearing loss. The method for treating acute sensorineural hearing loss described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in acute sensorineural hearing loss the next day. The method for treating acute sensorineural hearing loss described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in the patient for more than 6 hours after administration to the patient. Described herein is a method of treating acute sensorineural hearing loss comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of treatment, wherein said method provides an in vivo plasma profile with a Cmax of less than about 400 ng / ml, and said method provides patient improvement for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof.A method of treating acute sensorineural hearing loss comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of treatment, wherein said method provides an AUC of less than about 900 ng·hr / ml. 6-12and wherein the method provides an improvement in the patient for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. Described herein is a method for treating a patient comprising administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC at least 20% lower than the first pharmaceutical composition. 0-∞ Described herein is a method for treating acute sensorineural hearing loss, which provides an in vivo plasma profile comprising:

[0020] The method for treating Ménière's disease described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in one or more symptoms of Ménière's disease. The method for treating Ménière's disease described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in Ménière's disease the next day. The method for treating Ménière's disease described herein comprises administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the method provides improvement in the patient for more than 6 hours after administration to the patient. Described herein is a method of treating Meniere's disease, comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of treatment, wherein said method provides an in vivo plasma pro- file with a Cmax of less than about 400 ng / ml, and said method provides patient improvement for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. Described herein is a method of treating Meniere's disease, comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of treatment, wherein said method provides an in vivo plasma pro- file with an AUC of less than about 900 ng·hr / ml. 6-12and wherein the method provides an improvement in the patient for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. Described herein is a method for treating a patient comprising administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC at least 20% lower than the first pharmaceutical composition. 0-∞ Described herein is a method for treating Meniere's disease, which provides an in vivo plasma profile comprising:

[0021] Embodiments described herein provide for administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, which may be provided as an acid addition salt, a zwitterion hydrate, an anhydrous zwitterion, a hydrochloride or hydrobromide salt, or in the form of a zwitterion monohydrate. Acid addition salts include, but are not limited to, maleic acid addition salts, fumaric acid addition salts, benzoic acid addition salts, ascorbic acid addition salts, succinic acid addition salts, oxalic acid addition salts, bismethylenesalicylic acid addition salts, methanesulfonic acid addition salts, ethanedisulfonic acid addition salts, acetic acid addition salts, propionic acid addition salts, tartaric acid addition salts, salicylic acid addition salts, citric acid addition salts, gluconic acid addition salts, lactic acid addition salts, malic acid addition salts, mandelic acid addition salts, cinnamic acid addition salts, citraconic acid addition salts, aspartic acid addition salts, stearic acid addition salts, palmitic acid addition salts, itaconic acid addition salts, glycolic acid addition salts, p-amino-benzoic acid addition salts, glutamic acid addition salts, benzenesulfonic acid addition salts or theophylline acetic acid addition salts, as well as 8-halotheophylline, e.g., 8-bromo-theophylline. In other suitable embodiments, inorganic acid addition salts may be used, including but not limited to hydrochloric acid addition salts, hydrobromic acid addition salts, sulfuric acid addition salts, sulfamic acid addition salts, phosphoric acid addition salts, or nitric acid addition salts.

[0022] In some embodiments, gaboxadol is provided as gaboxadol monohydrate.Those skilled in the art can easily understand that the amount of active ingredient in pharmaceutical composition depends on the form of gaboxadol provided.For example, pharmaceutical composition containing 5.0mg, 10.0mg or 15.0mg of gaboxadol corresponds to 5.6mg, 11.3mg or 16.9mg of gaboxadol monohydrate.

[0023] In certain embodiments, gaboxadol is crystalline, such as a crystalline hydrochloride, a crystalline hydrobromide, or a crystalline zwitterionic monohydrate. In certain embodiments, gaboxadol is provided as a crystalline monohydrate.

[0024] Deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD) and toxicity profile has been previously demonstrated with several classes of drugs. Therefore, the use of deuterium-enriched gaboxadol is contemplated and is within the scope of the methods and compositions described herein. Deuterium can be synthetically incorporated into any position instead of hydrogen by known synthetic methods in the art. For example, deuterium can be incorporated into various positions that have exchangeable protons, such as amine N--H, by proton-deuterium equilibrium exchange. Thus, deuterium can be selectively or non-selectively incorporated into deuterium-enriched gaboxadol by known methods in the art. See Journal of Labeled Compounds and Radiopharmaceuticals 19(5) 689-702 (1982).

[0025] Deuterium-enriched gaboxadol can be expressed by the percentage of deuterium incorporated at a given position of a molecule instead of hydrogen.For example, 1% deuterium enrichment at a given position means that 1% of the molecules of a given sample contain deuterium at that particular position. Deuterium enrichment can be determined using conventional analytical methods such as mass spectrometry and nuclear magnetic resonance spectroscopy.In some embodiments, deuterium-enriched gaboxadol means that a particular deuterium is enriched with deuterium above the naturally occurring distribution (i.e., above about .0156%).In some embodiments, deuterium enrichment is about 1% or more, about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or more, about 90% or more, or about 98% or more deuterium at a particular position.

[0026] In some embodiments, the method for treating tinnitus comprises administering to a patient in need of treatment a pharmaceutical composition comprising about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. In some embodiments, the method for treating acute sensorineural hearing loss comprises administering to a patient in need of treatment a pharmaceutical composition comprising about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. In some embodiments, the method for treating Meniere's disease comprises administering to a patient in need of treatment a pharmaceutical composition comprising about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof.

[0027] In certain embodiments, the pharmaceutical composition comprises 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg of gaboxadol or a pharma- ceutically acceptable salt thereof.

[0028] In certain embodiments, the pharmaceutical composition comprises 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg of gaboxadol or a pharma- ceutically acceptable salt thereof.

[0029] In some embodiments, pharmaceutical composition comprises 0.1mg, 0.25mg, 0.5mg, 1mg, 2.5mg, 3mg, 4mg, 5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 10.5mg, 11mg, 12mg, 12.5mg, 13mg, 14mg, 15mg, 16mg, 17mg, 17.5mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg or 30mg of gaboxadol or its pharmaceutically acceptable salt or multiples of such doses.In some embodiments, pharmaceutical composition comprises 2.5mg, 5mg, 7.5mg, 10mg, 15mg or 20mg of gaboxadol or its pharmaceutically acceptable salt.

[0030] The pharmaceutical compositions herein may have immediate release, delayed release, extended release or modified release profiles. In some embodiments, pharmaceutical compositions with different drug release profiles may be combined to produce biphasic or triphasic release profiles. For example, the pharmaceutical compositions may have immediate release and extended release profiles. In some embodiments, the pharmaceutical compositions may have extended release and delayed release profiles. Such compositions may be provided as pulsatile formulations, multi-layer tablets or tablets, beads, capsules containing granules, etc. The compositions may be prepared using pharma- ceutical acceptable "carriers" made of materials considered safe and effective. "Carriers" include all ingredients other than the active ingredient or ingredients present in the pharmaceutical formulation. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers and coating compositions.

[0031] In some embodiments, the pharmaceutical compositions described herein are administered once, twice or three times a day or every other day. In some embodiments, the pharmaceutical compositions described herein are provided to a patient at night. In some embodiments, the pharmaceutical compositions described herein are provided to a patient once at night and once in the morning. In some embodiments, the total amount of gaboxadol or a pharma- ceutically acceptable salt thereof administered to a subject in a 24-hour period is 1 mg to 30 mg. In some embodiments, the total amount of gaboxadol or a pharma- ceutically acceptable salt thereof administered to a subject in a 24-hour period is 1 mg to 20 mg. In some embodiments, the total amount of gaboxadol or a pharma- ceutically acceptable salt thereof administered to a subject in a 24-hour period is 5 mg, 10 mg or 15 mg. In some embodiments, the total amount of gaboxadol or a pharma- ceutically acceptable salt thereof administered to a subject in a 24-hour period is 20 mg.

[0032] In one embodiment, a method for treating tinnitus is provided herein, comprising administering a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, wherein the composition provides an improvement in at least one symptom of tinnitus.The symptoms may include, but are not limited to, ringing, rolling, static, buzzing, hissing, whoosing, cricket noise, and jackhammer noise and / or whistling in one or both ears.The symptoms may be intermittent or continuous.The improvement of tinnitus symptoms by administration of gaboxadol is surprising in view of Sametsky et al. supra.

[0033] In one embodiment, provided herein is a method for treating acute sensorineural hearing loss, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein said composition provides improvement of at least one symptom of acute sensorineural hearing loss.Symptoms may include, but are not limited to, hearing loss, ear fullness and tinnitus.

[0034] In one embodiment, provided herein is a method for treating Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or its pharma- ceutical acceptable salt, wherein said composition provides improvement of at least one symptom of Meniere's disease.Symptoms may include but are not limited to vertigo, hearing loss, tinnitus, hypersensitivity to sound and ear fullness in affected ear.

[0035] In some embodiments, a method for treating tinnitus is provided herein, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides an improvement in at least one tinnitus symptom for more than 4 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one tinnitus symptom for more than 6 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one tinnitus symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one tinnitus symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one tinnitus symptom for more than 12 hours after administration of the pharmaceutical composition to the patient.

[0036] In one embodiment, a method for treating ASNHL is provided, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides improvement of at least one ASNHL symptom for more than 4 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 6 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 12 hours after administration of the pharmaceutical composition to the patient.

[0037] In some embodiments, a method for treating Meniere's disease is provided herein, comprising administering a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, wherein the composition provides an improvement in at least one Meniere's disease symptom for more than 4 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one Meniere's disease symptom for more than 6 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one Meniere's disease symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one Meniere's disease symptom for at least 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In some embodiments, the present invention provides an improvement in at least one Meniere's disease symptom for 12 hours after administration of the pharmaceutical composition.

[0038] In some embodiments, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol in combination with a second pharmacologic active agent.In some embodiments, provided herein is a method for treating ASNHL, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol in combination with a second pharmacologic active agent.In some embodiments, provided herein is a method for treating Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol in combination with a second pharmacologic active agent.

[0039] The second active agent may include analgesics, anti-inflammatory agents, antidepressants, calcium channel antagonists, glutamate receptor antagonists, CGRP agonists, CGRP antagonists, anticonvulsants (e.g., baclofen-type), osmoregulators, sodium channel blockers, anticonvulsants, antiarrhythmic agents, and neuroprotectants. In some embodiments, the analgesics may include opioids, nonsteroidal analgesics, gabapentin, and α-adrenergic agonists. In some embodiments, the second active agent may include a sulfonamide, such as acetazolamide, azosemide, bumetanide, chlorthiaridone, clopamide, furosemide, hydrochlorothiazide (HCT, HCTZ, HZT), indapamide, mefruside, metolazone, piretanide, tripamide, xipamidamide, dichlorphenamide (DCP), dorzolamide, ethoxzolamide, sulthiame, or sonisamide. In some embodiments, the second active agent may include a thiazide, such as bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, or quinethazone.

[0040] In certain embodiments, the second active agent is an NK1 receptor antagonist, such as 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide or a pharma- ceutically acceptable salt or solvate thereof, 4-(S)-(4-acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or a pharma- ceutically acceptable salt or solvate thereof, and 2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2- -a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or a pharma- ceutically acceptable salt or solvate thereof.

[0041] In some embodiments, the second active agent may include a benzodiazepine, which may include diazepam, alprazolam, estazolam, clobazam, clonazepam, clorazepate, chlordiazepoxide, flurazepam, triazolam, temazepam, midazolam, halazepam, quazepam, lorazepam, oxazepam, derivatives thereof, or pharma- ceutically acceptable salts thereof.

[0042] In some embodiments, the second active agent may include lonazepam and / or clobazam. In some embodiments, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising any of the above amounts of gaboxadol or a pharmaceutical salt thereof and clonazepam. In some embodiments, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising any of the above amounts of gaboxadol or a pharmaceutical salt thereof and clobazam. In some embodiments, provided herein is a method for treating ASNHL, comprising administering to a patient in need of treatment a pharmaceutical composition comprising any of the above amounts of gaboxadol or a pharmaceutical salt thereof and clonazepam. In some embodiments, provided herein is a method for treating ASNHL, comprising administering to a patient in need of treatment a pharmaceutical composition comprising any of the above amounts of gaboxadol or a pharmaceutical salt thereof and clobazam. In some embodiments, provided herein is a method for treating Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising any of the above amounts of gaboxadol or a pharmaceutical salt thereof and clonazepam. In certain embodiments, provided herein is a method for treating Meniere's disease comprising administering to a patient in need of treatment a pharmaceutical composition comprising any of the above amounts of gaboxadol or a pharmaceutical salt thereof and clobazam.

[0043] The disclosed combinations can provide improved treatment compared to one active agent alone.For example, the combinations can provide synergistic effects.For example, low-dose treatment can be particularly effective for reducing or eliminating subjective tinnitus symptoms.Similarly, the combinations can provide synergistic effects.For example, low-dose treatment can be particularly effective for reducing or eliminating ASHNL symptoms.Similarly, the combinations can provide synergistic effects.For example, low-dose treatment can be particularly effective for reducing or eliminating Meniere's disease symptoms.

[0044] In certain embodiments, the pharmaceutical composition comprises 0.1 mg to 30 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, or 3 mg to 15 mg of clobazam or a pharma- ceutically acceptable salt thereof.

[0045] In certain embodiments, the pharmaceutical composition comprises 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg of clobazam or a pharma- ceutically acceptable salt thereof.

[0046] In some embodiments, the pharmaceutical composition comprises 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 17.5 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg of clobazam or a pharma- ceutically acceptable salt thereof, or a multiple of such doses. In some embodiments, the pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of clobazam or a pharma- ceutically acceptable salt thereof.

[0047] In some embodiments, the adult dose of clobazam can be 5-60 mg per day in divided doses or a single dose given at night. For example, the adult dose of clobazam can be 5-10 mg, 5-20 mg, 5-25 mg, 5-30 mg, 5-35 mg, 5-40 mg, 5-50 mg, 5-55 mg, 10-15 mg, 10-20 mg, 10-25 mg, 10-30 mg, 10-35 mg, 10-40 mg, 10-45 mg, 10-50 mg, 10-55 mg, 10-60 mg, 15-20 mg, 15-25 mg, 15-30 mg, 15-35 mg, 15-40 mg, 15-50 mg, 15-55 mg, 15-60 mg, 20-25 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-60 mg, 20-70 mg, 20-80 mg, 20-90 mg, 20-100 mg, 20-120 mg, 20-140 mg, 20-160 mg, 20-180 mg, 20-220 mg, 20-240 mg, 20-260 mg, 20-280 mg, 20-300 mg, 20-320 mg, 20-360 mg, 20-360 mg, 20-400 mg, 20-400 mg, 20-500 mg, 20-55 mg, 20-600 mg, 20-240 mg, 20-360 mg, 20-360 mg, 20-400 mg, It may be 0-30mg, 20-35mg, 20-40mg, 20-45mg, 20-50mg, 20-55mg, 20-60mg, 25-30mg, 25-35mg, 25-40mg, 25-50mg, 25-55mg, 25-60mg, 30-35mg, 30-40mg, 30-45mg, 30-50mg, 30-55mg, 30-60mg, 35-40mg, 35-50mg, 35-55mg, 35-60mg, 40-45mg, 40-50mg, 40-55mg, 40-60mg, 45-50mg, 45-55mg, 45-60mg, 50-55mg or 55-60mg.

[0048] In some embodiments, the present invention provides a method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof and clobazam or a pharma- ceutically acceptable salt thereof simultaneously or separately to a patient in need of such treatment, wherein the patient experiences an improvement in at least one tinnitus symptom for more than 4 hours after administration of the pharmaceutical composition to the patient.In some embodiments, the present invention provides an improvement in at least one tinnitus symptom for more than 6 hours after administration of gaboxadol or a pharma-ceutically acceptable salt thereof and clobazam or a pharma-ceutically acceptable salt thereof to a patient.In some embodiments, the present invention provides an improvement in at least one tinnitus symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of gaboxadol or a pharma-ceutically acceptable salt thereof and clobazam or a pharma-ceutically acceptable salt thereof to a patient. In certain embodiments, the present invention provides for improvement of at least one tinnitus symptom for at least, e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof and clobazam or a pharma- ceutically acceptable salt thereof to a patient. In certain embodiments, the present invention provides for improvement of at least one tinnitus symptom for 12 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof and clobazam or a pharma- ceutically acceptable salt thereof to a patient.

[0049] In one embodiment, the present invention provides a method for treating ASNHL, comprising administering gaboxadol or its pharmaceutically acceptable salt and clobazam or its pharmaceutically acceptable salt simultaneously or separately to a patient in need of treatment, wherein the patient experiences improvement of at least one ASNHL symptom for more than 4 hours after administering the pharmaceutical composition to the patient.In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 6 hours after administering gaboxadol or its pharmaceutically acceptable salt and clobazam or its pharmaceutically acceptable salt to a patient.In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administering gaboxadol or its pharmaceutically acceptable salt and clobazam or its pharmaceutically acceptable salt to a patient. In some embodiments, the present invention provides an improvement in at least one ASNHL symptom for at least, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of gaboxadol or a pharmaceutically acceptable salt thereof and clobazam or a pharmaceutically acceptable salt thereof to a patient.In some embodiments, the present invention provides an improvement in at least one ASNHL symptom for at least 12 hours after administration of gaboxadol or a pharmaceutically acceptable salt thereof and clobazam or a pharmaceutically acceptable salt thereof to a patient.

[0050] In some embodiments, the present invention provides a method for treating Meniere's disease, comprising administering gaboxadol or its pharmaceutically acceptable salt and clobazam or its pharmaceutically acceptable salt simultaneously or separately to a patient in need of treatment, wherein the patient experiences improvement of at least one Meniere's disease symptom for more than 4 hours after administration of the pharmaceutical composition to the patient.In some embodiments, the present invention provides improvement of at least one Meniere's disease symptom for more than 6 hours after administration of gaboxadol or its pharmaceutically acceptable salt and clobazam or its pharmaceutically acceptable salt to a patient.In some embodiments, the present invention provides improvement of at least one Meniere's disease symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of gaboxadol or its pharmaceutically acceptable salt and clobazam or its pharmaceutically acceptable salt to a patient. In some embodiments, the present invention provides an improvement in at least one Meniere's disease symptom for at least, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof and clobazam or a pharma- ceutically acceptable salt thereof to a patient. In some embodiments, the present invention provides an improvement in at least one Meniere's disease symptom for 12 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof and clobazam or a pharma- ceutically acceptable salt thereof to a patient.

[0051] In one embodiment, a method for treating tinnitus is provided herein, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam or a pharma- ceutically acceptable salt thereof, wherein the composition provides an improvement in at least one tinnitus symptom for more than 4 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides an improvement in at least one tinnitus symptom for more than 6 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides an improvement in at least one tinnitus symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides an improvement in at least one tinnitus symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides an improvement in at least one tinnitus symptom for more than 12 hours after administration of the pharmaceutical composition to the patient.

[0052] In one embodiment, a method for treating ASNHL is provided herein, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam or a pharma- ceutically acceptable salt thereof, wherein the composition provides improvement of at least one ASNHL symptom for more than 4 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 6 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides improvement of at least one ASNHL symptom for more than 12 hours after administration of the pharmaceutical composition to the patient.

[0053] In one embodiment, a method for treating Meniere's disease is provided herein, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam or a pharma- ceutically acceptable salt thereof, wherein the composition provides an improvement in at least one Meniere's disease symptom for more than 4 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides an improvement in at least one Meniere's disease symptom for more than 6 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides an improvement in at least one Meniere's disease symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In one embodiment, the present invention provides an improvement in at least one Meniere's disease symptom for more than 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after administration of the pharmaceutical composition to the patient. In certain embodiments, the present invention provides improvement in at least one symptom of Meniere's disease 12 hours after administration of the pharmaceutical composition to the patient.

[0054] In one embodiment, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides next-day improvement of tinnitus.In one embodiment, provided herein is a method for treating ASNHL, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides next-day improvement of ASNHL.In one embodiment, provided herein is a method for treating Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides next-day improvement of Meniere's disease.

[0055] In one embodiment, provided herein is a method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, wherein the composition provides next-day improvement of tinnitus.In one embodiment, provided herein is a method for treating ASNHL, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, wherein the composition provides next-day improvement of ASNHL.In one embodiment, provided herein is a method for treating Meniere's disease, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in combination with clobazam or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, wherein the composition provides next-day improvement of Meniere's disease.

[0056] In certain embodiments, provided herein is a method for treating tinnitus comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and clobazam or a pharma- ceutical acceptable salt thereof, wherein said composition provides next day improvement in tinnitus.

[0057] 1 shows the arithmetic mean plasma concentration-time profiles of gaboxadol after a single oral dose (2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg), with the horizontal line Δ indicating the change between 6 hours and 12 hours (see Example 1 below). In certain embodiments, provided herein is a method of treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 50% and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method for treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 55%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method for treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 60%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.In certain embodiments, provided herein is a method for treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 65%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method for treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 70%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method for treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 75%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.

[0058] In some embodiments, the present invention provides a method for treating tinnitus, wherein the amount of gaboxadol or its pharmaceutically acceptable salt in a patient about 4 hours after administration of the pharmaceutical composition is less than about 75% of the amount administered.In some embodiments, the present invention provides a method for treating tinnitus, wherein the amount of gaboxadol or its pharmaceutically acceptable salt in a patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours or about 20 hours after administration of the pharmaceutical composition is less than about 75%.

[0059] In some embodiments, the present invention provides a method for treating tinnitus, wherein the amount of gaboxadol or its pharmaceutically acceptable salt in a patient about 4 hours after administration of the pharmaceutical composition is less than about 80% of the amount administered.In some embodiments, the present invention provides a method for treating tinnitus, wherein the amount of gaboxadol or its pharmaceutically acceptable salt in a patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours or about 20 hours after administration of the pharmaceutical composition is less than about 80% of the amount administered.

[0060] In some embodiments, the present invention provides a method for treating tinnitus, in which the amount of gaboxadol or a pharma- ceutically acceptable salt thereof in a patient about 4 hours after administration of the pharmaceutical composition is about 65% to about 85% of the amount administered. In some embodiments, for example, the amount of gaboxadol or a pharma- ceutically acceptable salt thereof in a patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours, or about 20 hours after administration of the pharmaceutical composition is about 65% to about 85% of the amount administered.

[0061] In one embodiment, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides an in vivo plasma concentration of less than 75% of the amount administered 6 hours after administration, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides an in vivo plasma concentration of less than 80% of the amount administered 6 hours after administration, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides an in vivo plasma concentration of less than 85% of the amount administered 6 hours after administration, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides an in vivo plasma concentration of less than 90% of the amount administered 6 hours after administration, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.In one embodiment, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides an in vivo plasma concentration of less than 95% of the amount administered 6 hours after administration, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutically acceptable salt thereof, wherein the composition provides an in vivo plasma concentration of less than 100% of the amount administered 6 hours after administration, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.

[0062] In certain embodiments, provided herein is a method of treating ASNHL or Meniere's disease comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 50%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method of treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, which provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 55%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method of treating ASNHL or Meniere's disease comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 60%, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.In certain embodiments, provided herein is a method of treating ASNHL or Meniere's disease comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 65%, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method of treating ASNHL or Meniere's disease comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 70%, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, provided herein is a method of treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof that provides an in vivo plasma profile, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by greater than 75%, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.

[0063] In some embodiments, the present invention provides a method for treating ASNHL or Meniere's disease, wherein the amount of gaboxadol or its pharmaceutical acceptable salt in patient about 4 hours after administration of pharmaceutical composition is less than about 75% of the amount administered.In some embodiments, the present invention provides a method for treating ASNHL or Meniere's disease, wherein the amount of gaboxadol or its pharmaceutical acceptable salt in patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours or about 20 hours after administration of pharmaceutical composition is less than about 75%.

[0064] In some embodiments, the present invention provides a method for treating ASNHL or Meniere's disease, wherein the amount of gaboxadol or its pharmaceutical acceptable salt in a patient about 4 hours after administration of pharmaceutical composition is less than about 80% of the amount administered.In some embodiments, the present invention provides a method for treating ASNHL or Meniere's disease, wherein the amount of gaboxadol or its pharmaceutical acceptable salt in a patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours or about 20 hours after administration of pharmaceutical composition is less than about 80% of the amount administered.

[0065] In one embodiment, the present invention provides a method for treating ASNHL or Meniere's disease, in which the amount of gaboxadol or its pharma- ceutical acceptable salt in a patient about 4 hours after administration of the pharmaceutical composition is about 65% to about 85% of the amount administered. In one embodiment, for example, the amount of gaboxadol or its pharma- ceutical acceptable salt in a patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours, or about 20 hours after administration of the pharmaceutical composition is about 65% to about 85% of the amount administered.

[0066] In one embodiment, provided herein is a method for treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein said composition provides an in vivo plasma concentration of less than 75% of the amount administered 6 hours after administration, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.In one embodiment, provided herein is a method for treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein said composition provides an in vivo plasma concentration of less than 80% of the amount administered 6 hours after administration, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, provided herein is a method for treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein said composition provides an in vivo plasma concentration of less than 85% of the amount administered 6 hours after administration, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.In one embodiment, provided herein is a method for treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein said composition provides an in vivo plasma concentration of less than 90% of the amount administered 6 hours after administration, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.In one embodiment, provided herein is a method for treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein said composition provides an in vivo plasma concentration of less than 95% of the amount administered 6 hours after administration, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.In one embodiment, provided herein is a method for treating ASNHL or Meniere's disease, comprising administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein said composition provides an in vivo plasma concentration of less than 100% of the amount administered 6 hours after administration, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration.

[0067] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has a C of less than about 500 ng / ml. max Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having: In certain embodiments, the composition provides improvement for greater than 6 hours after administration to the patient.

[0068] In some embodiments, the compositions have an in vivo plasma profile, e.g., less than about 450 ng / ml, less than about 400 ng / ml, less than about 350 ng / ml, or less than about 300 ng / ml, wherein the compositions provide improvement of one or more tinnitus symptoms one day after administration. In some embodiments, the compositions have a C profile, e.g., less than about 250 ng / ml, less than about 200 ng / ml, less than about 150 ng / ml, or less than about 100 ng / ml. max wherein the composition provides an improvement in one or more tinnitus symptoms one day after administration.

[0069] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than about 900 ng·hr / ml. 0-∞ Provided herein are methods for treating tinnitus, which provide an in vivo plasma profile having an AUC of less than about 850 ng·hr / ml, less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, or less than about 700 ng·hr / ml. In certain embodiments, the composition provides improvement of one or more tinnitus symptoms one day after administration. In certain embodiments, the composition provides an AUC of less than about 850 ng·hr / ml, less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, or less than about 700 ng·hr / ml. 0-∞ wherein the composition provides an improvement in one or more tinnitus symptoms one day after administration. In some embodiments, the composition provides an improvement in one or more tinnitus symptoms for more than six hours after administration.

[0070] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than about 900 ng·hr / ml. 0-∞ Provided herein are methods for treating tinnitus, which provide an in vivo plasma profile having an AUC of less than about 850 ng·hr / ml, less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, or less than about 700 ng·hr / ml. In certain embodiments, the composition provides improvement of one or more tinnitus symptoms one day after administration. In certain embodiments, the composition provides an AUC of less than about 850 ng·hr / ml, less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, or less than about 700 ng·hr / ml. 0-∞ In one embodiment, the composition provides an in vivo plasma profile having an AUC of less than about 650 ng·hr / ml, less than about 600 ng·hr / ml, less than about 550 ng·hr / ml, or less than about 500 ng·hr / ml, or less than 450 ng·hr / ml, wherein the composition provides an improvement in one or more tinnitus symptoms one day after administration. In one embodiment, the composition provides an improvement in one or more tinnitus symptoms for more than 6 hours ... AUC of less than about 650 ng·hr / ml, less than about 600 ng·hr / ml, less than about 550 ng·hr / ml, or less than about 500 ng·hr / ml, or less than 450 ng·hr / ml, wherein the composition provides an AUC of less than about 650 ng·hr / ml, less than about 600 ng·hr / ml, less than about 550 ng·hr / ml, or less than about 500 ng·hr / ml, or less than 450 ng·hr / ml. 0-∞Provided herein are methods for treating tinnitus, which provide an in vivo plasma profile having an AUC of less than about 400 ng·hr / ml, less than about 350 ng·hr / ml, less than about 300 ng·hr / ml, less than about 250 ng·hr / ml, or less than about 200 ng·hr / ml. 0-∞ In certain embodiments, the compositions provide an in vivo plasma profile having an AUC of less than about 150 ng·hr / ml, less than about 100 ng·hr / ml, less than about 75 ng·hr / ml, or less than about 50 ng·hr / ml. 0-∞ In certain embodiments, the composition provides an improvement in the symptoms of tinnitus for more than 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours after administration of the composition to a patient.

[0071] In one embodiment, a patient in need of treatment is administered max AUC less than 75% of 6-12 Provided herein is a method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in an amount that provides an in vivo plasma profile having a C max AUC less than 80% of 6-12 Provided herein is a method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in an amount that provides an in vivo plasma profile having a C max AUC less than 85% of 6-12Provided herein is a method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in an amount that provides an in vivo plasma profile having a C max AUC less than 90% 6-12 Provided herein is a method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in an amount that provides an in vivo plasma profile having a C max AUC less than 95% of 6-12 Provided herein is a method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutically acceptable salt thereof in an amount that provides an in vivo plasma profile having a C max AUC less than 100% 6-12 and providing patient improvement for more than 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration.

[0072] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein said composition is max AUC less than 75% of 6-12Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 80% of 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 85% of 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 90% 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 95% of 6-12Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 100% 6-12 and providing patient improvement for greater than 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration.

[0073] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having an AUC of less than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 80% of the amount administered. 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having an AUC of less than 85% of the amount administered, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 85% of the amount administered. 6-12Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having an AUC of less than 90% of the amount administered, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 90% of the amount administered. 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having an AUC of less than 95% of the amount administered, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 95% of the amount administered. 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having an AUC of less than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In certain embodiments, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 100% of the amount administered. 6-12 Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having a mean AUC of at least about 20% lower than the first pharmaceutical composition, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC of at least about 20% lower than the first pharmaceutical composition. 0-∞ Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having:

[0074] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has a C of less than about 500 ng / ml. max Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having: In some embodiments, the composition provides improvement for more than 6 hours after administration to the patient.

[0075] In certain embodiments, the composition has a C of less than about 450 ng / ml, less than about 400 ng / ml, less than about 350 ng / ml, or less than about 300 ng / ml. max In one embodiment, the composition provides an in vivo plasma profile having a C of less than about 250 ng / ml, less than about 200 ng / ml, less than about 150 ng / ml, or less than about 100 ng / ml, wherein the composition provides improvement of one or more symptoms of ASNHL or Meniere's disease one day after administration. max wherein the composition provides an improvement in one or more symptoms of ASNHL or Meniere's disease one day after administration.

[0076] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than about 900 ng·hr / ml. 0-∞ Provided herein is a method for treating ASNHL or Meniere's disease, the method providing an in vivo plasma profile having an AUC of less than about 850 ng·hr / ml, less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, or less than about 700 ng·hr / ml. In certain embodiments, the composition provides improvement of one or more symptoms of ASNHL or Meniere's disease one day after administration. In certain embodiments, the composition provides an AUC of less than about 850 ng·hr / ml, less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, or less than about 700 ng·hr / ml, for example. 0-∞ wherein the composition provides an improvement in one or more symptoms of ASNHL or Meniere's disease one day after administration.

[0077] In certain embodiments, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC 0-∞ Provided herein are methods for treating ASNHL or Meniere's disease, which provide an in vivo plasma profile having an AUC of less than about 400 ng·hr / ml, less than about 350 ng·hr / ml, less than about 300 ng·hr / ml, less than about 250 ng·hr / ml, or less than about 200 ng·hr / ml. 0-∞ In certain embodiments, the compositions provide an in vivo plasma profile having an AUC of less than about 150 ng·hr / ml, less than about 100 ng·hr / ml, less than about 75 ng·hr / ml, or less than about 50 ng·hr / ml. 0-∞ In certain embodiments, the composition provides an improvement in symptoms of ASNHL or Meniere's disease, e.g., more than 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours, after administration of the composition to a patient.

[0078] In one embodiment, a patient in need of treatment is administered max AUC less than 75% of 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, comprising administering gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, a patient in need of treatment is administered gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: max AUC less than 80% of 6-12Provided herein is a method for treating ASNHL or Meniere's disease, comprising administering gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, a patient in need of treatment is administered gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: max AUC less than 85% of 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, comprising administering gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, a patient in need of treatment is administered gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: max AUC less than 90% 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, comprising administering gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, a patient in need of treatment is administered gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: max AUC less than 95% of 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, comprising administering gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, a patient in need of treatment is administered gaboxadol or a pharmacologic acceptable salt thereof in an amount that provides an in vivo plasma profile having the following formula: max AUC less than 100% 6-12and providing patient improvement for more than 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration.

[0079] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein said composition is max AUC less than 75% of 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 80% of 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 85% of 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. maxAUC less than 90% 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 95% of 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having a C value of 0.01, and provides improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition is C. max AUC less than 100% 6-12 Provided herein are methods for treating ASNHL or Meniere's disease, which provide an in vivo plasma profile having the formula:

[0080] In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having an AUC of less than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration and provides patient improvement. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 80% of the amount administered. 6-12Provided herein is a method for treating ASNHL or Meniere's disease, the method providing an in vivo plasma profile having an AUC of less than 85% of the amount administered, and providing patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 85% of the amount administered. 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, the method providing an in vivo plasma profile having an AUC of less than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration, and providing improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 90% of the amount administered. 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having an AUC of less than 95% of the amount administered, and provides patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 95% of the amount administered. 6-12 Provided herein is a method for treating ASNHL or Meniere's disease, the method providing an in vivo plasma profile having an AUC of less than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration, and providing improvement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the composition has an AUC of less than 100% of the amount administered. 6-12Provided herein is a method for treating ASNHL or Meniere's disease, the method providing an in vivo plasma profile having a mean AUC of 0.01 to 0.05 and providing patient improvement for more than 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours after administration. In one embodiment, the method comprises administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC of 0.01 to 0.05 and a mean AUC of 0.01 to 0.05, respectively, that is at least about 20% lower than the first pharmaceutical composition. 0-∞ Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having:

[0081] In some embodiments, the first and / or second pharmaceutical composition is administered once, twice or three times a day or every other day. In some embodiments, the first or second pharmaceutical composition is given to the patient at night. In some embodiments, the second pharmaceutical composition comprises gaboxadol in an amount at least one-third of the amount of gaboxadol provided in the first pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises gaboxadol in an amount at least half of the amount of gaboxadol provided in the first pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises clozapam or a pharmaceutically acceptable salt thereof. In some embodiments, the second pharmaceutical composition comprises clobazam or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the first or second pharmaceutical composition is provided to the patient once in the evening and once in the morning. In some embodiments, the total amount of gaboxadol or its pharmaceutically acceptable salt administered to the subject in a 24-hour period is 1 mg to 30 mg. In some embodiments, the total amount of gaboxadol or its pharmaceutically acceptable salt administered to the subject in a 24-hour period is 1 mg to 20 mg. In some embodiments, the total amount of gaboxadol or its pharmaceutically acceptable salt administered to the subject in a 24-hour period is 10 mg, 15 mg or 20 mg. In some embodiments, the total amount of gaboxadol or its pharmaceutically acceptable salt administered to the subject in a 24-hour period is 20 mg.

[0083] In some embodiments, the first and / or second pharmaceutical composition may have an immediate release, delayed release, extended release or modified release profile. The first and second pharmaceutical compositions may be provided simultaneously or at a time interval, such as 6 hours, 12 hours, etc. In some embodiments, the first and second pharmaceutical compositions may have different drug release profiles to produce a two-stage release profile. For example, the first pharmaceutical composition may have an immediate release profile and the second pharmaceutical composition may have an extended release profile. In some embodiments, one or both of the first and second pharmaceutical compositions may have an extended or delayed release profile. Such compositions may be provided as pulsatile formulations, multi-layer tablets or tablets, beads, capsules containing granules, etc. In some embodiments, the first pharmaceutical composition is an immediate release composition. In some embodiments, the second pharmaceutical composition is an immediate release composition. In some embodiments, the first and second pharmaceutical compositions are provided as separate immediate release compositions, such as tablets or capsules. In some embodiments, the first and second pharmaceutical compositions are provided 12 hours apart.

[0084] In one embodiment, the method comprises administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC 0-∞ Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having the following characteristics: In some embodiments, the composition provides an improvement in one or more symptoms of tinnitus one day after administration. For example, the composition may provide an improvement in one or more symptoms for more than 6 hours, 8 hours, 10 hours, or 12 hours after administration of the first and / or second pharmaceutical composition.

[0085] In one embodiment, a patient in need of treatment is provided with a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein said second pharmaceutical composition has a mean AUC 0-∞ Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having an AUC of less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, less than about 700 ng·hr / ml, less than about 650 ng·hr / ml, or less than about 600 ng·hr / ml. 0-∞ In certain embodiments, the second pharmaceutical composition provides an in vivo plasma profile having an AUC of less than about 550 ng·hr / ml, less than about 500 ng·hr / ml, less than about 450 ng·hr / ml, less than about 400 ng·hr / ml, or less than about 350 ng·hr / ml. 0-∞ In certain embodiments, the second pharmaceutical composition provides an in vivo plasma profile having an AUC of less than about 300 ng·hr / ml, less than about 250 ng·hr / ml, less than about 200 ng·hr / ml, less than about 150 ng·hr / ml, or less than about 100 ng·hr / ml. 0-∞In some embodiments, a first and a second pharmaceutical composition are administered, wherein said compositions provide an improvement in the patient's next day function. In some embodiments, the first pharmaceutical composition provides an improvement in one or more symptoms, e.g., more than 6 hours, 8 hours, or 12 hours after administration of the first pharmaceutical composition.

[0086] In one embodiment, the method comprises administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the first composition is a C111 provided by administration of the second pharmaceutical composition. max C is about 50% higher than max Provided herein is a method for treating tinnitus, which provides an in vivo plasma profile having a C max may or may not include the plasma profile contribution of the first pharmaceutical composition. In certain embodiments, administration of the second pharmaceutical composition does not include the plasma profile contribution of the first pharmaceutical composition. In certain embodiments, the first composition provides a C profile that is greater than, for example, about 60%, about 70%, about 80%, or about 90% greater than, provided by administration of the second pharmaceutical composition. max The present invention provides an in vivo plasma profile having:

[0087] In certain embodiments, the T max In some embodiments, the T of the first pharmaceutical composition is less than 3 hours. max In some embodiments, the T of the first pharmaceutical composition is less than 2.5 hours. max In some embodiments, the T of the first pharmaceutical composition is less than 2 hours. max In some embodiments, the T of the first pharmaceutical composition is less than 1.5 hours. max is less than an hour.

[0088] In some embodiments, the first pharmaceutical composition provides at least about 80% dissolution within the first 20 minutes of administration to a patient in need of treatment.In some embodiments, the first pharmaceutical composition provides at least about 85%, about 90% or about 95% dissolution within the first 20 minutes of administration to a patient in need of treatment.In some embodiments, the first pharmaceutical composition provides at least about 80% dissolution within the first 10 minutes of administration to a patient in need of treatment.

[0089] In some embodiments, the method comprises administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC 0-∞ Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having the following characteristics:

[0090] In one embodiment, the method comprises administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein said second pharmaceutical composition has a mean AUC 0-∞ Provided herein is a method for treating ASNHL or Meniere's disease, the method providing an in vivo plasma profile having an AUC of less than about 800 ng·hr / ml, less than about 750 ng·hr / ml, less than about 700 ng·hr / ml, less than about 650 ng·hr / ml, or less than about 600 ng·hr / ml. 0-∞In certain embodiments, the second pharmaceutical composition provides an in vivo plasma profile having an AUC of less than about 550 ng·hr / ml, less than about 500 ng·hr / ml, less than about 450 ng·hr / ml, less than about 400 ng·hr / ml, or less than about 350 ng·hr / ml. 0-∞ In certain embodiments, the second pharmaceutical composition provides an in vivo plasma profile having an AUC of less than about 300 ng·hr / ml, about 250 ng·hr / ml, about 200 ng·hr / ml, about 150 ng·hr / ml, or about 100 ng·hr / ml. 0-∞ In some embodiments, a first and a second pharmaceutical composition are administered, wherein the compositions provide an improvement in the patient's next day function. In some embodiments, the first pharmaceutical composition provides an improvement in one or more symptoms of ASNHL or Meniere's disease, for example, more than 6 hours, 8 hours, or 12 hours after administration of the first pharmaceutical composition.

[0091] In one embodiment, the method comprises administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the first composition is a C111 provided by administration of the second pharmaceutical composition. max C, which is about 50% higher than max Provided herein is a method for treating ASNHL or Meniere's disease, which provides an in vivo plasma profile having a C max may or may not include the plasma profile of the first pharmaceutical composition. In certain embodiments, administration of the second pharmaceutical composition does not include the plasma profile contribution of the first pharmaceutical composition. In certain embodiments, the first composition provides a C profile that is greater than, for example, about 60%, about 70%, about 80%, or about 90% greater than, provided by administration of the second pharmaceutical composition. max The present invention provides an in vivo plasma profile having:

[0092] In some embodiments, the first and / or second pharmaceutical composition is a sub-therapeutic dose. A sub-therapeutic dose is an amount of gaboxadol or a pharma- ceutically acceptable salt thereof that is less than the amount required for a therapeutic effect. In some embodiments, a sub-therapeutic dose is an amount of gaboxadol or a pharma- ceutically acceptable salt thereof that is sufficient to maintain at least one symptom of tinnitus, but does not provide an improvement of at least one symptom of ASNHL or Meniere's disease. In some embodiments, a sub-therapeutic dose is an amount of gaboxadol or a pharma- ceutically acceptable salt thereof that is sufficient to maintain at least one symptom of tinnitus, but does not provide an improvement of at least one symptom of ASNHL or Meniere's disease. In some embodiments, a method provides for administering a first pharmaceutical composition that provides an improvement of at least one symptom of tinnitus and a second composition that maintains the improvement. In some embodiments, a method provides for administering a first pharmaceutical composition that provides an improvement of at least one symptom of ASNHL or Meniere's disease and a second composition that maintains the improvement. In some embodiments, after administration of the first pharmaceutical composition, the second pharmaceutical composition can provide a synergistic effect and improve at least one symptom of tinnitus. In some embodiments, after administration of the first pharmaceutical composition, the second pharmaceutical composition provides a synergistic effect and improves at least one symptom of ASNHL or Meniere's disease.In some embodiments, the second pharmaceutical composition can provide a synergistic effect and improve at least one symptom of tinnitus.In some embodiments, the second pharmaceutical composition can provide a synergistic effect and improve at least one symptom of ASNHL or Meniere's disease.

[0093] In some embodiments, provided herein is a method for treating tinnitus, comprising administering to a patient in need of treatment a pharmaceutical composition comprising a first pharmaceutical dose comprising gaboxadol or a pharmaceutically acceptable salt thereof, which provides improvement for more than 6 hours after administration, and a second pharmaceutical composition comprising a subtherapeutic dose of gaboxadol or a pharmaceutically acceptable salt thereof.In some embodiments, provided herein is a method for treating ASNHL or Meniere's disease, comprising administering a pharmaceutical composition comprising a first pharmaceutical dose comprising gaboxadol or a pharmaceutically acceptable salt thereof, which provides improvement for more than 6 hours after administration, and a second pharmaceutical composition comprising a subtherapeutic dose of gaboxadol or a pharmaceutically acceptable salt thereof.

[0094] To achieve long-term improvement in at least one symptom of tinnitus, the administration of the first and second pharmaceutical compositions can be separated. In some embodiments, the first and second pharmaceutical compositions can be administered 6 hours apart. In some embodiments, the first and second pharmaceutical compositions can be administered 12 hours apart. In some embodiments, the first and second pharmaceutical compositions can be administered, for example, within 6 hours, 12 hours, 18 hours, 24 hours, etc. In some embodiments, the first and second pharmaceutical compositions can be administered at least, for example, 6 hours, 12 hours, 18 hours, 24 hours, etc. apart. In some embodiments, an improvement of at least one symptom of tinnitus is provided for more than 8 hours after administration to a patient. In some embodiments, an improvement of at least one symptom of tinnitus is provided for more than about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 20 hours, or about 24 hours after administration to a patient. In some embodiments, an improvement of at least one symptom of tinnitus is provided for more than 8 hours after administration to a patient. In certain embodiments, improvement is provided, for example, greater than about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 20 hours, or about 24 hours after administration to the patient.

[0095] To achieve long-term improvement in at least one symptom of ASNHL or Meniere's disease, the administration of the first and second pharmaceutical compositions can be separated. In some embodiments, the first and second pharmaceutical compositions can be administered 6 hours apart. In some embodiments, the first and second pharmaceutical compositions can be administered 12 hours apart. In some embodiments, the first and second pharmaceutical compositions can be administered, for example, within 6 hours, 12 hours, 18 hours, 24 hours, etc. In some embodiments, the first and second pharmaceutical compositions can be administered at least 6 hours, 12 hours, 18 hours, 24 hours, etc. apart. In some embodiments, an improvement of at least one symptom of ASNHL or Meniere's disease is provided for more than 8 hours after administration to a patient. In some embodiments, an improvement of at least one symptom of ASNHL or Meniere's disease is provided for more than about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 20 hours, or about 24 hours after administration to a patient. In some embodiments, an improvement of at least one symptom of ASNHL or Meniere's disease is provided for more than 8 hours after administration to a patient. In certain embodiments, improvement is provided, for example, greater than about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 20 hours, or about 24 hours after administration to the patient.

[0096] In some embodiments, the first pharmaceutical composition and / or the second pharmaceutical composition comprises about 0.1 mg to about 40 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. The amount of gaboxadol or a pharma- ceutically acceptable salt thereof in the first pharmaceutical composition and the second pharmaceutical composition may be the same or different. In some embodiments, administration of the first and second pharmaceutical compositions may provide a synergistic effect for improving at least one symptom of tinnitus. In some embodiments, administration of the first and second pharmaceutical compositions may provide a synergistic effect for improving at least one symptom of ASNHL or Meniere's disease.

[0097] In certain embodiments, the first and / or second pharmaceutical composition comprises 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg or 3 mg to 15 mg of gaboxadol or a pharma- ceutically acceptable salt thereof.

[0098] In certain embodiments, the first and / or second pharmaceutical composition comprises 5 mg to 15 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg or 18 mg to 20 mg of gaboxadol or a pharma- ceutically acceptable salt thereof.

[0099] In some embodiments, the first and / or second pharmaceutical composition comprises 0.1mg, 0.25mg, 0.5mg, 1mg, 2.5mg, 3mg, 4mg, 5mg, 7mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg of gaboxadol or a pharmaceutically acceptable salt thereof or a multiple of such doses.In some embodiments, the first pharmaceutical composition comprises 2.5mg, 5mg, 7.5mg, 10mg, 15mg or 20mg of gaboxadol or a pharmaceutically acceptable salt thereof.In some embodiments, the second pharmaceutical composition comprises 2.5mg, 5mg, 7.5mg, 10mg, 15mg or 20mg of gaboxadol or a pharmaceutically acceptable salt thereof.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0101] The term "about" or "approximately" as used herein refers to an acceptable error range for a particular value as determined by one skilled in the art, which depends in part on how the value is measured or determined, i.e., on the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, as is customary in the art. Alternatively, "about" can mean within a range of up to 20%, up to 10%, up to 5% and / or up to 1% of a given value. Alternatively, particularly for biological systems or processes, the term means within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value.

[0102] "Amelioration" refers to treatment of tinnitus, ASNHL or Meniere's disease as measured in relation to at least one symptom.

[0103] "Improvement of one or more symptoms of tinnitus, ASNHL or Meniere's disease one day after administration" indicates that the beneficial effect on at least one symptom persists over a period of time, such as, for example, 6 hours, 12 hours, 24 hours, etc.

[0104] "PK" stands for pharmacokinetic profile. max is defined as the highest plasma drug concentration (ng / ml) measured during the study. max is C max is defined as the time (in minutes) over which the AUC is measured. 0-∞ is the total area (ng·hour / ml) under the plasma drug concentration-time curve from administration to excretion. The area under the curve is determined by clearance, which is defined as the volume of blood or plasma that is completely cleared of the drug content per unit time (ml / min).

[0105] "Treat" or "treatment" refers to alleviating or delaying the onset of a disease or condition in a subject who is afflicted or susceptible to a disease or condition, but who has not experienced or developed clinical or subclinical symptoms of the disease or condition. In certain embodiments, "treat" or "treatment" may refer to preventing the onset of a disease or condition in a subject who is afflicted or susceptible to a disease or condition, but who has not experienced or developed clinical or subclinical symptoms of the disease or condition. "Treat" or "treatment" also refers to inhibiting a disease or condition, e.g., arresting or reducing its onset or at least one of its clinical or subclinical symptoms. "Treat" or "treatment" further refers to alleviating a disease or condition, e.g., causing the regression of a disease or condition or at least one of its clinical or subclinical symptoms. The benefit to the treated patient may be statistically significant, mathematically significant, or at least perceptible to the subject and / or the physician. Nevertheless, preventative (prophylactic) and therapeutic (curative) treatments are separate aspects described herein.

[0106] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally considered safe" - e.g., physiologically tolerated and generally do not cause allergic or similar adverse reactions, such as acute gastric irritation, when administered to humans. In certain embodiments, the term refers to whole molecules and compositions that are approved by a federal or government regulatory agency as being on the GRAS list or similar list under Chapters 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act, subject to premarket review and approval by the FDA, the United States Pharmacopeia, or another pharmacopoeia that is generally recognized for use in animals, and more specifically, in humans.

[0107] By "effective amount" or "therapeutically effective amount" is meant a dosage sufficient to alleviate one or more symptoms of the disorder, disease or condition being treated, e.g., tinnitus, ASNHL or Meniere's disease, or to otherwise provide the desired pharmacological and / or physiological effect.

[0108] "Co-administered with," "in combination with," "a combination of," or "administered along with" may be used interchangeably and refer to the administration of two or more agents during the course of treatment. The agents may be administered simultaneously or separately at intervals. The agents may be administered in a single dosage form or in separate dosage forms.

[0109] A "patient in need of treatment" includes an individual diagnosed with tinnitus. The methods may be provided to any individual, including, for example, a neonate, an infant, a pediatric patient (6 months to 12 years of age), an adolescent patient (12 to 18 years of age), or an adult (over 18 years of age). "Patient" and "subject" may be used interchangeably herein. EXAMPLES

[0110] The examples provided herein are included merely to supplement the disclosure herein and should not be construed as limiting in any way.

[0111] Example 1 The following examples provide the plasma concentration profiles and dose proportionality of gaboxadol monohydrate following single oral doses ranging from 2.5 to 20 mg. The absolute bioavailability of gaboxadol monohydrate capsules ranging from 2.5 to 20 mg is also evaluated.

[0112] The study consisted of separate groups of 10 healthy adult subjects (at least 4 of each sex) who participated in a six-period, double-blind, randomized, crossover study designed to evaluate the dose proportionality and absolute bioavailability of five single oral doses of gaboxadol across a dose range of 2.5 to 20 mg. The order of subjects receiving the five single doses of gaboxadol (2.5 mg; 5 mg; 10 mg; 15 mg; and 20 mg) was randomized during treatment periods 1 to 5. Each subject was expected to complete all six treatment periods, with a washout period of at least 4 days between each treatment period.

[0113] Each oral dose during the treatment period consisted of two capsules of study drug taken simultaneously at each scheduled dose. Treatment designations for study drug administered orally were as follows: Treatment A - one 2.5 mg gaboxadol capsule and one matching placebo capsule; Treatment B - one 5 mg gaboxadol capsule and one matching placebo capsule; Treatment C - one 10 mg gaboxadol capsule and one matching placebo capsule; Treatment D - one 15 mg gaboxadol capsule and one matching placebo capsule; and Treatment E - 20 mg gaboxadol (two 10 mg gaboxadol capsules). Subjects were given study drug with 240 ml of water at approximately 8:00 AM after an overnight fast. Water was allowed ad libitum, except prior to and within 1 hour after study drug administration. No food was allowed for 4 hours after dosing.

[0114] For each subject in each treatment, pharmacokinetic parameters (e.g., AUC, C, max , T max , apparent t 1 / 2 Plasma and urine samples were collected for 16 hours after dosing for determination of cumulative urinary excretion, renal clearance, clearance, and steady-state volume of distribution. AUC and C for gaboxadol maxThe strengths were adjusted to facilitate comparison of pharmacokinetic data during the clinical trial. Table 1 provides the pharmacokinetic parameters following single oral doses of gaboxadol (2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg) adjusted for individual strengths. [Table 1]

[0115] FIG. 2 shows the calculated mean plasma concentration-time profiles of gaboxadol after single oral doses (2.5 mg, 5 mg, 10 mg, 15 mg and 20 mg). The bioavailability of gaboxadol is approximately 92%. Plasma AUC of gaboxadol 0-∞ and C max The peak plasma concentration (T max 30-60 min) and half-life (t 1 / 2 The time to onset of gaboxadol appears to be independent of dose over the dose range of 2.5 to 20 mg. Excretion of gaboxadol is primarily via the urine, where 96.5% of the dose is recovered; 75% is recovered within 4 hours after administration.

[0116] Example 2 Assessment of residual effects due to gaboxadol administration The study was a double-blind, double-dummy, randomized, active- and placebo-controlled, single-dose, three-period crossover study followed by an open-label, single-dose, one-period study in healthy elderly men and women. Subjects were randomized to each of the three treatments (treatments A, B, and C) and administered in a crossover fashion for the first three treatment periods. For treatment A, subjects received a single dose of gaboxadol 10 mg; for treatment B, subjects received a single dose of flurazepam 30 mg; for treatment C, subjects received a single dose of placebo. One dose was administered orally at bedtime on day 1. Subjects remained at home during each treatment period from early in the evening of dosing until approximately 36 hours after dosing (the morning of day 3). Subjects who participated in treatment periods 1-3 participated in the fourth treatment period. During this period, a single dose of gaboxadol 10 mg (Treatment D) was administered orally in an open-label fashion on the morning of Day 1 for gaboxadol PK. There was a washout of at least 14 days between doses of successive treatment periods. Study participants included healthy elderly male and female subjects aged 65-80 years, with a Mini-Mental State Score of 24, and weighing at least 55 kg.

[0117] All subjects received 10 mg gaboxadol monohydrate capsules and 30 mg flurazepam (provided as 2 x 15 mg capsules), and were provided with matching placebos for both gaboxadol and flurazepam.

[0118] Primary endpoints evaluated included (measures of psychomotor performance, memory, attention and daytime sleepiness after an afternoon dose), gaboxadol pharmacokinetics and safety. Gaboxadol (single dose 10 mg) showed no residual effects 9 hours after dosing on the primary endpoints choice reaction time and critical flicker fusion, whereas the active control flurazepam (single dose 30 mg) showed a significant effect in the same test. Furthermore, gaboxadol did not show any signs of residual effects on other measures applied in the study (Multiple Sleep Latency Test (MSLT); Digit symbol substitution test (DSST), tracking, memory test, body sway and Leeds Sleep Assessment Questionnaire).

[0119] Example 3 Driving ability test after administration of gaboxadol The study was a double-blind, randomized, placebo- and active-controlled, five-way crossover study investigating the effects of evening and nighttime dosing of gaboxadol on driving ability. Study participants included healthy male and female subjects aged 21-45 years, with a valid driver's license for at least 3 years.

[0120] The effect of gaboxadol on driving performance was investigated using a real driving on road setting. Subjects were given 15 mg of gaboxadol either in the evening before going to bed or at 4:00 am in the middle of the night after a wake-up call. After a series of cognitive and psychomotor tests, the driving test started at 9:00 am and lasted for 1 hour. Gaboxadol 15 mg had a clinically relevant impairing effect on driving after midnight administration.

[0121] A statistically significant effect of gaboxadol 15 mg on driving was observed after evening administration. However, this effect was smaller than that observed at a blood alcohol concentration of 0.05%, the limit at which driving is prohibited in most European countries. In general, there were numerically greater effects after evening and midnight administration of zopiclone (7.5 mg) and zolpidem (10 mg), respectively. Evening and midnight administration of gaboxadol was well tolerated, with the most frequent adverse events being dizziness, nausea and somnolence for midnight treatment, and headache and somnolence for nighttime treatment.

[0122] Subjects on the active control zopiclone had numerically larger effects in the same tests. There were no effects on memory tests, body sway, DSST or critical tracking, although zopiclone did have an effect on some of these tests.

[0123] Example 4 Daytime behavioral testing after sleep restriction This was a 4-night, parallel-group, randomized, double-blind (with in-house blinding) study to evaluate the effects of gaboxadol on daytime behavior in healthy adults undergoing a 5-h sleep restriction. The study included a 2-night single-blind placebo run-in period during which sleep was restricted to 5 h, a 4-night double-blind treatment period, and a 2-night single-blind placebo withdrawal period. The study included healthy male and female volunteers aged 18 to <55 years.

[0124] 2-night run-in period: all patients received placebo Four-night double-blind treatment period: Patients were randomized to receive gaboxadol 15 mg or matching placebo Two-night withdrawal period: all patients received placebo

[0125] Primary outcome measures included observations based on the Multiple Sleep Latency Test (MSLT) and slow wave sleep (SWS) assessment. The primary objective was to evaluate the efficacy of gaboxadol (15 mg) compared with placebo in reducing daytime sleepiness as measured by the MSLT. Gaboxadol subjects had significantly less daytime sleepiness than placebo subjects during the sleep restriction period (p=0.047, one-tailed). The MSLT was on average 2.01 minutes longer in subjects treated with gaboxadol (15 mg) than in placebo-treated subjects on the last two sleep restriction days.

[0126] Additionally, a secondary objective was to evaluate the efficacy of gaboxadol compared to placebo in increasing the amount of slow wave sleep (SWS) during the last 2 nights of sleep restriction. Subjects given gaboxadol experienced statistically more SWS than placebo subjects during the sleep restriction period (p<0.001, one-tailed). Furthermore, subjects treated with gaboxadol had an average of 20.53 minutes more SWS than subjects treated with placebo during the last 2 nights of sleep restriction.

[0127] Finally, we tested the efficacy of gaboxadol compared to placebo during the last 2 nights / days of sleep restriction in: (1) improving memory and attention as assessed by a battery of neurobehavioral measures; (2) reducing subjective sleep as assessed by the Karolinska Sleepiness Score (KSS); (3) changing sleep parameters (e.g., total sleep time, slow-wave sleep (SWS) latency, slow-wave activity (SWA)); and (4) reducing biological stress as represented by increased heart rate variability, reduced cortisol levels, reduced catecholamine levels, and reduced body temperature.

[0128] Gaboxadol subjects tended to report less subjective daytime sleepiness during the sleep restriction period compared to placebo subjects. Karolinska Sleepiness Score (KSS) was on average 0.68 lower in gaboxadol-treated subjects than in placebo-treated subjects during the last 2 days of sleep restriction, as assessed by a longitudinal data analysis (LDA) model adjusting for baseline KSS, sex, and age (p=0.058, one-tailed). Prescriptive analysis of covariance (ANCOVA) also supports this finding. Effect sizes calculated for a range of neurocognitive outcomes indicated that there was no strong evidence that gaboxadol improves daytime behavior. There were no differences between gaboxadol and placebo with respect to biophysiological measures of stress (heart rate variability, cortisol levels, catecholamine levels, body temperature).

[0129] Compared to placebo, gaboxadol has a protective effect on reducing daytime sleepiness as measured by MSLT on the last 2 days of 4 nights of sleep restriction.Compared to placebo, gaboxadol increases the amount of slow wave sleep (SWS) during the last 2 nights of 4 nights of sleep restriction.

[0130] Example 5 A prospective evaluation of the efficacy of gaboxadol in patients with tinnitus This study was designed to determine whether gaboxadol provides improvement in tinnitus. The primary objective of this study may be to evaluate the safety and tolerability of gaboxadol from baseline to 6 and 12 weeks in adult subjects with tinnitus across different dose levels and two dosing schedules. The following doses may be evaluated against placebo: (1) once daily (od): evening dose titrated to a target dose of 15 mg unless not tolerated; and (2) twice daily (bid): evening and morning dose titrated to an evening dose of 15 mg and a morning dose of 10 mg unless not tolerated.

[0131] Safety endpoints for this study may include: (1) frequency and severity of adverse events (AEs); (2) vital signs (weight, blood pressure, temperature); (3) laboratory values ​​(electrolytes, lipids, glucose, liver and pancreatic function tests, hematology, creatinine); (4) suicidality as assessed by the ABC-Irritability Subscale; (5) EEG (background frequency changes, intensity of epileptiform discharges); and / or (6) caregiver maintenance of an electronic seizure diary (on the same device as the sleep log).

[0132] A secondary objective of this study may include identifying a set of parameters that may best characterize the efficacy of gaboxadol in adult tinnitus subjects for subsequent efficacy trials. These tests may be performed during four full-day visits (screening, baseline, mid-treatment and end-of-treatment) by professionals appropriately trained to provide the tests to adult tinnitus patients. Evaluation may be based on the patient's perception of symptoms.

[0133] Tinnitus Sound Pressure - Visual Analogue Scale (VAS) [Time Frame: Each week: Time between the results of the questionnaire at the start and comparison with the results each week after the first dose. Tinnitus Sound Pressure Scale: Scale ranges from 1-10. Patient selects which number reflects the subjective sound pressure of the tinnitus they have. Higher numbers - louder tinnitus. Tinnitus Distress Scale: Scale ranges from 1-10. Patient selects which number best reflects the extent to which the tinnitus is distressing to them. The higher the score, the more severe the tinnitus.

[0134] Sleep assessments may include analysis by actigraphy measuring (1) sleep onset latency (SOL); (2) total sleep time (TST); (3) wake after sleep onset (WASO) = total number of awake epochs after sleep onset; (4) nighttime awakenings (NA); and / or (5) sleep effectiveness = total sleep time (TST) at bedtime (TIB). Further sleep assessments may include analysis of parent / caregiver sleep pattern diaries, which may include (1) time to bed; (2) time to fall asleep; (3) number and duration of awakenings; (4) number of sleeplessness behaviors; (5) most recent awakening time; and (6) daytime sleepiness.

[0135] The study may include three treatment arms. For example, a total of about 75 subjects may be enrolled, and upon completion of the study, there may be about 25 subjects in each of the three treatment arms: 1) a single evening dose, 2) morning and evening dose, and 3) placebo.

[0136] All subjects may receive a morning dose (active or placebo) and an evening dose (active or placebo) for the entire duration of treatment. For example, as shown in Figure 3, two dosing schedules of gaboxadol may be tested: a single evening dose (od; Schedule A) and a morning and evening dose (bid; Schedule B) designed to provide a more sustained exposure. Schedule C is morning and evening placebo. All subjects may be titrated to the target dose (titration methods below) unless the target dose is not tolerated. All subjects may be treated for up to 12 weeks at the best tolerated dose.

[0137] The dose may be titrated in 5 mg increments (active or placebo) up to a target dose of capsule 3, which is the evening dose in Schedules A and B, and capsule 2, which is the morning dose in Schedule B. Each dose escalation may be performed after adequate tolerability is assessed by the caregiver and the investigator. For example, treatment begins on day 1 with one capsule (active (Act) or placebo (Plc)) in the evening. Target escalation may begin on day 3 (window + 2 days): if no adverse events (AEs) related to the study drug are observed by the caregiver and / or investigator, one more capsule (active or placebo) is added in the evening. Again on days 7 (window + 2 days), 7 (window + 2 days) and 14 (window + 2 days), one more capsule (active or placebo) may be added in the morning if no AEs related to the study drug are observed by the caregiver and / or investigator. Table II below provides an illustration of the titration schedule. [Table 2]

[0138] Slow or delayed up-titration is permitted on any of the days indicated above (days 3, 7, 10, 14) if tolerance does not permit immediate further dose escalation. Tapering after a previous titration step or if tolerance is not observed during the course of 12 weeks of treatment (e.g., somnolence, dizziness, behavioral changes), the dose may be reduced to the previous level or even further. However, once a tolerated dose is reached, it remains constant for the duration of treatment. Once the target dose is achieved, treatment may be continued. For example, Day 14 : The earliest the target dose can be reached (2 capsules in the morning and 3 capsules in the evening), and subjects may remain stable until the end of treatment visit (Week 12) unless intolerance requires tapering.

[0139] All subjects were screened for study participation up to 28 days prior to receiving the first dose. Inclusion criteria were (1) age ≥ 18 and ≤ 40 years; (2) must have a clinical diagnosis of tinnitus. Descriptive statistics can be used to summarize all primary and secondary endpoints and baseline changes by treatment group. For continuous changes, n, number of missing values, mean, standard deviation, median, minimum and maximum are provided. For categorical changes, frequencies and percentages are present for each category. Confidence intervals (CI) are provided when significant. All confidence intervals are two-sided 95% confidence intervals.

[0140] Example 6 A prospective evaluation of the efficacy of gaboxadol and clobazam in patients with tinnitus. This study was designed to determine whether the combination of gaboxadol and clobazam would result in improvement of tinnitus. The primary objective of this study would be to evaluate the safety and tolerability of gaboxadol and clobazam from baseline to 6 and 12 weeks in adult subjects with tinnitus across various dose levels and two dosing schedules. The following doses may be evaluated versus placebo: (1) once daily (od): an evening dose titrated to a target dose of gaboxadol 10 mg and clobazam 10 mg unless not tolerated; and (2) twice daily (bid): an evening dose of gaboxadol 10 mg and clobazam 10 mg unless not tolerated, and an evening and morning dose titrated to a morning dose of gaboxadol 10 mg and clobazam 10 mg unless not tolerated.

[0141] Safety endpoints for this study may include: (1) frequency and severity of adverse events (AEs); (2) vital signs (weight, blood pressure, temperature); (3) laboratory values ​​(electrolytes, lipids, glucose, liver and pancreatic function tests, hematology, creatinine); (4) suicidality as assessed by the ABC-Irritability Subscale; (5) EEG (background frequency changes, intensity of epileptiform discharges); and / or (6) caregiver maintenance of an electronic seizure diary (on the same device as the sleep diary).

[0142] A secondary objective of this study may include identifying a set of parameters that may best characterize the efficacy of gaboxadol in adult tinnitus subjects for subsequent efficacy trials. These tests may be performed during four full-day visits (screening, baseline, mid-treatment and end-of-treatment) by professionals appropriately trained to provide the tests to adult tinnitus patients. Evaluation may be based on the patient's perception of symptoms.

[0143] Tinnitus Sound Pressure - Visual Analogue Scale (VAS) [Time Frame: Each week: Time between the results of the questionnaire at the start and comparison with the results each week after the first dose. Tinnitus Sound Pressure Scale: Scale ranges from 1-10. Patient selects which number reflects the subjective sound pressure of the tinnitus they have. Higher numbers - louder tinnitus. Tinnitus Distress Scale: Scale ranges from 1-10. Patient selects which number best reflects the extent to which the tinnitus is distressing to them. The higher the score, the more severe the tinnitus.

[0144] Sleep assessments may include analysis by actigraphy measuring (1) sleep onset latency (SOL); (2) total sleep time (TST); (3) wake after sleep onset (WASO) = total number of awake epochs after sleep onset; (4) nighttime awakenings (NA); and / or (5) sleep effectiveness = total sleep time (TST) at bedtime (TIB). Further sleep assessments may include analysis of parent / caregiver sleep pattern diaries, which may include (1) time to bed; (2) time to fall asleep; (3) number and duration of awakenings; (4) number of sleeplessness behaviors; (5) most recent awakening time; and (6) daytime sleepiness.

[0145] The study may include three treatment arms. For example, a total of about 75 subjects may be enrolled, and upon completion of the study, there may be about 25 subjects in each of the three treatment arms: 1) a single evening dose, 2) morning and evening dose, and 3) placebo.

[0146] All subjects may receive a morning dose (active or placebo) and an evening dose (active or placebo) for the entire duration of treatment. For example, as shown in Figure 3, two dosing schedules of gaboxadol may be tested: a single evening dose (od; Schedule A) and a morning and evening dose (bid; Schedule B) designed to provide a more sustained exposure. Schedule C is morning and evening placebo. All subjects may be titrated to the target dose (titration methods below) unless the target dose is not tolerated. All subjects may be treated for up to 12 weeks at the best tolerated dose.

[0147] The dose may be titrated in 5 mg increments (active or placebo) to a target dose of one capsule, which is the evening dose in Schedules A and B, and one capsule, which is the morning dose in Schedule B. Each dose escalation may be performed after adequate tolerability is assessed by the caregiver and the investigator. For example, treatment begins on day 1 with one capsule (active (Act) or placebo (Plc)) in the evening. Then, the target titration may begin on day 3 (window + 2 days): if no adverse events (AEs) related to the study drug are observed by the caregiver and / or the investigator, one more capsule (active or placebo) is added in the evening. Again on days 7 (window + 2 days), 7 (window + 2 days) and 14 (window + 2 days), one more capsule (active or placebo) may be added in the morning if no AEs related to the study drug are observed by the caregiver and / or the investigator. Table III below provides an illustration of the titration schedule. [Table 3]

[0148] Slow or delayed up-titration is permitted on any of the days indicated above (days 3, 7, 10, 14) if tolerance does not permit immediate further dose escalation. Tapering after a previous titration step or if tolerance is not observed during the course of 12 weeks of treatment (e.g., somnolence, dizziness, behavioral changes), the dose may be reduced to the previous level or even further. However, once a tolerated dose is reached, it remains constant for the duration of treatment. Once the target dose is achieved, treatment may be continued. For example, Day 14 : The earliest the target dose can be reached (1 capsule in the morning and 1 capsule in the evening), and subjects may remain stable until the end of treatment visit (Week 12) unless intolerance requires tapering.

[0149] All subjects were screened for study participation up to 28 days prior to receiving the first dose. Inclusion criteria were (1) age ≥ 18 and ≤ 40 years; (2) must have a clinical diagnosis of tinnitus. Descriptive statistics can be used to summarize all primary and secondary endpoints and baseline changes by treatment group. For continuous changes, n, number of missing values, mean, standard deviation, median, minimum and maximum are provided. For categorical changes, frequencies and percentages are present for each category. Confidence intervals (CI) are provided when significant. All confidence intervals are two-sided 95% confidence intervals.

[0150] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, equivalents to the embodiments described herein. Such equivalents are intended to be encompassed by the claims. Furthermore, the present invention includes the following aspects. Item 1. A method for treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, the method providing improvement to the patient for more than 6 hours after administration. Item 2. The method according to Item 1, wherein a composition comprising about 1 mg to about 15 mg of gaboxadol or a pharma- ceutically acceptable salt thereof is administered to a patient. Item 3. The method according to Item 1, wherein a composition comprising about 1 mg to about 10 mg of gaboxadol or a pharma- ceutically acceptable salt thereof is administered to a patient. Item 4. The method according to Item 1, wherein a composition comprising about 1 mg to about 5 mg of gaboxadol or a pharma- ceutically acceptable salt thereof is administered to a patient. Item 5. The method according to item 1, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by more than 50%. Item 6. AUC of patients 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof 6-12 The method of claim 1, wherein the amount of the administered dose is less than 75%. Clause 7. The method of clause 1, which provides improvement in at least one symptom in one or both ears selected from the group consisting of ringing, rolling, static, buzzing, hissing, whoosing, cricket noise, and jackhammer noise and / or whistling. Item 8. The method of item 1, which provides patient improvement for more than 6 hours. Item 9. The method of item 1, providing patient improvement for more than 8 hours. Item 10. The method of item 1, wherein the composition provides improvement in the patient for at least 12 hours. Item 11. A method for treating tinnitus comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of such treatment, the method providing an in vivo plasma profile comprising a Cmax of less than about 400 ng / ml and providing improvement in the patient for more than 6 hours after administration of gaboxadol or a pharma-ceutical acceptable salt thereof. Item 12. A method for treating tinnitus, comprising administering gaboxadol or a pharma- ceutical acceptable salt thereof to a patient in need of such treatment, wherein the AUC 6-12 and providing an improvement in the patient for more than 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof. Item 13. A method for treating tinnitus, comprising administering to a patient in need of treatment a first pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharma- ceutical acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC 0-∞ The method provides an in vivo plasma profile comprising: Item 14. The second pharmaceutical composition has a mean AUC of less than about 900 ng·hr / ml. 0-∞ The method of claim 13, further comprising providing an in vivo plasma profile comprising: Item 15. The method of item 13, wherein the Cmax of the first pharmaceutical composition is more than 20% greater than the Cmax of the second pharmaceutical composition. Item 16. The method according to Item 13, wherein the Tmax of the first pharmaceutical composition is less than 2 hours. Item 17. The method of item 13, wherein the first pharmaceutical composition comprises at least 80% dissolution within the first 10 minutes. Item 18. The method of item 13, wherein the first pharmaceutical composition and the second pharmaceutical composition are provided in a single dosage form. Item 19. The method of item 13, wherein the first pharmaceutical composition provides the patient with about 0.05 mg / kg / day to about 5 mg / kg / day of gaboxadol or a pharma- ceutically acceptable salt thereof. Item 20. The method according to Item 13, wherein the first pharmaceutical composition comprises about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. Item 21. The method according to Item 13, wherein the second pharmaceutical composition comprises about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. Item 22. A method for treating tinnitus comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof in combination with about 1 mg to about 30 mg of clobazam or a pharma-ceutically acceptable salt thereof, which provides improvement in one or more symptoms of tinnitus in the patient. Item 23. The method according to Item 22, wherein the amount of gaboxadol or a pharma- ceutically acceptable salt thereof is 5 mg to 20 mg. Item 24. The method according to Item 22, wherein the amount of clobazam or a pharma- ceutically acceptable salt thereof is 5 mg to 20 mg. Item 25. The method according to Item 23, wherein the amount of gaboxadol or a pharma- ceutically acceptable salt thereof is 10 mg. Item 26. The method according to Item 24, wherein the amount of clobazam or a pharma- ceutically acceptable salt thereof is 10 mg. Item 27. A method for treating acute sensorineural hearing loss, comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, the method providing improvement in the patient for more than 6 hours after administration. Item 28. The method according to Item 27, wherein a composition comprising about 1 mg to about 15 mg of gaboxadol or a pharma- ceutically acceptable salt thereof is administered to the patient. Item 29. The method according to Item 27, wherein a composition comprising about 1 mg to about 10 mg of gaboxadol or a pharma- ceutically acceptable salt thereof is administered to a patient. Item 30. The method according to Item 27, wherein a composition comprising about 1 mg to about 5 mg of gaboxadol or a pharma- ceutically acceptable salt thereof is administered to the patient. Item 31. The method according to Item 27, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by more than 50%. Item 32. AUC of a patient 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof 6-12 The method of claim 27, wherein the amount of the administered dose is less than 75%. Item 33. The method according to item 27, which provides improvement in at least one symptom selected from hearing loss, ear fullness, and tinnitus. Item 34. A method for treating acute sensorineural hearing loss, comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutical acceptable salt thereof in combination with about 1 mg to about 30 mg of clobazam or a pharma- ceutical acceptable salt thereof, which provides improvement in one or more symptoms of acute sensorineural hearing loss in the patient. Item 35. The method according to Item 34, wherein the amount of gaboxadol or a pharma- ceutically acceptable salt thereof is 5 mg to 20 mg. Item 36. The method according to Item 34, wherein the amount of clobazam or a pharma- ceutically acceptable salt thereof is 5 mg to 20 mg. Item 37. The method according to Item 34, wherein the amount of gaboxadol or a pharma- ceutically acceptable salt thereof is 10 mg. Item 38. The method according to Item 34, wherein the amount of clobazam or a pharma- ceutically acceptable salt thereof is 10 mg. Item 39. A method for treating Meniere's disease, comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutically acceptable salt thereof, the method providing improvement in the patient for more than 6 hours after administration. Item 40. The method according to Item 39, wherein the patient is administered a composition comprising about 1 mg to about 15 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. Item 41. The method according to Item 39, wherein the patient is administered a composition comprising about 1 mg to about 10 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. Item 42. The method according to Item 39, wherein the patient is administered a composition comprising about 1 mg to about 5 mg of gaboxadol or a pharma- ceutically acceptable salt thereof. Clause 43. The method of clause 39, wherein the patient's in vivo plasma profile 6 hours after administration of gaboxadol or a pharma- ceutically acceptable salt thereof is reduced by more than 50%. Item 44. AUC of a patient 6 hours after administration of gaboxadol or a pharma- ceutical acceptable salt thereof 6-12 The method of claim 39, wherein the amount of the administered dose is less than 75%. Item 45. The method of item 39, which provides improvement in at least one symptom selected from hearing loss, vertigo, tinnitus, hypersensitivity to sound, and ear fullness. Item 46. A method for treating Meniere's disease, comprising administering to a patient in need of treatment about 0.05 mg to about 30 mg of gaboxadol or a pharma- ceutical acceptable salt thereof in combination with about 1 mg to about 30 mg of clobazam or a pharma- ceutical acceptable salt thereof, which provides improvement in one or more symptoms of acute sensorineural hearing loss in the patient. Item 47. The method according to Item 46, wherein the amount of gaboxadol or a pharma- ceutically acceptable salt thereof is 5 mg to 20 mg. Item 48. The method according to Item 46, wherein the amount of clobazam or a pharma- ceutically acceptable salt thereof is 5 mg to 20 mg. Item 49. The method according to Item 46, wherein the amount of gaboxadol or a pharma- ceutically acceptable salt thereof is 10 mg. Item 50. The method according to Item 46, wherein the amount of clobazam or a pharma- ceutically acceptable salt thereof is 10 mg.

Claims

[Claim 1] The invention as herein described or illustrated in the drawings.

Images