WO2022140636A1

WO2022140636A1 - Gacyclidine otic formulations and uses thereof

Info

Publication number: WO2022140636A1
Application number: PCT/US2021/065006
Authority: WO
Inventors: Jeff Anderson
Original assignee: Otonomy, Inc.
Priority date: 2020-12-22
Filing date: 2021-12-22
Publication date: 2022-06-30

Abstract

Disclosed herein are gacyclidine formulations, compositions, and methods for the treatment of otic diseases and conditions, such as tinnitus.

Description

GACYCLIDINE OTIC FORMULATIONS AND USES THEREOF

BACKGROUND OF THE DISCLOSURE

[0001] Vertebrates have a pair of ears, placed symmetrically on opposite sides of the head. The ear serves as both the sense organ that detects sound and the organ that maintains balance and body position. The ear is generally divided into three portions: the outer ear, auris media (or middle ear), and the auris interna (or inner ear).

SUMMARY OF THE DISCLOSURE

[0002] Provided in one aspect is a method of treating tinnitus in a human subject, comprising intratypamically administering an otic formulation to the human subject, wherein the otic composition comprises from about 0.01 wt% to about 10 wt% gacyclidine and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of gacycldine into the inner ear.

[0003] In some embodiments, the gacyclidine is in free base form. The method of claim 1-2, wherein the composition comprises from 0.05mg to 0.70mg gacyclidine.

[0004] In some embodiments, the composition comprises about 0.1 Img gacyclidine. In some embodiments, the composition comprises from 0.05mg to 0.25mg gacyclidine.

[0005] In some embodiments, the composition comprises about 0.32mg gacyclidine. In some embodiments, the composition comprises from 0.25mg to 0.40mg gacyclidine.

[0006] In some embodiments, the composition comprises about 0.44mg gacyclidine. In some embodiments, the composition comprises from 0.40mg to 0.55mg gacyclidine.

[0007] In some embodiments, the composition comprises about 0.64mg or 0.66mg gacyclidine. In some embodiments, the composition comprises from 0.55mg to 0.70mg gacyclidine.

[0008] In some embodiments, the auris acceptable vehicle comprises a triglyceride of a medium chain fatty acid, and wherein the otic formulation comprises least about 50 wt% of the triglyceride. [0009] In some embodiments, the triglyceride are present in an amount that is sufficient to provide sufficient retention time in the ear. In some embodiments, the triglycerids are present in an amount that is sufficient to sufficient to allow delivery of the formulation via a narrow gauge needle.

[0010] In some embodiments, the medium chain fatty acid comprises 6 to 12 carbon atoms in the carbon chain. In some embodiments, the medium chain fatty acid 8 to 12 carbon atoms in the carbon chain.

[0011] In some embodiments, the medium chain fatty acid is selected from the group consisting of saturated medium chain fatty acids, unsaturated medium chain fatty acids, or a combination thereof. In some embodiments, the medium chain fatty acid is selected from the group consisting of caproic acid (hexanoic acid), enanthic acid (heptanoic acid), caprylic acid (octanoic acid), pelargonic acid (nonanoic acid), capric acid (decanoic acid), undecylenic acid (undec- 10-enoic acid), lauric acid (dodecanoic acid), or a combination thereof. In some embodiments, the triglyceride is selected from the group consisting of balassee oil, coconut oil, cohune oil, palm kernel oil, tucum oil, or combinations thereof.

[0012] In some embodiments, the otic pharmaceutical formulation comprises between about 55% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 65% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 75% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 85% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 95% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 97% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 98% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 99% to about 99.99% by weight of the triglyceride. In some embodiments, the otic pharmaceutical formulation comprises between about 99.5% to about 99.99% by weight of the triglyceride.

[0013] In some embodiments, the otic pharmaceutical formulation has a viscosity between about 10 cP to about 10,000 cP. In some embodiments, the otic pharmaceutical formulation has a viscosity between about 10 cP to about 5,000 cP. In some embodiments, the otic pharmaceutical formulation has a viscosity between about 10 cP to about 1,000 cP. In some embodiments, the otic pharmaceutical formulation has a viscosity between about 10 cP to about 500 cP. In some embodiments, the otic pharmaceutical formulation has a viscosity between about 10 cP to about 250 cP. In some embodiments, the otic pharmaceutical formulation has a viscosity between about 10 cP to about 100 cP. In some embodiments, the otic pharmaceutical formulation has a viscosity between about 10 cP to about 50 cP.

[0014] In some embodiments, the otic pharmaceutical formulation is free or substantially free of water, C1-C6 alcohols or C1-C6 glycols, C1-C4 alcohols or C1-C4 glycols, poloxamer, or any combination thereof. In some embodiments, the otic pharmaceutical formulation is free or substantially free of water. In some embodiment, the otic pharmaceutical formulation is free of poloxamer (e.g. Poloxamer 407). In some embodiments, the otic pharmaceutical formulation is free or substantially free of C1-C6 alcohols or C1-C6 glycols. In some embodiments, the otic pharmaceutical formulation is free or substantially free of C1-C4 alcohols or C1-C4 glycols.

[0015] In some embodiments, the otic formulation has an osmolarity from about 100 mOsm/L to about 1000 mOsm/L. [0016] In some embodiments, the gacyclidine is dissolved in the otic formulation. In some embodiments, the gacyclidine is suspended in the otic formulation.

[0017] In some embodiments, the otic pharmaceutical formulation comprises between about 0.001% to about 10% by weight of the gacyclidine.

[0018] In some embodiments, the otic pharmaceutical formulation comprises between about 0.01% to about 1% by weight of the gacyclidine. In some embodiments, the otic pharmaceutical formulation comprises between about 0.01% to about 0.5% by weight of the gacyclidine. In some embodiments, the otic pharmaceutical formulation comprises between about 0.05% to about 0.35% by weight of the gacyclidine.

[0019] In some embodiments, the otic formulation provides sustained release of gacyclidine in the ear for at least 3 days. In some embodiments, the otic formulation provides sustained release of gacyclidine in the ear for at least 5 days. In some embodiments, the otic formulation provides sustained release of gacyclidine in the ear for at least 7 days. In some embodiments, the otic formulation provides sustained release of gacyclidine in the ear for at least 14 days.

[0020] In some embodiments, the otic formulation is injected into the middle ear. In some embodiments, the otic formulation is deposited close to the round window membrane. In some embodiments, the otic formulation is administered through intratympanic injection, such as unilateral or bilateral intratympanic injection. In some embodiments, the otic formulation is deposited close to the round window membrane.

[0021] In some embodiment, the tinnitus is moderate to severe tinnitus. In some embodiment, the tinnitus is persistent tinnitus. In some embodiment, the tinnitus is moderate to severe, and persistent tinnitus.

[0022] In some embodiments, the tinnitus is associated with an otic disease or condition selected from the group consisting of ear pruritus, otitis externa, otalgia, tinnitus, vertigo, ear fullness, hearing loss, Meniere’s disease, sensorineural hearing loss, noise induced hearing loss, age related hearing loss (presbycusis), auto immune ear disease, ototoxicity, excitotoxicity, endolymphatic hydrops, labyrinthitis, Ramsay Hunt’s Syndrome, vestibular neuronitis, or microvascular compression syndrome, hyperacusis, presbystasis, central auditory processing disorder, auditory neuropathy, and combinations thereof.

INCORPORATION BY REFERENCE

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

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The novel features of the disclosure are set forth with particularity in the appended claims.

A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0025] FIG. 1 illustrates the anatomy of the ear.

[0026] FIG. 2 illustrates inner ear perilymph kinetics of gacyclidine racemate following a single IT administration of GCY-MCT formulations in rats. Data are presented as Mean ± SEM. 0.16% GCY (orange squares), 0.5% GCY (blue circles), 1.5% GCY (green triangles) and 4.5% GCY (inverted purple triangles). Limit of quantification is 1 ng/mL.

[0027] FIG. 3 illustrates inner ear cochlear epithelium tissues kinetics of gacyclidine racemate following a single IT administration of GCY-MCT formulations in rats. Data are presented as Mean ± SEM. 0.16% GCY (orange squares), 0.5% GCY (blue circles), 1.5% GCY (green triangles) and 4.5% GCY (inverted purple triangles). Limit of quantification is 6 ng/mL.

[0028] FIG. 4 illustrates plasma kinetics of gacyclidine racemate following a single IT administration of GCY-MCT formulations in rats. Data are presented as Mean ± SEM. 0.16% GCY (orange squares), 0.5% GCY (blue circles), 1.5% GCY (green triangles) and 4.5% GCY (inverted purple triangles). Limit of quantification is 0.2 ng/mL.

[0029] FIG. 5 is a comparison of the perilymph, cochlear epithelium, and plasma kinectics at 0.5% GYC in FIGs. 2-4.

[0030] FIG. 6 Illustrates hearing function following a single intratympanic administration of COMPOSITION A in rats. ABR threshold shifts (4, 10 and 20 kHz) in the treated ear at termination from baseline values are reported as mean ± SEM for male and female rats. Treatment groups were: saline (black), MCT vehicle (purple), 0.5% COMPOSITION A (light blue), 1.5% COMPOSITION A (blue), 4.5% COMPOSITION A (dark blue) and gentamicin (red).

[0031] FIG. 7 illustrates hearing function following a single intratympanic administration of COMPOSITION A in cats. ABR threshold shifts (4, 10 and 20 kHz) in the treated ear at termination from baseline values are reported as mean ± SEM for male and female cats. Treatment groups were: saline (black), MCT vehicle (purple), 0.5% COMPOSITION A (light blue), 1.5% COMPOSITION A (blue), 4.5% COMPOSITION A (dark blue) and gentamicin (red).

[0032] FIG. 8 illustrates patient disposition in a clinical study according to Example 5.

[0033] FIG. 9 illustrates the mean TFI overall score reduction from baseline trended in favor of COMPOSITION A at each visit in a clinical study according to Example 5.

[0034] FIG. 10. illustrates plasma kinetics of gacyclidine racemate following a single IT administration of GCY-MCT formulations in rats. Data are presented as Mean ± SEM. 0.16% GCY (orange squares), 0.5% GCY (blue circles), 1.5% GCY (green triangles) and 4.5% GCY (inverted purple triangles). Limit of quantification is 0.2 ng/mL.

[0035] FIG. 11 illustrates subgroup analyses of efficacy data in a clinical study according to Example 5, showing differences for the patient subgroup with baseline TFI scores of 40-100. [0036] FIG. 12 illustrates subgroup analyses of efficacy data in a clinical study according to Example 5, showing differences for the patient subgroup with tinnitus duration of 3-6 months.

[0037] FIG. 13. illustrates subgroup analyses of efficacy data in a clinical study according to Example 5, showing differences for the patient subgroup with change in TFI auditory subscale questions at Day 57.

[0038] FIG. 14 Illustrate NRS loudness and NRS annoyance reduction from baseline trended in favor of COMPOSITION A at each visit.

[0039] FIG. 15. illustrates the safty profile of COMPOSITION A in a clinical study according to Example 5, showing that patients who received COMPOSITION A had a lower incidence of adverse events than placebo.

DETAILED DESCRIPTION

[0040] Systemic administration of active agents is, in some instances, ineffectual in the treatment of diseases that affect inner ear structures. The cochlear canals and the cochlea, for example, are isolated from the circulatory system limiting systemic delivery of active agents to target sites in the inner ear. In some instances, systemic drug administration creates a potential inequality in drug concentration with higher circulating levels in the serum, and lower levels in the target auris interna organ structures. In certain instances, large amounts of drug are required to overcome this inequality in order to deliver sufficient, therapeutically effective quantities of a drug to auditory structures. In some instances, systemic drug administration also increases the likelihood of secondary systemic accumulation and consequent adverse side effects.

[0041] Currently available treatment for inner ear diseases also carries the risk of attendant side effects. For example, available methods require multiple daily doses (e.g., intratympanic injection or infusion) of drugs. In certain instances, multiple daily intratympanic injections cause patient discomfort and non-compliance. In certain instances, delivery of active agents to the inner ear via otic drops administered in the ear canal or via intratympanic injection is hindered by the biological barrier presented by the blood-labyrinth-barrier (BLB), the oval window membrane and/or the round window membrane. In some instances, delivery of active agents to the inner ear via otic drops or intratympanic injection causes osmotic imbalance in inner ear structures, introduces infections or other immune disorders as a result of microbial or endotoxin presence, or results in permanent structural damage (e.g. perforation of the tympanic membrane), resulting in hearing loss and the like.

[0042] Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the auris media and/or auris interna. Some challenges remain with intratympanic injections. For example, access to the round window membrane, the site of drug absorption into the auris interna, is challenging in some instances. In addition, current regimens using intratympanic injections do not address changing the osmolarity and pH of the perilymph and endolymph, and introducing pathogens and endotoxins that directly or indirectly damage inner ear.

[0043] Provided herein are otic formulations and compositions that are triglyceride based otic pharmaceutical formulations. Such triglycerides include medium chain triglycerides (MCT). These otic formulations and compositions comprise a therapeutic agent, or a pharmaceutically acceptable prodrug or salt thereof; and triglycerides comprising medium chain fatty acids. In some embodiments, the triglycerides are derived from glycerol and medium chain fatty acids.

[0044] In some embodiments, the otic triglyceride based pharmaceutical formulations have triglycerides in an amount that is sufficient to stabilize the therapeutic agent for injection into the ear. In some embodiments, the injection is into the outer ear. In some embodiments, the injection is into the middle ear. In some embodiments, the injection is intratympanic. In some embodiments, the injection is into the inner ear. In some embodiments, the otic triglyceride based pharmaceutical formulations have triglycerides in an amount that is sufficient to provide sufficient retention time in the ear. In some embodiments, the sufficient retention time in the ear is for the middle ear. In some embodiments, the sufficient retention time in the ear is for the inner ear. In some embodiments, the sufficient retention time in the ear is for the outer ear. In some embodiments, the outer ear is the external auditory canal, the outer surface of the tympanic membrane, or a combination thereof. In some embodiments, the outer ear is the external auditory canal. In some embodiments, the otic triglyceride based pharmaceutical formulations have triglycerides in an amount that is sufficient to provide sustained release of the therapeutic agent. In some embodiments, the sustained release of the therapeutic agent is in the outer ear. In some embodiments, the sustained release of the therapeutic agent is in the middle ear. In some embodiments, the sustained release of the therapeutic agent is in the inner ear. In some embodiments, the triglycerides are present in an amount that is sufficient to allow delivery of the formulation via a narrow gauge needle.

[0045] These otic triglyercide based pharmaceutical formulations are suitable for drug delivery into the external, middle and/or inner ear. In some instances, these otic pharmaceutical formulations and compositions are suitable for administration to humans. In some instances, the otic formulations and compositions disclosed herein also meet stringent criteria for pH, osmolarity, ionic balance, sterility, endotoxin and/or pyrogen levels. In some instances, the otic formulations and compositions are compatible with the microenvironment of the inner ear (e.g., the perilymph). [0046] Accordingly, provided herein, in certain embodiments, are otic formulations and compositions that are controlled release auris-acceptable formulations and compositions that locally treat auris target structures and provide extended exposure of otic active agents to the target auris structures. In certain embodiments, the otic formulations and compositions described herein are designed for stringent osmolarity and pH ranges that are compatible with auditory structures and/or the endolymph and perilymph. In some embodiments, the otic formulations and compositions described herein are controlled release formulations that provide extended release for a period of at least 3 days and meet stringent sterility requirements. In some instances, otic formulations and compositions described herein contain lower endotoxin levels (e.g. < 0.5 EU/mL when compared to typically acceptable endotoxin levels of 0.5 EU/mL. In some instances, the otic formulations and compositions described herein contain low levels of colony forming units (e.g., <50 CFUs) per gram of the formulation or composition. In some instances, the otic formulations or compositions described herein are substantially free of pyrogens and/or microbes. In some instances the otic formulations or compositions described herein are formulated to preserve the ionic balance of the endolymph and/or the perilymph.

[0047] In some instances, local administration of the otic formulations and compositions described herein avoids potential adverse side effects as a result of systemic administration of active agents. In some instances, the locally applied otic formulations and compositions described herein are compatible with auris structures. Such compatible auris structures include those associated with the outer, middle, and/or inner ear. In some embodiments, the otic formulations and compositions are administered either directly to the desired auris structure, e.g. the cochlear region, or administered to a structure in direct communication with areas of the auris structure; in the case of the cochlear region, for example, including but not limited to the round window membrane, the crista fenestrae cochleae or the oval window membrane.

[0048] In certain instances, the otic formulations and compositions disclosed herein controlled release formulations or compositions that provide a constant rate of release of a drug from the formulation and provide a constant prolonged source of exposure of an otic active agent to the inner ear of an individual or patient suffering from an otic disorder, reducing or eliminating any variabilities associated with other methods of treatment (such as, e.g., otic drops and/or multiple intratympanic injections).

[0049] In some embodiments, the otic formulations and compositions described herein provide extended release of the active ingredient(s) into the external ear. In some embodiments, the otic formulations and compositions described herein provide extended release of the active ingredient(s) into the middle and/or inner ear (auris interna), including the cochlea and vestibular labyrinth. In some embodiments, the otic formulations and compositions further comprise an immediate or rapid release component in combination with a controlled release component.

Certain Definitions

[0050] The term “auris-acceptable” with respect to a formulation, composition or ingredient, as used herein, includes having no persistent detrimental effect on the auris externa (or external ear or outer ear), auris media (or middle ear) and/or the auris interna (or inner ear) of the subject being treated. By “auris-pharmaceutically acceptable,” as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound in reference to the auris externa (or external ear or outer ear), auris media (or middle ear) and/or the auris interna (or inner ear), and is relatively or is reduced in toxicity to the auris externa (or external ear or outer ear), auris media (or middle ear) and the auris interna (or inner ear), i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0051] As used herein, amelioration or lessening of the symptoms of a particular otic disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any decrease of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that is attributed to or associated with administration of the compound or composition.

[0052] As used herein, the term “otic agent” or “otic structure modulating agent” or “otic therapeutic agent” or “otic active agent” or “active agent” or “therapeutic agent” refers to compounds that are effective for the treatment of otic disorders, e.g., otitis media, otosclerosis, autoimmune diseases of the ear and cancer of the ear, and are suitable for use in the formulations disclosed herein. An “otic agent” or “otic structure modulating agent” or “otic therapeutic agent” or “otic active agent” or “active agent” includes, but is not limited to, compounds that act as an agonist, a partial agonist, an antagonist, a partial antagonist, an inverse agonist, a competitive antagonist, a neutral antagonist, an orthosteric antagonist, an allosteric antagonist, a positive allosteric modulator of an otic structure modulating target, a negative allosteric modulator of an otic structure modulating target or combinations thereof.

[0053] “Auris externa” refers to the external (or outer) ear, and includes the pinna and the external auditory canal (EAC).

[0054] “Auris interna” refers to the inner ear, including the cochlea and the vestibular labyrinth, and the round window that connects the cochlea with the middle ear.

[0055] “Auris-intema bioavailability” or “Auris media bioavailability” refers to the percentage of the administered dose of compounds disclosed herein that becomes available in the inner or middle ear, respectively, of the animal or human being studied.

[0056] “Auris media” refers to the middle ear, including the tympanic cavity, auditory ossicles and oval window, which connects the middle ear with the inner ear.

[0057] “Blood plasma concentration” refers to the concentration of compounds provided herein in the plasma component of blood of a subject.

[0058] “Auris-intema bioavailability” refers to the percentage of the administered dose of compounds disclosed herein that becomes available in the inner ear of the animal or human being studied.

[0059] The term “auris-acceptable penetration enhancer” with respect to a formulation, composition or ingredient, as used herein, refers to the property of reducing barrier resistance. [0060] “Carrier materials” are excipients that are compatible with the otic agent, the auris media, the auris interna and the release profile properties of the auris-acceptable pharmaceutical formulations. Such carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. “Auris-pharmaceutically compatible carrier materials” include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like.

[0061] The term “diluent” are chemical compounds that are used to dilute the otic agent prior to delivery and which are compatible with the auris media and/or auris interna.

[0062] “Dispersing agents,” and/or “viscosity modulating agents” and/or “thickening agents” are materials that control the diffusion and homogeneity of the otic agent through liquid media. Examples of diffusion facilitators/dispersing agents include but are not limited to hydrophilic polymers, electrolytes, Tween ® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and the carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, HPMC E10M, and HPMC K100M), carboxymethylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxy ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630), 4-(l,l,3,3-tetramethylbutyl)- phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, F108®, and F127®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafimctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)), polyvinylpyrrolidone KI 2, polyvinylpyrrolidone KI 7, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, e.g., the polyethylene glycol has a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans, silicon dioxide, and combinations thereof. Plasticizers such as cellulose or triethyl cellulose are also be used as dispersing agents, optional dispersing agents useful in liposomal dispersions and self-emulsifying dispersions of the otic agents disclosed herein are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate. In some embodiments, the “dispersing agent,” and/or “viscosity modulating agent” and/or “thickening agent” is not a poloxamer.

[0063] “Drug absorption” or “absorption” refers to the process of movement of the otic agent from the localized site of administration, by way of example only, the round window membrane of the inner ear, and across a barrier (the round window membranes, as described below) into the auris interna or inner ear structures. The terms “co-administration” or the like, as used herein, are meant to encompass administration of the otic agent to a single patient, and are intended to include treatment regimens in which the otic agents are administered by the same or different route of administration or at the same or different time.

[0064] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of the otic agent being administered that would be expected to relieve to some extent one or more of the symptoms of the disease or condition being treated. For example, the result of administration of the otic agents disclosed herein is reduction and/or alleviation of the signs, symptoms, or causes of any one of the diseases or conditions disclosed herein. For example, an “effective amount” for therapeutic uses is the amount of the otic agent, including a formulation as disclosed herein required to provide a decrease or amelioration in disease symptoms without undue adverse side effects. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a otic agent composition disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effective amount” or “a therapeutically effective amount” varies, in some embodiments, from subject to subject, due to variation in metabolism of the compound administered, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. In some instances, it is also understood that “an effective amount” in an extended-release dosing format differs from “an effective amount” in an immediate-release dosing format based upon pharmacokinetic and pharmacodynamic considerations.

[0065] The terms “enhance” or “enhancing” refers to an increase or prolongation of either the potency or duration of a desired effect of the otic agent, or a diminution of any adverse symptomatology. For example, in reference to enhancing the effect of the otic agents disclosed herein, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents that are used in combination with the otic agents disclosed herein. An “enhancing-effective amount,” as used herein, refers to an amount of an otic agent or other therapeutic agent that is adequate to enhance the effect of another therapeutic agent or otic agent in a desired system. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0066] The term “inhibiting” includes preventing, slowing, or reversing the development of a condition, including any of one of the conditions described herein, or advancement of a condition in a patient necessitating treatment.

[0067] The terms “kit” and “article of manufacture” are used as synonyms.

[0068] “Pharmacodynamics” refers to the factors which determine the biologic response observed relative to the concentration of drug at the desired site within the auris media and/or auris interna. [0069] “Pharmacokinetics” refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at the desired site within the auris media and/or auris interna.

[0070] In prophylactic applications, compositions containing the otic agents described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like.

[0071] “Solubilizers” refers to auris-acceptable compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol®, propylene glycol, and dimethyl isosorbide and the like.

[0072] “Stabilizers” refers to compounds such as any antioxidation agents, buffers, acids, preservatives and the like that are compatible with the environment of the auris media and/or auris interna. Stabilizers include but are not limited to agents that will do any of (1) improve the compatibility of excipients with a container, or a delivery system, including a syringe or a glass bottle, (2) improve the stability of a component of the composition, or (3) improve formulation stability.

[0073] As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject are used interchangeably.

[0074] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating a disease or condition or the associated symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or controlling or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. [0075] In any of the aforementioned embodiments, the term “substantially low degradation products” means less than 5% by weight of the active agent are degradation products of the active agent. In further embodiments, the term means less than 3% by weight of the active agent are degradation products of the active agent. In yet further embodiments, the term means less than 2% by weight of the active agent are degradation products of the active agent. In further embodiments, the term means less than 1% by weight of the active agent are degradation products of the active agent.

[0076] The term “otic intervention” means an external insult or trauma to one or more auris structures and includes implants, otic surgery, injections, cannulations, or the like. Implants include auris-intema or auris-media medical devices, examples of which include cochlear implants, hearing sparing devices, hearing-improvement devices, short electrodes, micro- prostheses or piston-like prostheses; needles; stem cell transplants; drug delivery devices; any cellbased therapeutic; or the like. Otic surgery includes middle ear surgery, inner ear surgery, tympanostomy, cochleostomy, labyrinthotomy, mastoidectomy, stapedectomy, stapedotomy, endolymphatic sacculotomy or the like. Injections include intratympanic injections, intracochlear injections, injections across the round window membrane or the like. Cannulations include intratympanic, intracochlear, endolymphatic, perilymphatic or vestibular cannulations or the like. [0077] Pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N' -dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N- methylglucamine, procaine, N-benzylphenethylamine, l-para-chlorobenzyl-2- pyrrolidin-1'- ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfuric acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0078] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0079] The instant disclosure is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers are prepared in some instances using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0080] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only.

Anatomy of the Ear

[0081] The ear serves as both the sense organ that detects sound and the organ that maintains balance and body position. The ear is generally divided into three portions: the outer ear, middle ear and the inner ear (or auris interna). As shown in FIG. 1, the outer ear is the external portion of the organ and is composed of the pinna (auricle), the auditory canal (external auditory meatus) and the outward facing portion of the tympanic membrane, also known as the ear drum. The middle ear is an air-filled cavity, called the tympanic cavity, behind the tympanic membrane. The tympanic membrane, also known as the ear drum, is a thin membrane that separates the external ear from the middle ear. The middle ear lies within the temporal bone, and includes within this space the three ear bones (auditory ossicles): the malleus, the incus and the stapes. Sound waves from the outer ear first cause the tympanic membrane to vibrate. The vibration is transmitted across to the cochlea through the auditory ossicles and oval window, which transfers the motion to the fluids in the auris interna.

[0082] The tympanic cavity also connects to the throat via the eustachian tube. The eustachian tube provides the ability to equalize the pressure between the outside air and the middle ear cavity. The round window, a component of the auris interna but which is also accessible within the tympanic cavity, opens into the cochlea of the auris interna. The round window is covered by a membrane, which consists of three layers: an external or mucous layer, an intermediate or fibrous layer, and an internal membrane, which communicates directly with the cochlear fluid. The round window, therefore, has direct communication with the auris interna via the internal membrane. [0083] Auditory signal transduction takes place in the auris interna. The fluid-filled inner ear, or auris interna, consists of two major components: the cochlear and the vestibular apparatus. The cochlea is the portion of the auris interna related to hearing. The cochlea is a tapered tube-like structure which is coiled into a shape resembling a snail. The inside of the cochlea is divided into three regions, which is further defined by the position of the vestibular membrane and the basilar membrane. The portion above the vestibular membrane is the scala vestibuli, which extends from the oval window to the apex of the cochlea and contains perilymph fluid, an aqueous liquid low in potassium and high in sodium content. The basilar membrane defines the scala tympani region, which extends from the apex of the cochlea to the round window and also contains perilymph. The basilar membrane contains thousands of stiff fibers, which gradually increase in length from the round window to the apex of the cochlea. The fibers of the basement membrane vibrate when activated by sound. In between the scala vestibuli and the scala tympani is the cochlear duct, which ends as a closed sac at the apex of the cochlea. The cochlear duct contains endolymph fluid, which is similar to cerebrospinal fluid and is high in potassium. The Organ of Corti, the sensory organ for hearing, is located on the basilar membrane and extends upward into the cochlear duct. The Organ of Corti contains hair cells, which have hairlike projections that extend from their free surface, and contacts a gelatinous surface called the tectorial membrane. Although hair cells have no axons, they are surrounded by sensory nerve fibers that form the cochlear branch of the vestibulocochlear nerve (cranial nerve VIII).

[0084] The auris interna is located in part within the osseous or bony labyrinth, an intricate series of passages in the temporal bone of the skull. The vestibular apparatus is the organ of balance and consists of the three semi-circular canals and the vestibule. The three semi-circular canals are arranged relative to each other such that movement of the head along the three orthogonal planes in space is detected by the movement of the fluid and subsequent signal processing by the sensory organs of the semi-circular canals, called the crista amupllaris. The crista ampullaris contains hair cells and supporting cells, and is covered by a dome-shaped gelatinous mass called the cupula. The hairs of the hair cells are embedded in the cupula. The semi-circular canals detect dynamic equilibrium, the equilibrium of rotational or angular movements. When the head turns rapidly, the semicircular canals move with the head, but endolymph fluid located in the membranous semicircular canals tends to remain stationary. The endolymph fluid pushes against the cupula, which tilts to one side. As the cupula tilts, it bends some of the hairs on the hair cells of the crista ampullaris, which triggers a sensory impulse. Because each semicircular canal is located in a different plane, the corresponding crista ampullaris of each semi-circular canal responds differently to the same movement of the head. This creates a mosaic of impulses that are transmitted to the central nervous system on the vestibular branch of the vestibulocochlear nerve. The central nervous system interprets this information and initiates the appropriate responses to maintain balance. Of importance in the central nervous system is the cerebellum, which mediates the sense of balance and equilibrium.

[0085] The vestibule is the central portion of the auris interna and contains mechanoreceptors bearing hair cells that ascertain static equilibrium, or the position of the head relative to gravity. Static equilibrium plays a role when the head is motionless or moving in a straight line. The membranous labyrinth in the vestibule is divided into two sac-like structures, the utricle and the saccule. Each structure in turn contains a small structure called a macula, which is responsible for maintenance of static equilibrium. The macula consists of sensory hair cells, which are embedded in a gelatinous mass (similar to the cupula) that covers the macula. Grains of calcium carbonate, called otoliths, are embedded on the surface of the gelatinous layer. When the head is in an upright position, the hairs are straight along the macula. When the head tilts, the gelatinous mass and otoliths tilts correspondingly, bending some of the hairs on the hair cells of the macula. This bending action initiates a signal impulse to the central nervous system, which travels via the vestibular branch of the vestibulocochlear nerve, which in turn relays motor impulses to the appropriate muscles to maintain balance.

[0086] In some instances, the otic formulations described herein are placed in the middle or inner ear, including the cochlea and vestibular labyrinth: one option is to use a syringe/needle or pump and inject the formulation across the tympanic membrane (the eardrum). In some instances, for cochlear and vestibular labyrinth delivery, one option is to deliver the active ingredient across the round window membrane or even by microinjection directly into the auris interna also known as cochlear microperfusion.

Diseases or Conditions of the Ear

[0087] In some embodiments, the otic formulations and compositions described herein are suitable for the treatment and/or prevention of diseases or conditions associated with the outer, middle, and/or inner ear. In some embodiments, the otic formulations and compositions described herein are suitable for the treatment and/or prevention of diseases or conditions associated with the outer ear. In some embodiments, the otic formulations and compositions described herein are suitable for the treatment and/or prevention of diseases or conditions associated with the middle ear. In some embodiments, the otic formulations and compostions described herein are suitable for the treatment and/or prevention of diseases or conditions associated with the inner ear. In some embodiments, the otic formulations and compositions described herein reduce, reverse and/or ameliorate symptoms of otic diseases or conditions, such as any one of these disclosed herein. In some embodiments, the otic formulations and compositions are used for the treatment and/or prevention of tinnitus. In some embodiment, the tinnitus is caused by or associated with one or more otic diseases and conditions, including but not limited to, sensorineural hearing loss, acute hearing loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma), age-related hearing loss, Meniere’s disease, otitis media, ototoxic drug use, and head and neck injuries.

[0088] Tinnitus

[0089] Tinnitus or “ringing in the ears,” is defined as a perception of sounds without a correlated external auditory stimulus. Estimates indicate that approximately 10% of the US adult population, or 21.4 million people, suffer from tinnitus. The prevalence of tinnitus increases with age, peaking between 60 to 69 years of age. Exposure to recreational, firearm, and occupational noise increases the odds of experiencing tinnitus, and tinnitus is the leading service-related cause of disability among US military veterans. Tinnitus is often a long-term condition. Based on a 2007 US National Health Interview survey, 56% of individuals with tinnitus had symptoms longer than 5 years and 36% had nearly constant symptoms.

[0090] Tinnitus can be distressful, negatively impacting quality of life as affected patients report associated symptoms of insomnia, anxiety, depression, and cognitive difficulties. While some habituate to the sound, approximately 1 in 4 people with tinnitus believe it to be a moderate to severe problem and nearly half will seek medical treatment. At present, however, there is no cure or approved medication. Current management of tinnitus largely focuses on modulation of the patient’s attention and responses to the sensation. Approaches include education and counseling, sound therapy, use of hearing aids, and cognitive behavioral therapy.

[0091] Causes and conditions associated with tinnitus include sensorineural hearing loss, acute hearing loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma), age-related hearing loss, Meniere’s disease, otitis media, ototoxic drug use, and head and neck injuries. In many cases, tinnitus arises as a consequence of cochlear insults and therefore one pharmacotherapy approach to the treatment of tinnitus is directed at normalizing altered neural activity within the cochlea. Excessive activation of NMDA receptors at the level of the inner hair cell synapses with subsequent deafferentation may be a key mechanism of abnormal sensory signaling in tinnitus.

[0092] A number of systemically administered agents have been tested in clinical studies in tinnitus, aimed at influencing the putative imbalance in auditory firing rates produced by cochlear insults. However, efficacy of systemic pharmacotherapies and other interventions for tinnitus has yet to be proven. The presen disclosure recognizes that intratympanic delivery of drugs permits deposition of drugs over the round window membrane, which enables access to the inner ear for more localized delivery to the cochlea and less systemic drug exposure, in some embodiments. Excitotoxicity

[0093] Excitotoxicity refers to the death or damaging of neurons and/or otic hair cells by glutamate and/or similar substances. [0094] Glutamate is the most abundant excitatory neurotransmitter in the central nervous system. Pre-synaptic neurons release glutamate upon stimulation. It flows across the synapse, binds to receptors located on post-synaptic neurons, and activates these neurons. The glutamate receptors include the NMD A, AMP A, and kainate receptors. Glutamate transporters are tasked with removing extracellular glutamate from the synapse. Certain events (e.g. ischemia or stroke) damage the transporters. This results in excess glutamate accumulating in the synapse. Excess glutamate in synapses results in the over-activation of the glutamate receptors.

[0095] The AMPA receptor is activated by the binding of both glutamate and AMPA. Activation of certain isoforms of the AMPA receptor results in the opening of ion channels located in the plasma membrane of the neuron. When the channels open, Na⁺ and Ca²⁺ ions flow into the neuron and K⁺ ions flow out of the neuron.

[0096] The NMDA receptor is activated by the binding of both glutamate or NMDA together with a co-agonist glycine or D-serine. Activation of the NMDA receptor, results in the opening of ion channels located in the plasma membrane of the neuron. However, these channels are blocked by Mg²⁺ ions. Activation of the AMPA receptor results in the expulsion of Mg²⁺ ions from the ion channels into the synapse. When the ion channels open, and the Mg²⁺ ions evacuate the ion channels, Na⁺ and Ca²⁺ ions flow into the neuron, and K⁺ ions flow out of the neuron.

[0097] Excitotoxicity occurs when the NMDA receptor and AMPA receptors are over-activated by the binding of excessive amounts of ligands, for example, abnormal amounts of glutamate. The over-activation of these receptors causes excessive opening of the ion channels under their control. This allows abnormally high levels of Ca²⁺ and Na⁺ to enter the neuron. The influx of these levels of Ca²⁺ and Na⁺ into the neuron causes the neuron to fire more often, resulting in a rapid buildup of free radicals and inflammatory compounds within the cell. The free radicals eventually damage the mitochondria, depleting the cell’s energy stores. Furthermore, excess levels of Ca²⁺ and Na⁺ ions activate excess levels of enzymes including, but not limited to, phospholipases, endonucleases, and proteases. The over-activation of these enzymes results in damage to the cytoskeleton, plasma membrane, mitochondria, and DNA of the sensory neuron.

Local Otic Administration

[0098] Also provided herein are methods, formulations, and compositions for local delivery of therapeutic agents (otic agents) to auris externa, auris media, and/or auris interna structures. In some embodiments, local delivery of the therapeutic agent (otic agent) overcomes the toxic and attendant side effects of systemic delivery. In some embodiments, access to the vestibular and cochlear apparatus is through the auris media and includes the round window membrane, the oval window/stapes footplate, the annular ligament and through the otic capsule/temporal bone.

[0099] Provided herein, in certain embodiments, are otic formulations and compositions that remain in contact with the target auditory surfaces (e.g., the round window) for extended periods of time. In some embodiments, the otic formulations and compositions further comprise mucoadhesives that allow the otic formulations to adhere to otic mucosal surfaces. In some instances, the formulations and compositions described herein avoid attenuation of therapeutic benefit due to drainage or leakage of active agents via the eustachian tube.

[00100] In some embodiments, the localized treatment of the auris externa, auris media and/or auris interna affords the use of previously undesired therapeutic agents, including agents with poor PK profiles, poor uptake, low systemic release and/or toxicity issues. In some embodiments, localized targeting of the otic agent formulations and compositions reduces the risk of adverse effects with previously characterized toxic or ineffective therapeutic agents (otic active agents). Accordingly, also contemplated within the scope of the embodiments described herein is the use of active agents and/or agents that have been previously rejected by practitioners because of adverse effects or ineffectiveness of the therapeutic agent (otic agent).

[00101] In some embodiments, specifically targeting the auris externa, auris media and/or auris interna structures avoids the adverse side effects usually associated with systemic treatment. In some embodiments, the otic formulations and compositions described herein are controlled release therapeutic agent formulations (e.g., immunomodulating agent or auris pressure modulator formulation) and compositions that treat otic disorders by providing a constant, variable and/or extended source of a therapeutic agent (otic agent) to the individual or patient suffering from an otic disorder, thereby reducing or eliminating the variability of treatment. Accordingly, one embodiment disclosed herein is to provide a formulation or composition that enables at least one therapeutic agent (otic agent) to be released in therapeutically effective doses either at variable or constant rates such as to ensure a continuous release of the at least one therapeutic agent (otic agent). In some embodiments, the therapeutic agents (otic agents) disclosed herein are administered as an immediate release formulation or composition. In other embodiments, the therapeutic agents (otic agents) are administered as a controlled release formulation, released either continuously or in a pulsatile manner, or variants of both. In still other embodiments, the therapeutic agent (otic agent) formulation or composition is administered as both an immediate release and controlled release formulation or composition, released either continuously or in a pulsatile manner, or variants of both.

[00102] In addition, the otic compositions or formulations included herein also optionally include carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. Such carriers, adjuvants, and other excipients are compatible with the environment in the auris externa, auris media and/or auris interna. Accordingly, specifically contemplated are carriers, adjuvants and excipients that lack ototoxicity or are minimally ototoxic in order to allow effective treatment of the otic disorders contemplated herein with minimal side effects in the targeted regions or areas. To prevent ototoxicity, otic compositions or formulations disclosed herein are optionally targeted to distinct regions of the auris externa, auris media and/or auris interna, including but not limited to the tympanic cavity, vestibular bony and membranous labyrinths, cochlear bony and membranous labyrinths and other anatomical or physiological structures located within the auris interna.

Sustained Release

[00103] Provided herein are otic formulations and compositions suitable for the treatment of otic condition, disease or disorder (e.g., outer, middle and/or inner ear disorders) described herein, comprising administration of a therapeutic agent (otic agent) described herein to an individual or patient in need thereof. The formulations and compositions described herein are suitable for the treatment of any disease described herein. In some instances, the treatment is long-term treatment for chronic recurring disease. In some instances, the treatment is prophylactic administration of an otic formulation described herein for the treatment of any otic disease or disorder described herein. In some instances, prophylactic administration avoids occurrence of disease in individuals suspected of having a disease or in individuals genetically predisposed to an otic disease or disorder. In some instances the treatment is preventive maintenance therapy. In some instances, preventive maintenance therapy avoids recurrence of a disease.

[00104] In some instances, because of their otic compatibility and improved sterility, the otic formulations and compositions described herein are safe for long-term administration. In some embodiments, the otic formulations and compositions described herein have very low ototoxicity. [00105] In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least one day, three days, five days, one week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, or a year. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least three days. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least five days. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least one week. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least two weeks. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least three weeks. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least a month. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least two months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least three months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least four months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least five months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least six months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of at least a year.

[00106] In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about a day, three days, five days, one week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, or a year. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about three days. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about five days. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about one week. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent for a period of about two weeks. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about three weeks. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about a month. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about two months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about three months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about four months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about five months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about six months. In some embodiments, the otic formulations and compositions described herein provide a steady sustained release of a therapeutic agent (otic agent) for a period of about a year.

[00107] In one aspect, provided herein are controlled release compositions and formulations to treat and/or prevent diseases or conditions associated with the ear. In some instances, these diseases or conditions associated with the ear include the outer, the middle ear and/or inner ear. Such otic diseases or conditions include ceruminosis or ceruminosis is associated with a disease or condition. In some embodiments, the disease or condition is tinnitus.

Gacyclidine

[00108] In some embodiments, the otic formulations and compositions described herein comprises an NMDA receptor antagonist, such as gacyclidien. In some embodiments, the gacyclidine in the otic formulation is in free base form. In some embodiments, the gacyclidine in the otic formulation is in the form of a pharmaceutically acceptable salt of gacyclidne. Pharmaceutical agents that are used in conjunction with the formulations and compositions disclosed herein include agents that ameliorate or lessen otic disorders, including auris interna disorders, and their attendant symptoms, which include but are not limited to tinnitus. Otic disorders have many causes and include infection, injury, inflammation, tumors and adverse response to drugs or other chemical agents that are responsive to the pharmaceutical agents disclosed herein. In some embodiments, pharmaceutically active metabolites, salts, polymorphs, prodrugs, analogues, and derivatives of the otic agents disclosed herein are used in the formulations.

Triglyceride Formulations

[00109] Provided herein are otic formulations and compositions comprising triglycerides. Triglycerides are esters derived from glycerol and three fatty acids. In some instances, these fatty acids are saturated fatty acids, unsaturated fatty acids, or a combination thereof. Provided herein in one aspect, is an otic formulation or a composition comprising a therapeutic agent, or pharmaceutically acceptable prodrug or salt thereof; and triglycerides comprising medium chain fatty acids; wherein the triglycerides are present in an amount that is sufficient to stabilize the therapeutic agent for injection into the ear, and wherein the otic pharmaceutical formulation or composition comprises at least about 50% by weight of the triglycerides.

[00110] In some instances, these triglycerides are medium chain triglycerides (MCTs). In some embodiments, these triglycerides comprise medium chain fatty acids.

[00111] In some embodiments, the triglycerides are derived from glycerol and medium chain fatty acids. In some embodiments, each medium chain fatty acid independently comprises 6 to 12 carbon atoms in the carbon chain. In some embodiments, each medium chain fatty acid independently comprises 8 to 12 carbon atoms in the carbon chain. In some embodiments, each medium chain fatty acid independently comprises 6, 7, 8, 9, 10, 11, or 12 carbon atoms in the carbon chain. In some embodiments, each medium chain fatty acid independently comprises 8 or 10 carbon atoms in the carbon chain. In some embodiments, the medium chain fatty acids are caproic acid (hexanoic acid), enanthic acid (heptanoic acid), caprylic acid (octanoic acid), pelargonic acid (nonanoic acid), capric acid (decanoic acid), undecylenic acid (undec- 10-enoic acid), lauric acid (dodecanoic acid), or a combination thereof. In some embodiments, the medium chain faty acids are caprylic acid (octanoic acid), capric acid (decanoic acid), or a combination thereof.

[00112] In some embodiments, the triglycerides comprising medium chain faty acids are balassee oil, coconut oil, cohune oil, palm kernel oil, tucum oil, or combinations thereof. In some embodiments, the triglycerides comprising medium chain faty acids are balassee oil. In some embodiments, the triglycerides comprising medium chain faty acids are coconut oil. In some embodiments, the triglycerides comprising medium chain faty acids are cohune oil. In some embodiments, the triglycerides comprising medium chain faty acids are palm kernel oil. In some embodiments, the triglycerides comprising medium chain faty acids are tucum oil.

[00113] In some embodiments, the otic pharmaceutical formulation has triglycerides in an amount that is sufficient to stabilize the therapeutic agent for injection into the ear. In some embodiments, the otic pharmaceutical formulation has triglycerides in an amount that is sufficient to provide sufficient retention time in the ear. In some embodiments, the ear is the outer ear, middle ear, or inner ear. In some embodiments, the otic pharmaceutical formulation has triglycerides in an amount that is sufficient to provide sustained release of the therapeutic agent. In some embodiments, the triglycerides are present in an amount that is sufficient to allow delivery of the formulation via a narrow gauge needle.

[00114] In some embodiments, the otic pharmaceutical formulation comprises between about 50% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 55% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 60% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 65% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 70% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 75% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 80% to about 99.9% by the weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 85% to about 99.9% by the weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 99.9% by the weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 95% to about 99.9% by the weight of the triglycerides.

[00115] In some embodiments, the otic pharmaceutical formulation comprises between about 50% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 55% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 60% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 65% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 70% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 75% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 80% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 85% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 99.99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 95% to about 99.99% by weight of the triglycerides.

[00116] In some embodiments, the otic pharmaceutical formulation comprises between about 50% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 55% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 60% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 65% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 70% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 75% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 80% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 85% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 95% by weight of the triglycerides.

[00117] In some embodiments, the otic pharmaceutical formulation comprises between about 50% to about 55% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 55% to about 60% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 60% to about 65% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 65% to about 70% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 70% to about 75% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 75% to about 80% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 80% to about 85% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 85% to about 90% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 95% to about 99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 95% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 95% to about 99.99% by weight of the triglycerides.

[00118] In some embodiments, the otic pharmaceutical formulation comprises between about 50% to about 60% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 60% to about 70% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 70% to about 80% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 80% to about 90% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 99% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 99.9% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises between about 90% to about 99.99% by weight of the triglycerides.

[00119] In some embodiments, the otic pharmaceutical formulation comprises about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% , or about 99% by weight of the triglycerides.

[00120] In some embodiments, the otic pharmaceutical formulation comprises about 50% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 51% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 52% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 53% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 54% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 55% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 56% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 57% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 58% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 59% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 60% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 61% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 62% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 63% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 64% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 65% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 66% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 67% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 68% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 69% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 70% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 71% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 72% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 73% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 74% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 75% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 76% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 77% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 78% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 79% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 80% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 81% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 82% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 83% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 84% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 85% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 86% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 87% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 88% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 89% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 90% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 91% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 92% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 93% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 94% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 95% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 96% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 97% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 98% by weight of the triglycerides. In some embodiments, the otic pharmaceutical formulation comprises about 99% by weight of the triglycerides.

[00121] In some embodiments, the triglycerides in any one of the otic formulations and compositions described herein are replaced with at least one of the following components in the corresponding amounts of triglyceride in the formulation or composition disclosed herein: mineral oil or any corresponding higher alkanes; Vaseline (petroleum jelly); silicone oil (polydimethylsiloxane) in different molecular weights; beeswax dissolved in any of the oils disclosed herein.

[00122] In some embodiments, the otic formulation or composition further comprises at least one viscosity modulating agent. In some embodiments, the at least one viscosity modulating agent is silicon dioxide, povidone, carbomer, poloxamer, or a combination thereof. In some embodiments, the viscosity modulating agent is silicon dioxide. In some embodiments, the viscosity modulating agent is povidone. In some embodiments, the viscosity modulating agent is carbomer. In some embodiments, the viscosity modulating agent is poloxamer. In some embodiments, the viscosity modulating agents are silicon dioxide and povidone. In some embodiments, the viscosity modulating agents are silicon dioxide and carbomer. In some embodiments, the viscosity modulating agents are silicon dioxide and poloxamer. In some embodiments, the poloxamer is P407.

[00123] In some embodiments, the viscosity modulating agent is silicon dioxide. In some embodiments, the viscosity modulating agent is a polymer, such as povidone, carbomer, or poloxamer. In some embodiments, the viscosity modulating agent is a polysaccharide, such as dextran or alginate. In some embodiments, the viscosity modulating agent is cellulose-based, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxy ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), and noncrystalline cellulose. In some embodiments, the viscosity modulating agent is polyvinyl alcohol (PVA). In some embodiments, the viscosity modulating agent is polyethylene glycol (PEG) based. [00124] In some embodiments, the otic formulation or composition comprises between about 0.01% to about 40% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises between about 0.01% to about 35% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises between about 0.01% to about 30% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises between about 0.01% to about 25% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises between about 0.01% to about 20% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises between about 0.01% to about 15% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises between about 0.01% to about 10% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.01% to about 7% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises comprises between about 0.01% to about 5% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises comprises between about 0.01% to about 3% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises comprises between about 0.01% to about 2% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises comprises about 0.01% to about 1% by weight of the viscosity modulating agent(s).

[00125] In some embodiments, the otic formulation or composition comprises about 0.01% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.02% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.03% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.04% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.05% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.06% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.07% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.08% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.09% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0. 1% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.2% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.3% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.4% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.5% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.6% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.7% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.8% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 0.9% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 1% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 2% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 3% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 4% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 5% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 6% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 7% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 8% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 9% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 10% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 11% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 12% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 13% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 14% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 15% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 16% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 17% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 18% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 19% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 20% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 25% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 30% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 35% by weight of the viscosity modulating agent(s). In some embodiments, the otic formulation or composition comprises about 40% by weight of the viscosity modulating agent(s).

Viscosity

[00126] In some embodiments, the otic formulations or compositions described herein are thickened liquid formulations or compositions. The otic formulations or compositions described herein are suspension formulations or compositions. The otic formulations or compositions described herein are solution formulations or compositions. In some embodiments, the otic formulations or compositions have greater viscosity than an aqueous liquid composition. In some embodiments, the formulation or composition has a viscosity of greater than 1 cP (centipoise). In some embodiments, the formulation or composition has a viscosity of at least about 10 cP, about 20 cP, about 30 cP, about 40 cP, about 50 cP, about 60 cP, about 70 cP, about 80 cP, about 90 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, about 600 cP, about 700 cP, about 800 cP, about 900 cP, about 1,000 cP, about 2,000 cP, about 3,000 cP, about 4,000 cP, about 5,000 cP, about 6,000 cP, about 7,000 cP, about 8,000 cP, about 9,000 cP, about 10,000 cP, about 15,000 cP, or about 20,000 cP. In some embodiments, the formulation or composition has a viscosity of less than about 1,000 cP. In some embodiments, the formulation or composition has a viscosity of less than about 10,000 cP. In some embodiments, the formulation or composition has a viscosity of about 2 cP to about 250,000 cP, about 2 cP to about 100,000 cP, about 2 cP to about 50,000 cP, about 2 cP to about 25,000 cP, about 2 cP to about 10,000 cP, about 2 cP to about 5,000 cP, about 2 cP to about 1,000 cP, about 2 cP to about 500 cP, about 2 cP to about 250 cP, about 2 cP to about 100 cP, about 2 cP to about 90 cP, about 2 cP to about 80 cP, about 2 cP to about 70 cP, about 2 cP to about 60 cP, about 2 cP to about 50 cP, about 2 cP to about 40 cP, about 2 cP to about 30 cP, about 2 cP to about 20 cP, or about 2 cP to about 10 cP. In some embodiments, the liquid formulation or composition has a viscosity of about 2 cP, about 5 cP, about 10 cP, about 20 cP, about 30 cP, about 40 cP, about 50 cP, about 60 cP, about 70 cP, about 80 cP, about 90 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, about 600 cP, about 700 cP, about 800 cP, about 900 cP, about 1,000 cP, about 5,000 cP, about 10,000 cP, about 20,000 cP, about 50,000 cP, about 100,000 cP, or about 250,000 cP.

[00127] In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 20,000 cP. In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 10,000 cP. In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 5,000 cP. In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 1,000 cP. In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 500 cP. In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 250 cP. In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 100 cP. In some embodiments, the formulation or composition has a viscosity between about 10 cP to about 50 cP.

[00128] In some embodiments, the otic composition or formulation is free or substantially free of water. In some embodiments, the otic composition or formulation comprises less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% by weight of water. In some embodiments, the otic composition or formulation comprises less than 0.5% by weight of water. In some embodiments, the otic composition or formulation comprises less than 0.1% by weight of water. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 50, 20, 10, or 5 ppm of water. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 1 ppm of water.

[00129] In some embodiments, the otic composition or formulation is free or substantially free of poloxamer. In some embodiments, the otic composition or formulation is free or substantially free of poloxamer 407. In some embodiments, the otic composition or formulation is free or substantially free of C1-C6 alcohols or C1-C6 glycols. In some embodiments, the otic composition or formulation is free or substantially free of C1-C6 alcohols. In some embodiments, the otic composition or formulation is free or substantially free of C1-C6 glycols.

[00130] By way of non-limiting example, the use of the following commonly used solvents should be limited, reduced or eliminated when formulating agents for administration to the ear: alcohols, propylene glycol, and cyclohexane. Thus, in some embodiments, an otic composition or formulation disclosed herein is free or substantially free of alcohols, propylene glycol, and cyclohexane. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 50 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 25 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 20 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 10 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 5 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, an otic composition or formulation disclosed herein comprises less than about 1 ppm of each of alcohols, propylene glycol, and cyclohexane.

General Methods of Sterilization

[00131] The environment of the inner ear is an isolated environment. The endolymph and the perilymph are static fluids and are not in contiguous contact with the circulatory system. The blood - labyrinth - barrier (BLB), which includes a blood-endolymph barrier and a bloodperilymph barrier, consists of tight junctions between specialized epithelial cells in the labyrinth spaces (i.e., the vestibular and cochlear spaces). The presence of the BLB limits delivery of active agents (e.g., immunomodulators, aural pressure modulators, antimicrobials) to the isolated microenvironment of the inner ear. Anris hair cells are bathed in endolymphatic or perilymphatic fluids and cochlear recycling of potassium ions is important for hair cell function. When the inner ear is infected, there is an influx of leukocytes and/or immunoglobins (e.g. in response to a microbial infection) into the endolymph and/or the perilymph and the delicate ionic composition of inner ear fluids is upset by the influx of leukocytes and/or immunoglobins. In certain instances, a change in the ionic composition of inner ear fluids results in hearing loss, loss of balance and/or ossification of auditory structures. In certain instances, even trace amounts of pyrogens and/or microbes trigger infections and related physiological changes in the isolated microenvironment of the inner ear.

[00132] In one aspect, provided herein are otic formulations or compositions that are sterilized with stringent sterility requirements and are suitable for administration to the middle and/or inner ear. In some embodiments, the otic formulations or compositions described herein are auris compatible compositions. In some embodiment, the otic formulations or compostions are substantially free of pyrogens and/or microbes.

[00133] Provided herein are otic formulations or compositions that ameliorate or lessen otic disorders described herein. Further provided herein are methods comprising the administration of said otic formulations or compositions. In some embodiments, the formulations or compositions are sterilized. Included within the embodiments disclosed herein are means and processes for sterilization of a pharmaceutical composition disclosed herein for use in humans. The goal is to provide a safe pharmaceutical product, relatively free of infection causing micro-organisms. The U. S. Food and Drug Administration has provided regulatory guidance in the publication “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing” available at: http://www.fda.gov/cder/guidance/5882fhl.htm, which is incorporated herein by reference in its entirety. No specific guidelines are available for safe pharmaceutical products for treatment of the inner ear.

[00134] As used herein, sterilization means a process used to destroy or remove microorganisms that are present in a product or packaging. Any suitable method available for sterilization of objects and formulations or compositions is used. Available methods for the inactivation of microorganisms include, but are not limited to, the application of extreme heat, lethal chemicals, or gamma radiation. In some embodiments is a process for the preparation of an otic therapeutic formulation comprising subjecting the formulation to a sterilization method selected from heat sterilization, chemical sterilization, radiation sterilization or filtration sterilization. The method used depends largely upon the nature of the device or composition to be sterilized. Detailed descriptions of many methods of sterilization are given in Chapter 40 of Remington: The Science and Practice of Pharmacy published by Lippincott, Williams & Wilkins, and is incorporated by reference with respect to this subject matter. Sterilization by Heat

[00135] Many methods are available for sterilization by the application of extreme heat. One method is through the use of a saturated steam autoclave. In this method, saturated steam at a temperature of at least 121 °C is allowed to contact the object to be sterilized. The transfer of heat is either directly to the microorganism, in the case of an object to be sterilized, or indirectly to the microorganism by heating the bulk of an aqueous solution to be sterilized. This method is widely practiced as it allows flexibility, safety and economy in the sterilization process.

[00136] Dry heat sterilization is a method which is used to kill microorganisms and perform depyrogenation at elevated temperatures. This process takes place in an apparatus suitable for heating HEPA-filtered microorganism-free air to temperatures of at least 130-180 °C for the sterilization process and to temperatures of at least 230-250 °C for the depyrogenation process. Water to reconstitute concentrated or powdered formulations is also sterilized by autoclave. Chemical Sterilization

[00137] Chemical sterilization methods are an alternative for products that do not withstand the extremes of heat sterilization. In this method, a variety of gases and vapors with germicidal properties, such as ethylene oxide, chlorine dioxide, formaldehyde or ozone are used as the anti- apoptotic agents. The germicidal activity of ethylene oxide, for example, arises from its ability to serve as a reactive alkylating agent. Thus, the sterilization process requires the ethylene oxide vapors to make direct contact with the product to be sterilized.

Radiation Sterilization

[00138] One advantage of radiation sterilization is the ability to sterilize many types of products without heat degradation or other damage. The radiation commonly employed is beta radiation or alternatively, gamma radiation from a ⁶⁰Co source. The penetrating ability of gamma radiation allows its use in the sterilization of many product types, including solutions, compositions and heterogeneous mixtures. The germicidal effects of irradiation arise from the interaction of gamma radiation with biological macromolecules. This interaction generates charged species and free radicals. Subsequent chemical reactions, such as rearrangements and cross-linking processes, result in the loss of normal function for these biological macromolecules. The formulations described herein are also optionally sterilized using beta irradiation.

Filtration

[00139] Filtration sterilization is a method used to remove but not destroy microorganisms from solutions. Membrane filters are used to filter heat-sensitive solutions. Such filters are thin, strong, homogenous polymers of mixed cellulosic esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or polytetrafluoroethylene (PTFE) and have pore sizes ranging from 0.1 to 0.22 □m. Solutions of various characteristics are optionally filtered using different filter membranes. For example, PVF and PTFE membranes are well suited to filtering organic solvents while aqueous solutions are filtered through PVF or MCE membranes. Filter apparatus are available for use on many scales ranging from the single point-of-use disposable filter attached to a syringe up to commercial scale filters for use in manufacturing plants. The membrane filters are sterilized by autoclave or chemical sterilization. Validation of membrane filtration systems is performed following standardized protocols (Microbiological Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3. Washington, D.C: Health Industry Manufacturers Association, 1981) and involve challenging the membrane filter with a known quantity (ca. 10^7/cm²) of unusually small microorganisms, such as Brevundimonas diminuta (ATCC 19146).

[00140] In certain embodiments, the active ingredients are dissolved in a suitable vehicle (e.g. a buffer) and sterilized separately (e.g. by heat treatment, filtration, gamma radiation); the remaining excipients are sterilized in a separate step by a suitable method (e.g. filtration and/or irradiation of a cooled mixture of excipients); the two solutions that were separately sterilized are then mixed aseptically to provide a final otic formulation or composition.

Microorganisms

[00141] Provided herein are otic formulations or compositions that ameliorate or lessen otic disorders described herein. Further provided herein are methods comprising the administration of said otic formulations or compositions. In some embodiments, the formulations or compositions are substantially free of microorganisms. Acceptable sterility levels are based on applicable standards that define therapeutically acceptable otic formulations or compositions, including but not limited to United States Pharmacopeia Chapters <1111> et seq. For example, acceptable sterility levels include 10 colony forming units (cfu) per gram of formulation or composition, 50 cfu per gram of formulation or composition, 100 cfu per gram of formulation or composition, 500 cfu per gram of formulation or composition or 1000 cfu per gram of formulation or composition. In addition, acceptable sterility levels include the exclusion of specified objectionable microbiological agents. By way of example, specified objectionable microbiological agents include but are not limited to Escherichia coli (E. coli), Salmonella sp., Pseudomonas aeruginosa (P. aeruginosa) and/or other specific microbial agents.

[00142] In certain embodiments, any otic formulation or composition described herein has less than about 60 colony forming units (CFU), less than about 50 colony forming units, less than about 40 colony forming units, or less than about 30 colony forming units of microbial agents per gram of formulation. In certain embodiments, the otic formulations or compositions described herein are formulated to be isotonic with the endolymph and/or the perilymph.

Endotoxins

[00143] Provided herein are otic formulations or compositions that ameliorate or lessen otic disorders described herein. Further provided herein are methods comprising the administration of said otic formulations or compositions. In some embodiments, the otic formulations or compositions are substantially free of endotoxins. An additional aspect of the sterilization process is the removal of by-products from the killing of microorganisms (hereinafter, “Product”). The process of depyrogenation removes pyrogens from the sample. Pyrogens are endotoxins or exotoxins which induce an immune response. An example of an endotoxin is the lipopolysaccharide (LPS) molecule found in the cell wall of gram-negative bacteria. While sterilization procedures such as autoclaving or treatment with ethylene oxide kill the bacteria, the LPS residue induces a proinflammatory immune response, such as septic shock. Because the molecular size of endotoxins varies widely, the presence of endotoxins is expressed in “endotoxin units” (EU). One EU is equivalent to 100 picograms of E. coli LPS. In some embodiments, the otic formulation or composition has less than about 5 EU/kg of formulation. In other embodiments, the otic therapeutic formulation or composition has less than about 4 EU/kg of formulation. In additional embodiments, the otic formulation or composition has less than about 3 EU/kg of formulation. In some embodiments, the otic formulation or composition has less than about 5 EU/kg Product. In other embodiments, the otic formulation or composition has less than about 1 EU/kg Product. In additional embodiments, the otic formulation or composition has less than about 0.2 EU/kg Product. In some embodiments, the otic formulation or composition has less than about 5 EU/g of unit or Product. In other embodiments, the otic formulation or composition has less than about 4 EU/ g of unit or Product. In additional embodiments, the otic formulation or composition has less than about 3 EU/g of unit or Product. In some embodiments, the otic formulation or composition has less than about 5 EU/mg of unit or Product. In other embodiments, the otic formulation or composition has less than about 4 EU/ mg of unit or Product. In additional embodiments, the otic formulation or composition has less than about 3 EU/mg of unit or Product. In certain embodiments, otic formulations or compositions described herein contain from about 1 to about 5 EU/mL of formulation or composition. In certain embodiments, otic formulations or compositions described herein contain from about 2 to about 5 EU/mL of formulation or composition, from about 3 to about 5 EU/mL of formulation or composition, or from about 4 to about 5 EU/mL of formulation or composition.

[00144] In certain embodiments, otic formulations or compositions described herein contain lower endotoxin levels (e.g. < 0.5 EU/mL of formulation or composition) when compared to conventionally acceptable endotoxin levels (e.g., 0.5 EU/mL of formulation or composition). In some embodiments, the otic formulation or composition has less than about 0.5 EU/mL of formulation or composition. In other embodiments, the otic formulation or composition has less than about 0.4 EU/mL of formulation or composition. In additional embodiments, the otic formulation or composition has less than about 0.2 EU/mL of formulation or composition.

Osmolarty/Osmolarity

[00145] In general, the endolymph has a higher osmolality than the perilymph. For example, the endolymph has an osmolality of about 304 mOsm/kg H2O while the perilymph has an osmolality of about 294 mOsm/kg H2O. In some embodiments, formulations or compositions described herein are formulated to provide an osmolarity of about 250 to about 320 mM (osmolality of about 250 to about 320 mOsm/kg H2O) ; and preferably about 270 to about 320 mM (osmolality of about 270 to about 320 mOsm/kg H2O ). In specific embodiments, osmolarity/osmolality of the present formulations or compositions is adjusted, for example, by the use of appropriate salt concentrations (e.g., concentration of potassium salts) or the use of tonicity agents which renders the formulations or compositions endolymph-compatible and/or perilymph-compatible (i.e. isotonic with the endolymph and/or perilymph. In some instances, the endolymph-compatible and/or perilymph-compatible formulations or compositions described herein cause minimal disturbance to the environment of the inner ear and cause minimum discomfort (e.g., vertigo and/or nausea) to a mammal upon administration.

[00146] In some embodiments, any formulation or composition described herein is isotonic with the perilymph. Isotonic formulations or compositions are provided by the addition of a tonicity agent. Suitable tonicity agents include, but are not limited to any pharmaceutically acceptable sugar, salt or any combinations or mixtures thereof, such as, but not limited to dextrose, glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes.

[00147] Useful otic formulations or compositions include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[00148] In further embodiments, the tonicity agents are present in an amount as to provide a final osmolality of an otic formulation or composition of about 100 mOsm/kg to about 500 mOsm/kg, from about 200 mOsm/kg to about 400 mOsm/kg, from about 250 mOsm/kg to about 350 mOsm/kg or from about 280 mOsm/kg to about 320 mOsm/kg. In some embodiments, the formulations or compositions described herein have a osmolarity of about 100 mOsm/L to about 500 mOsm/L, about 200 mOsm/L to about 400 mOsm/L, about 250 mOsm/L to about 350 mOsm/L, or about 280 mOsm/L to about 320 mOsm/L. In some embodiments, the osmolarity of any formulation or composition described herein is designed to be isotonic with the targeted otic structure (e.g., endolymph, perilymph or the like).

Carriers

[00149] Suitable carriers for use in a formulation or composition described herein include, but are not limited to, any pharmaceutically acceptable solvent. For example, suitable solvents include polyalkylene glycols such as, but not limited to, polyethylene glycol (PEG) and any combinations or mixtures thereof. In other embodiments, the base is a combination of a pharmaceutically acceptable surfactant and solvent.

[00150] In some embodiments, other excipients include, sodium stearyl fumarate, diethanolamine cetyl sulfate, isostearate, polyethoxylated castor oil, benzalkonium chloride, nonoxyl 10, octoxynol 9, sodium lauryl sulfate, sorbitan esters (sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan dioleate, sorbitan sesqui-isostearate, sorbitan sesquistearate, sorbitan tri-isostearate), lecithins, phospholipids, phosphatidyl cholines (c8-cl8), phosphatidylethanolamines (c8-cl8), phosphatidylglycerols (c8-cl8), pharmaceutical acceptable salts thereof and combinations or mixtures thereof.

[00151] In further embodiments, the carrier is polyethylene glycol. Polyethylene glycol is available in many different grades having varying molecular weights. For example, polyethylene glycol is available as PEG 200; PEG 300; PEG 400; PEG 540 (blend); PEG 600; PEG 900; PEG 1000; PEG 1450; PEG 1540; PEG 2000; PEG 3000; PEG 3350; PEG 4000; PEG 4600 and PEG 8000. For purposes of the present disclosure, all grades of polyethylene glycol are contemplated for use in preparation of a formulation described herein. In some embodiments the polyethylene glycol used to prepare a formulation described herein is PEG 300.

[00152] In other embodiments, the carrier is a polysorbate. Polysorbates are nonionic surfactants of sorbitan esters. Polysorbates useful in the present disclosure include, but are not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (Tween 80) and any combinations or mixtures thereof. In further embodiments, polysorbate 80 is utilized as the pharmaceutically acceptable carrier.

[00153] In some embodiments, the percentage of active pharmaceutical ingredient is varied between about 0.01% and about 20%, between about 0.01% and about 10%, between about 0.01% and about 5% or more of the weight or volume of the total pharmaceutical formulation or composition. In some embodiments, the amount of the compound(s) in each therapeutically useful formulation or composition is prepared in such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations are contemplated herein and the preparation of such pharmaceutical formulations or compositions is presented herein.

Modes of Otic Administration

[00154] In some embodiments, the auris formulations or compositions described herein are administered into the ear canal, or in the vestibule of the ear. Access to, for example, the vestibular and cochlear apparatus occurs through the auris media including the round window membrane, the oval window/stapes footplate, the annular ligament and through the otic capsule/temporal bone. In some embodiments, otic administration of the formulations or compositions described herein avoids toxicity associated with systemic administration (e.g., hepatotoxicity, cardiotoxicity, gastrointestinal side effects, and renal toxicity) of the active agents. In some instances, localized administration in the ear allows an active agent to reach a target organ (e.g., inner ear) in the absence of systemic accumulation of the active agent. In some instances, local administration to the ear provides a higher therapeutic index for an active agent that would otherwise have dose-limiting systemic toxicity.

[00155] Provided herein are modes of treatment for otic formulations or compositions that ameliorate or lessen otic disorders described herein. Drugs delivered to the inner ear have been administered systemically via oral, intravenous or intramuscular routes. However, systemic administration for pathologies local to the inner ear increases the likelihood of systemic toxicities and adverse side effects and creates a non-productive distribution of drug in which high levels of drug are found in the serum and correspondingly lower levels are found at the inner ear.

[00156] Provided herein are methods comprising the administration of said auris formulations or compositions on or near the round window membrane via intratympanic injection. In some embodiments, a composition disclosed herein is administered on or near the round window or the crista fenestrae cochleae through entry via a post-auricular incision and surgical manipulation into or near the round window or the crista fenestrae cochleae area. Alternatively, a formulation or composition disclosed herein is applied via syringe and needle, wherein the needle is inserted through the tympanic membrane and guided to the area of the round window or crista fenestrae cochleae. In some embodiments, a formulation or composition disclosed herein is then deposited on or near the round window or crista fenestrae cochleae for localized treatment. In other embodiments, a formulation or composition disclosed herein is applied via microcathethers implanted into the patient, and in yet further embodiments a composition disclosed herein is administered via a pump device onto or near the round window membrane. In still further embodiments, a formulation or composition disclosed herein is applied at or near the round window membrane via a microinjection device. In yet other embodiments, a formulation or composition disclosed herein is applied in the tympanic cavity. In some embodiments, a formulation or composition disclosed herein is applied on the tympanic membrane. In still other embodiments, a formulation or composition disclosed herein is applied onto or in the auditory canal. The formulations or compositions described herein, and modes of administration thereof, are also applicable to methods of direct instillation or perfusion of the inner ear compartments. Thus, the formulations or compositions described herein are useful in surgical procedures including, by way of non-limiting examples, cochleostomy, labyrinthotomy, mastoidectomy, stapedectomy, endolymphatic sacculotomy or the like.

Intratympanic Injections

[00157] In some embodiments, a surgical microscope is used to visualize the tympanic membrane. In some embodiments, the tympanic membrane is anesthetized by any suitable method (e.g., use of phenol, lidocaine, and xylocaine). In some embodiments, the anterior-superior and posterior-inferior quadrants of the tympanic membrane are anesthetized.

[00158] In some embodiments, a puncture is made in the tympanic membrane to vent any gases behind the tympanic membrane. In some embodiments, a puncture is made in the anterior-superior quadrant of the tympanic membrane to vent any gases behind the tympanic membrane. In some embodiments, the puncture is made with a needle (e.g., a 25 gauge needle). In some embodiments, the puncture is made with a laser (e.g., a CO2 laser). In one embodiment the delivery system is a syringe and needle apparatus that is capable of piercing the tympanic membrane and directly accessing the round window membrane or crista fenestrae cochleae of the auris interna.

[00159] In one embodiment, the needle is a hypodermic needle used for instant delivery of the formulation. The hypodermic needle is a single use needle or a disposable needle. In some embodiments, a syringe is used for delivery of the pharmaceutically acceptable otic agentcontaining compositions as disclosed herein wherein the syringe has a press-fit (Luer) or twist-on (Luer-lock) fitting. In one embodiment, the syringe is a hypodermic syringe. In another embodiment, the syringe is made of plastic or glass. In yet another embodiment, the hypodermic syringe is a single use syringe. In a further embodiment, the glass syringe is capable of being sterilized. In yet a further embodiment, the sterilization occurs through an autoclave. In another embodiment, the syringe comprises a cylindrical syringe body wherein the formulation is stored before use. In other embodiments, the syringe comprises a cylindrical syringe body wherein the pharmaceutically acceptable otic formulations or compositions as disclosed herein is stored before use which conveniently allows for mixing with a suitable pharmaceutically acceptable buffer. In other embodiments, the syringe contains other excipients, stabilizers, suspending agents, diluents or a combination thereof to stabilize or otherwise stably store the otic agent or other pharmaceutical compounds contained therein.

[00160] In some embodiments, the syringe comprises a cylindrical syringe body wherein the body is compartmentalized in that each compartment is able to store at least one component of the auris-acceptable otic formulation. In a further embodiment, the syringe having a compartmentalized body allows for mixing of the components prior to injection into the auris media or auris interna. In other embodiments, the delivery system comprises multiple syringes, each syringe of the multiple syringes contains at least one component of the formulation such that each component is pre-mixed prior to injection or is mixed subsequent to injection. In a further embodiment, the syringes disclosed herein comprise at least one reservoir wherein the at least one reservoir comprises an otic agent, or a pharmaceutically acceptable buffer, or a viscosity enhancing agent, or a combination thereof. Commercially available injection devices are optionally employed in their simplest form as ready-to-use plastic syringes with a syringe barrel, needle assembly with a needle, plunger with a plunger rod, and holding flange, to perform an intratympanic injection.

[00161] In some embodiments, a needle is used to deliver the formulations or compositions described herein. In some embodiments, a needle punctures the posterior-inferior quadrant of the tympanic membrane. In some embodiments, the needle is a standard gauge needle. In some embodiments, the needle is a narrow gauge needle. In some embodiments, the needle is wider than an 18 gauge needle. In another embodiment, the needle gauge is from about 18 gauge to about 30 gauge. In some embodiments, the needle gauge is from about 20 gauge to about 30 gauge. In some embodiments, the needle gauge is from about 25 gauge to about 30 gauge. In some embodiments, the needle gauge is about 18 gauge, about 19 gauge, about 20 gauge, about 21 gauge, about 22 gauge, about 23 gauge, about 24 gauge, about 25 gauge, about 26 gauge, about 27 gauge, about 28 gauge, about 29 gauge, or about 30 gauge. In a further embodiment, the needle is a 25 gauge needle. Depending upon the thickness or viscosity of a formulation or composition disclosed herein, the gauge level of the syringe or hypodermic needle is varied accordingly. In some embodiments, the formulations or compositions described herein are liquids and are administered via narrow gauge needles or cannulas (e.g., 22 gauge needle, 25 gauge needle, or cannula), minimizing damage to the tympanic membrane upon administration. The formulations or compositions described herein are administered with minimal discomfort to a patient.

[00162] In some embodiments, an otoendoscope (e.g., about 1.7 mm in diameter) is used to visualize the round window membrane. In some embodiments, any obstructions to the round window membrane (e.g., a false round window membrane, a fat plug, fibrous tissue) are removed. [00163] In some embodiments, a formulation or composition disclosed herein is injected onto the round window membrane. In some embodiments, 0.1 to 0.5 cc of a formulation or composition disclosed herein is injected onto the round window membrane.

[00164] In some embodiments, the tympanic membrane puncture is left to heal spontaneously. In some embodiments, a paper patch myringoplasty is performed by a trained physician. In some embodiments, a tympanoplasty is performed by a trained physician. In some embodiments, an individual is advised to avoid water. In some embodiments, a cotton ball soaked in petroleumjelly is utilized as a barrier to water and other environmental agents.

Other Delivery Routes

[00165] In some embodiments, a formulation or composition disclosed herein is administered locally to the outer ear, such as the external auditory canal, the outer surface of the tympanic membrane, or a combination thereof. In some embodiments, the formulations or compositions described herein are not administered through the tympanic membrane.

[00166] In some embodiments, a formulation or composition disclosed herein is administered to the inner ear. In some embodiments, a formulation or composition disclosed herein is administered to the inner ear via an incision in the stapes footplate. In some embodiments, a formulation or composition disclosed herein is administered to the cochlea via a cochleostomy. In some embodiments, a formulation or composition disclosed herein is administered to the vestibular apparatus (e.g., semicircular canals or vestibule).

[00167] In some embodiments, a formulation or composition disclosed herein is applied via syringe and needle. In other embodiments, a formulation or composition disclosed herein is applied via microcatheters implanted into the patient. In some embodiments, a formulation or composition disclosed herein is administered via a pump device. In still further embodiments, a formulation or composition disclosed herein is applied via a microinjection device. In some embodiments, a formulation or composition disclosed herein is administered via a prosthesis, a cochlear implant, a constant infusion pump, or a wick.

Dosage

[00168] In some embodiments, the formulations or compositions described herein have a concentration of active pharmaceutical ingredient between about 1 DM and about 10 DM, between about 1 mM and about 100 mM, between about 0. 1 mM and about 100 mM, between about 0.1 mM and about 100 nM. In some embodiments, the formulations or compositions described herein have a pH and osmolarity as described herein, and have a concentration of active pharmaceutical ingredient between about 0.01 - about 20%, between about 0.01 - about 10%, between about 0.01

- about 7%, between about 0.01 - 5%, between about 0.01 - about 3%, between about 0.01 - about 2% of the active ingredient by weight of the formulation or composition. In some embodiments, the formulations or composition described herein have a pH and osmolarity as described herein, and have a concentration of active pharmaceutical ingredient between about 0. 1

- about 70 mg/mL, between about 1 mg - about 70 mg/mL, between about 1 mg - about 50 mg/mL, between about 1 mg/mL and about 20 mg/mL, between about 1 mg/mL to about 10 mg/mL, between about 1 mg/mL to about 5 mg/mL, or between about 0.5 mg/mL to about 5 mg/mL of the active agent by volume of the formulation or composition.

[00169] In some embodiments, auris formulations or compositions described herein are controlled release formulations, and are administered at reduced dosing frequency compared to the current standard of care. In certain instances, when an auris formulation or composition is administered via intratympanic injection, a reduced frequency of administration alleviates discomfort caused by multiple intratympanic injections in individuals undergoing treatment for a middle and/or inner ear disease, disorder or condition. In certain instances, a reduced frequency of administration of intratympanic injections reduces the risk of permanent damage (e.g., perforation) to the ear drum. In some embodiments, formulations or compositions described herein provide a constant, sustained, extended, delayed or pulsatile rate of release of an active agent into the inner ear environment and thus avoid any variability in drug exposure in treatment of otic disorders.

[00170] The formulations or compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the formulations or compositions are administered to a patient already suffering from a disease, condition or disorder, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition. Amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. [00171] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, but is nevertheless routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02- 50 mg per administration, preferably 1-15 mg per administration. In some embodiments, the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals.

Frequency of administration

[00172] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds is administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[00173] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compounds are given continuously; alternatively, the dose of drug being administered are temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday are from 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[00174] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms in some embodiments.

[00175] In some embodiments, the initial administration is of a particular formulation and the subsequent administration is of a different formulation or active pharmaceutical ingredient.

Kits and Other Articles of Manufacture

[00176] The disclosure also provides kits for preventing, treating or ameliorating the symptoms of a diseases or disorder in a mammal. Such kits generally will comprise one or more of the pharmaceutically acceptable compositions as disclosed herein, and instructions for using the kit. The disclosure also contemplates the use of one or more of the formulations or compositions, in the manufacture of medicaments for treating, abating, reducing, or ameliorating the symptoms of a disease, dysfunction, or disorder in a mammal, such as a human that has, is suspected of having, or at risk for developing an auris interna disorder.

[00177] In some embodiments, a kit disclosed herein comprises a needle that penetrates a tympanic membrane and/or a round window. In some embodiments, a kit disclosed herein further comprises a hydrogel with a penetration enhancer (e.g., an alkylglycoside and/or a saccharide alkyl ester).

[00178] In some embodiments, kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the containers are formed from a variety of materials such as glass or plastic.

[00179] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products presented herein. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations or compositions of the compounds and formulations or compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by extended release administration of a therapeutic agent to the auris interna.

[00180] In some embodiments, a kit will typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a formulation or composition described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[00181] In a further embodiment, a label is on or associated with the container. In yet a further embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In other embodiments a label is used to indicate that the contents are to be used for a specific therapeutic application. In yet another embodiment, a label also indicates directions for use of the contents, such as in the methods described herein.

[00182] In certain embodiments, the pharmaceutical formulations or compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. In another embodiment, the pack for example contains metal or plastic foil, such as a blister pack. In a further embodiment, the pack or dispenser device is accompanied by instructions for administration. In yet a further embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. In another embodiment, such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In yet another embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Non-Limiting Embodiments

[00183] Below are some non-limiting embodiments of the present disclosure.

1. A method of treating tinnitus in a human subject, comprising intratypamically administering an otic formulation to the human subject, wherein the otic composition comprises from about 0.01 wt% to about 10 wt% gacyclidine and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of gacycldine into the inner ear.

2. The method of Embodiment 1, wherein the gacyclidine is in free base form.

3. The method of Embodiment 1 or 2, wherein the composition comprises from 0.05mg to 0.70mg gacyclidine.

4. The method of Embodiments 1 or 2, wherein the composition comprises about 0.1 Img gacyclidine.

5. The method of Embodiments 1 or 2, wherein the composition comprises from 0.05mg to 0.25mg gacyclidine.

6. The method of Embodiments 1 or 2, wherein the composition comprises about 0.32mg gacyclidine.

7. The method of Embodiments 1 or 2, wherein the composition comprises from 0.25mg to 0.40mg gacyclidine.

8. The method of Embodiments 1 or 2, wherein the composition comprises about 0.44mg gacyclidine.

9. The method of Embodiments 1 or 2, wherein the composition comprises from 0.40mg to 0.55mg gacyclidine. 10. The method of Embodiments 1 or 2, wherein the composition comprises about 0.64mg or about 0.66mg gacyclidine.

11. The method of Embodiments 1 or 2, wherein the composition comprises from 0.55mg to 0.70mg gacyclidine.

12. The method of any one of Embodiments 1-11, wherein the auris acceptable vehicle comprises a triglyceride of a medium chain fatty acid, and wherein the otic formulation comprises least about 50 wt% of the triglyceride.

13. The method of Embodiment 12, wherein the triglyceride are present in an amount that is sufficient to provide sufficient retention time in the ear.

14. The method of Embodiment 12 or 13, wherein the triglycerids are present in an amount that is sufficient to sufficient to allow delivery of the formulation via a narrow gauge needle.

15. The method of any one of Embodiments 12-14, wherein the medium chain fatty acid comprises 6 to 12 carbon atoms in the carbon chain.

16. The method of any one of Embodiments 12-14, wherein the medium chain fatty acid 8 to 12 carbon atoms in the carbon chain.

17. The method of any one of Embodiments 12-14, wherein the medium chain fatty acid is selected from the group consisting of saturated medium chain fatty acids, unsaturated medium chain fatty acids, or a combination thereof.

18. The method of any one of Embodiments 12-14, wherein the medium chain fatty acid is selected from the group consisting of caproic acid (hexanoic acid), enanthic acid (heptanoic acid), caprylic acid (octanoic acid), pelargonic acid (nonanoic acid), capric acid (decanoic acid), undecylenic acid (undec- 10-enoic acid), lauric acid (dodecanoic acid), or a combination thereof.

19. The method of any one of Embodiments 12-14, wherein the triglyceride is selected from the group consisting of balassee oil, coconut oil, cohune oil, palm kernel oil, tucum oil, or combinations thereof.

20. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 55% to about 99.99% by weight of the triglyceride.

21. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 65% to about 99.99% by weight of the triglyceride. 22. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 75% to about 99.99% by weight of the triglyceride

23. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 85% to about 99.99% by weight of the triglyceride

24. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 90% to about 99.99% by weight of the triglyceride

25. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 95% to about 99.99% by weight of the triglyceride

26. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 97% to about 99.99% by weight of the triglyceride

27. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 98% to about 99.99% by weight of the triglyceride

28. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 99% to about 99.99% by weight of the triglyceride

29. The method of any one of Embodiments 12-19, wherein the otic pharmaceutical formulation comprises between about 99.5% to about 99.99% by weight of the triglyceride.

30. The method of any one of Embodiments 12-29, wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 10,000 cP.

31. The method of any one of Embodiments 12-29, wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 5,000 cP.

32. The method of any one of Embodiments 12-29, wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 1,000 cP.

33. The method of any one of Embodiments 12-29, wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 500 cP.

34. The method of any one of Embodiments 12-29, wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 250 cP.

35. The method of any one of Embodiments 12-29, wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 100 cP. 36. The method of any one of Embodiments 12-29, wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 50 cP.

37. The method of any one of Embodiments 12-36, wherein the otic pharmaceutical formulation is free or substantially free of poloxamer.

38. The method of any one of Embodiments 12-36, wherein the otic pharmaceutical formulation is free or substantially free of water.

39. The method of any one of Embodiments 12-36, wherein the otic pharmaceutical formulation is free or substantially free of C1-C6 alcohols or C1-C6 glycols.

40. The method of any one of Embodiments 12-36, wherein the otic pharmaceutical formulation is free or substantially free of C1-C4 alcohols or C1-C4 glycols.

41. The method of any one of Embodiments 1-40, wherein the otic formulation has an osmolarity from about 100 mOsm/L to about 1000 mOsm/L.

42. The method of Embodiments 1-41, wherein the gacyclidine is dissolved in the otic formulation.

43. The method of any one of Embodiments 1-41, wherein the gacyclidine is suspended in the otic formulation.

44. The method of any one of Embodiments 1-43, wherein the otic pharmaceutical formulation comprises between about 0.001% to about 10% by weight of the gacyclidine.

45. The method of any one of Embodiments 1-43, wherein the otic pharmaceutical formulation comprises between about 0.01% to about 1% by weight of the gacyclidine.

46. The method of any one of Embodiments 1-43, wherein the otic pharmaceutical formulation comprises between about 0.01% to about 0.5% by weight of the gacyclidine.

47. The method of any one of Embodiments 1-43, wherein the otic pharmaceutical formulation comprises between about 0.05% to about 0.35% by weight of the gacyclidine.

48. The method of any one of Embodiments 1-47, wherein the otic formulation provides sustained release of gacyclidine in the ear for at least 3 days.

49. The method of any one of Embodiments 1-47 wherein the otic formulation provides sustained release of gacyclidine in the ear for at least 5 days. 50. The method of any one of Embodiments 1-47, wherein the otic formulation provides sustained release of gacyclidine in the ear for at least 7 days.

51. The method of any one of Embodiments 1-47, wherein the otic formulation provides sustained release of gacyclidine in the ear for at least 14 days.

52. The method of any one of Embodiments 1-51, wherein the otic formulation is administered through intratympanic injection.

53. The method of any one of Embodiments 1-51, wherein the otic formulation is administered through unilateral intratympanic injection.

54. The method of any one of Embodiments 1-51, wherein the otic formulation is administered through bilatereal intratympanic injection

55. The method of any one of Embodiments 1-54, wherein the otic formulation is deposited close to the round window membrane.

56. The method of any one of Embodiments 1-55, wherein the tinnitus is moderate to severe tinnitus.

57. The method of any one of Embodiments 1-55, wherein the tinnitus is persistent tinnitus.

58. The method of any one of Embodiments 1-55, wherein the tinnitus is moderate to severe, and persistent tinnitus.

59. The method of any one of Embodiments 1-58, wherein the tinnitus is associated with an otic disease or condition selected from the group consisting of ear pruritus, otitis externa, otalgia, tinnitus, vertigo, ear fullness, hearing loss, Meniere’s disease, sensorineural hearing loss, noise induced hearing loss, age related hearing loss (presbycusis), auto immune ear disease, ototoxicity, excitotoxicity, endolymphatic hydrops, labyrinthitis, Ramsay Hunt’s Syndrome, vestibular neuronitis, or microvascular compression syndrome, hyperacusis, presbystasis, central auditory processing disorder, auditory neuropathy, and combinations thereof.

EXAMPLES

Example 1 - Gacyclidine Medium Chain Triglyceride (MCT) Formulations

Gacyclidine in MCTs [00184] MCT - 0.55 mg/mL, 1.6 mg/mL, 2.2 mg/mL, and 2.75 mg/mL gacyclidine formulations were prepared as follows. 0.55 mg/mL, 1.6 mg/mL, 2.2 mg/mL, and 2.75 mg/mL of free base gacyclidine (GYC) was dissolved in MCT (CRODAMOL, GTCC-LQ-(MV), PhEur). The solutions were fdtered through 0.2 um fdter.

[00185] Example formulations (sometimes referred to as “COMPOSITION A”) are provided in Table below.

Composition I

a Product density is approximately 0.95 g/mL.

Composition II

a Product density is approximately 0.95 g/mL.

Composition III

a Product density is approximately 0.95 g/mL.

Composition IV

a Product density is approximately 0.95 g/mL.

[00186] Example 2 - Inner Ear Pharmacokinetics Following a Single IT Administration of Various Doses of Gacyclidine MCT Formulations in Rats

[00187] In this study, female rats (n=4 ears per time point) received a single unilateral IT injection of 0.16%, 0.5%, 1.5% and 4.5% gacyclidine in MCT prepared according to Example 1. A single IT injection deposited 20 pL at the round window membrane, corresponding to doses of 0.032, 0.1, 0.3 and 0.9 mg per ear. Drug levels in the inner ear compartment (perilymph, cochlear epithelium tissues) and plasma were monitored over a 28-day period. The analysis quantified the presence of gacyclidine racemate, as well as each of the (+) and (-) enantiomers.

[00188] At Day 1 post-administration, perilymph concentrations of GCY peaked at 39.4 ± 19.7 ng/mL, 49.4 ± 24.7 ng/mL, 262 ± 131 ng/mL and 631 ± 315 ng/mL in animals treated with 0.16%, 0.5%, 1.5% and 4.5% gacyclidine MCT formulations, respectively (FIG. 2), and demonstrated a clear dose-dependent relationship. A steady decline was observed overtime, with GCY concentrations dropping to near the level of quantification (1 ng/mL) between Day 14 and Day 28. It was also evident that there exists a dose-dependency in the duration of exposure to GCY in the perilymph. AUC values were 4,165 ng«h/mL, 5,474 ng«h/mL, 23,676 ng«h/mL and 50,484 ng«h/mL for the 0.16%, 0.5%, 1.5% and 4.5% COMPOSITION A groups, respectively. Half-life ranged from 59 to 132 h, and MRT from 158 to 260 h, depending on the dose.

[00189] In the cochlear epithelium, concentrations of GCY peaked at 1,582 ± 791 ng/mL, 1,660 ± 830 ng/mL, 3,449 ± 1,724 ng/mL and 7,263 ± 3632 ng/mL in animals treated with 0.16%, 0.5%, 1.5% and 4.5% COMPOSITION A, respectively (FIG. 3), and demonstrated a clear dose-dependent relationship. A steady decline was observed overtime, with GCY levels dropping to near the level of quantification (6 ng/mL) between Day 14 and Day 28. It was also evident that there exists a dosedependency in the duration of exposure to GCY in the perilymph. AUC values were 130,113 ng«h/mL. 196,179 ng«h/mL, 440,623 ng«h/mL and 618,661 ng«h/mL for the 0.16%, 0.5%, 1.5% and 4.5% COMPOSITION A groups, respectively. Half-life ranged from 42 to 67 h, and MRT from 65 to 108 h, depending on the dose.

[00190] In plasma, GCY concentrations peaked at Day 1, reaching levels of 0.36 ± 0.18 ng/mL, 0.60 ±0.30 ng/mL, 1.96±0.98 ng/mL and 5.50±2.75 ng/mL following administration of 0.16%, 0.5%, 1.5% and 4.5% COMPOSITION A, respectively (FIG. 4). GCY concentrations demonstrated a clear dose-dependent relationship. A sharp decline was observed within the first 3 days, with GCY concentrations becoming undetectable by 7-14 days. Systemic exposure was limited, typically 80 to 130-fold lower than perilymph GCY concentrations, and 1300-4300-fold lower than cochlear epithelium GCY concentrations. FIG. 5 is a comparison chart of the perilymph, cochlear epithelium, and plasma kinectics in FIGs. 2-4

Example 3 - Preclinical Toxicology Studies of Gacyclidine Formulations

[00191] Single-dose toxicology studies evaluated COMPOSITION A following administration using the intended clinical route, i.e., IT. The rat and cat were the primary rodent and non-rodent species used in the toxicological assessment, as they are particularly suitable for otological studies. As IT is considered a local route of administration, studies addressing the local tolerance of COMPOSITION A were conducted in guinea pigs and rats.

[00192] Evaluation of the toxicology of gacyclidine was conducted. Studies evaluated COMPOSITION A and OTO-311 following administration using the intended clinical route, i.e. intratympanic injection. The rat and cat were the primary rodent and non-rodent species used in the toxicology assessment, as they are particularly suitable for otological purposes. As IT injection is considered a local route of administration, studies addressing the local tolerance and antigenicity of COMPOSITION A and OTO-311 were conducted in guinea pigs and rats. MCT was included as a vehicle control in all studies in which COMPOSITION A was evaluated and 16% Polaxamer 407 solution was included as a vehicle control in all studies in which OTO-311 was evaluated.

[00193] Additional studies examined the acute and repeat dose toxicology profile of the active pharmaceutical ingredient (API) gacyclidine (racemate and both enantiomeric forms) following various routes of administration (intravenous, intraperitoneal, subcutaneous) in rodents (mouse, rat) and non-rodents (dog, monkey). These routes provide systemic exposure to gacyclidine and allow for the assessment of the toxicological potential of this potent NMDA antagonist.

[00194] The main objectives of the studies described herein were: (1) to characterize the degree of toxicity in the otic compartment and systemically following IT injection of COMPOSITION A and OTO-311, (2) to characterize the toxicity of gacyclidine following acute and repeat dose administration via systemic routes (intravenous, intraperitoneal, subcutaneous) in rodents and non- rodents, (3) to define the genotoxic potential of gacyclidine, (4) to characterize local tolerance and antigenicity, and (5) to evaluate the potential for neurotoxicity in the form of Olney’s lesions, known to be observed with NMDA antagonists.

[00195] Acute Ototoxicity Following IT Administration of COMPOSITION A in Rats

[00196] In this study, the potential toxicity of COMPOSITION A was evaluated following acute administration via the intratympanic route in rats. Subjects received a single unilateral intratympanic injection (20 pL) followed by a 3-month recovery period (n=8/gender/group) for a total duration of 3 months. The treatment group assignments are described in Table 1. Table 1 : Treatment Group Assignments

[00197] Assessment of ototoxicity was based on otoscopic examinations, auditory function using auditory brainstem response (ABR), as well as evaluations of the middle ear (histology) and inner ear (cytocochleogram). In addition, assessment of overall toxicity was based on mortality, clinical observations, body weight, physical examinations, as well as clinical and anatomic pathology.

[00198] No mortality was observed in any of the treatment groups, with the exception of one animal treated with saline, and one animal treated with 1.5% COMPOSITION A. Both deaths occurred following anesthesia procedures for auditory brainstem procedures, and therefore are considered procedural.

[00199] There were no signs of adverse clinical observations in any of the treatment groups, including up to the highest 4.5% COMPOSITION A dose.

[00200] Clinical pathology analysis revealed no test article related effects on hematology parameters or clinical chemistry parameters in either sex at any COMPOSITION A dose tested.

[00201] Hearing evaluation was conducted using ABR at three different frequencies (4, 10 and 20 KHz) at baseline and termination (3-month). Findings are presented in FIG. 6 The variability of the baseline ABR thresholds was similar between rats assigned to the different treatment groups at each tested frequency. In the saline group, no changes in ABR threshold were seen at the 3- month termination endpoint in the treated ears. Similarly, in the MCT vehicle group, no changes in ABR threshold were evident at any frequency. Administration of the positive control, gentamicin (2800 mg/mL), a known ototoxicant, produced the expected threshold increases over the course of the study in female animals and one male animal. These changes are consistent with the hair cell losses observed in the basal and mid-regions of the organ of Corti. A single administration of COMPOSITION A, up to and including highest dose of 4.5 %, had no effects on ABR hearing thresholds.

[00202] Macroscopic examination of the ears and organs revealed no findings related to the administration of Saline, MCT vehicle or COMPOSITION A at any of the doses tested.

[00203] Histological analysis of middle ear paraffin sections was conducted at the 3-month termination. In general, the treated ear had microscopic changes that were procedural and/or related to the introduction of foreign material into the middle ear compared to the untreated ear including proteinaceous/mixed cellular debris and bacteria in the external ear canal; tympanic membrane rupture or perforation, defined as a tear, break, cut or pinhole in the tissue (likely from the intratympanic injection), infiltration/inflammation of mixed leukocytes, and fibroplasia; fibroplasia of the tympanic cavity lining; proteinaceous material within the round window niche; and hemorrhage and increased incidence and severity of foamy/pigmented macrophages in multiple middle ear tissues. These changes were scattered across dose groups, including controls, were not dose responsive, and were not considered test article related. Microscopic changes in the treated ear associated with gentamicin, a known ototoxicant, included minimal decreased cellularity of the spiral ganglion and/or minimal hair cell loss in the organ of Corti associated with the basal turn of the cochlea in two females. This change was consistent with the overall trend of a hearing threshold increase in the Auditory Brainstem Response in this group. In addition, there was increased mucus in the tympanic cavity with minimal to mild cuboidal to columnar metaplasia of the tympanic cavity lining including Goblet cells consistent with the respiratory epithelium of the Eustachian tube. Microscopic changes observed following IT injection of MCT vehicle and COMPOSITION A were considered incidental and spontaneous, and not test-article related.

[00204] Cytocochleograms (assessment of inner ear integrity) were conducted at the 3 -month recovery period. There were no adverse effects on hair cell integrity in the saline, MCT vehicle and COMPOSITION A treatment groups. Administration of the known ototoxicant gentamicin produced hair cell losses between 10 and 100% in the mid- and basal regions of the cochlea in all treated ears. Untreated ears appeared normal in these animals.

[00205] Therefore, with respect to both the auditory -related function and systemic effects of COMPOSITION A, the acute IT administration of COMPOSITION A up to and including 4.5% produced no adverse effects in rats. Overall, a no-observed-adverse-effect-level (NOAEL) of 4.5% COMPOSITION A was established for both otic and systemic endpoints.

[00206] Acute Ototoxicity Following IT Administration of COMPOSITION A in Cats [00207] In this study, the potential toxicity of COMPOSITION A was evaluated following acute administration via the intratympanic route in cats. Subjects received a single unilateral IT injection (150 pL) followed by a 3 -month recovery period (n=8/gender/group), for a total duration of 3 months. The treatment group assignments are described in Table 2.

Table 2: Treatment Group Assignments

[00208] Assessment of ototoxicity was based on otoscopic examinations, auditory function using auditory brainstem response (ABR), as well as evaluations of the middle ear (histology) and inner ear (cytocochleogram). In addition, assessment of overall toxicity was based on mortality, clinical observations, body weight, physical examinations, as well as clinical and anatomic pathology.

[00209] No mortality was observed in any of the treatment groups. There were no signs of adverse clinical observations in the saline, MCT vehicle and COMPOSITION A including up to the highest 4.5% COMPOSITION A dose. Clinical observations were noted exclusively in a small number of animals in the gentamicin group. Animals presented with a right leaning head tilt (toward the treated ear), an expected finding with this known ototoxicant. Clinical pathology analysis revealed no test article related effects on hematology parameters or clinical chemistry parameters in either sex at any COMPOSITION A dose tested.

[00210] Hearing evaluation was conducted using ABR at three different frequencies (4, 10 and 20 KHz) at baseline and termination (3-month). Findings are presented in FIG. 7. The variability of the baseline ABR thresholds was similar between cats assigned to the different treatment groups at each tested frequency. In the saline group, no changes in ABR threshold were seen at the 3- month termination endpoint in the treated ears. Similarly, in the MCT vehicle group, no changes in ABR threshold were evident at any frequency. Administration of the positive control, gentamicin (1000 mg/mL), a known ototoxicant, produced the expected threshold increases over the course of the study in all male and female animals. A single administration of COMPOSITION A, up to and including highest dose of 4.5 %, had no effects on ABR hearing thresholds.

[00211] Macroscopic examination of the ears and organs revealed no findings related to the administration of Saline, MCT vehicle or COMPOSITION A at any of the doses tested. Histological analysis of middle ear paraffin sections was conducted at the 3-month termination. In general, the treated ear had microscopic changes that were procedural and/or related to the introduction of foreign material into the middle ear compared to the untreated ear including mixed cellular/proteinaceous debris in the external ear canal; fibroplasia, proteinaceous material, and foreign material (hair/keratin fragments) in the tympanic cavity lining; proteinaceous material and adhesions in the lateral compartment of the tympanic cavity; fibroplasia and new bone formation of the ossicles; and increased incidence and/or severity of foamy/pigmented macrophages and mixed leukocyte infiltration/inflammation in multiple middle ear tissues. These changes were scattered across dose groups, including controls, were not dose responsive, and were not considered test article related, nor adverse. Microscopic changes in the treated ear associated with gentamicin, a known ototoxicant, included epithelial cell hyperplasia, squamous cysts, and foreign material (keratin) in the lining of the external auditory canal; rupture and fibroplasia of the tympanic membrane; adhesions in the lateral compartment of the tympanic cavity; a squamous cyst in the tympanic cavity lining; and fibroplasia and mixed leukocyte infiltration/inflammation of the ossicles. Microscopic changes observed following IT injection of MCT vehicle and COMPOSITION A were considered incidental and spontaneous, and not test-article related.

[00212] Cytocochleograms (assessment of inner ear integrity) were conducted at the 3-month recovery period. There were no adverse effects on hair cell integrity in the saline, MCT vehicle and COMPOSITION A treatment groups. Administration of the known ototoxicant gentamicin produced hair cell losses between 10 and 100% in the mid- and basal regions of the cochlea in all treated ears. Untreated ears appeared normal in these animals.

[00213] Therefore, with respect to both the auditory -related function and systemic effects of COMPOSITION A, the acute IT administration of COMPOSITION A up to and including 4.5% produced no adverse effects in cats. Overall, a no-observed-adverse-effect-level (NOAEL) of 4.5% COMPOSITION A was established for both otic and systemic endpoints.

Example 4 — Local Tolerance Study of Gacyclidine Formulations

[00214] In this example, single dose nonclinical toxicology studies in rats and cats have been conducted and the results support the clinical investigation of COMPOSITION A in the current study. Additionally, pharmacokinetic assessments have been conducted in these species that provides a complete profile of exposure of COMPOSITION A to the inner ear compartment after intratympanic administration of COMPOSITION A, with negligible systemic exposure.

[00215] Studies characterizing local tolerance of COMPOSITION A and OTO-311, particularly relevant since the intended clinical route of administration of COMPOSITION A and OTO-311 is local, demonstrated that COMPOSITION A was well tolerated up to maximum tested dose of 4.5% and OTO- 311 is well tolerated up to the maximum tested dose of 10% when applied locally. No dermal irritation was noted in rats when up to 45 mg COMPOSITION A was applied topically and when up to 100 mg OTO-311 was applied topically. COMPOSITION A did not induce delayed hypersensitivity at doses up to 72 mg when applied topically in guinea pigs and OTO-311 did not induce delayed hypersensitivity at doses up to 160 mg when applied topically in guinea pigs.

[00216] Neurotoxicity Potential (Olney’s lesions)

[00217] Nonclinical studies were conducted to evaluate the potential of COMPOSITION A (solution of gacyclidine racemate free base in MCT) and OTO-311 (suspension of gacyclidine racemate free base in P407 solution) and its active pharmaceutical ingredient gacyclidine racemate (administered IV as the HC1 salt) to induce Olney’s lesions (neurotoxic finding associated with NMDA antagonists) in a single dose administration paradigm, using two routes of administration: Intravenous, in order to draw a correlation between systemic exposure and Olney’s lesions and; Intratympanic, in order to assess the potential of COMPOSITION A and OTO-311 to produce Olney’s lesions when administered via its intended clinical route. [00218] A total of five studies have been conducted (Table 3). All studies were done in Sprague Dawley rats, three in both males and females and the two in females only; all used the prototypical NMDA antagonist MK-801 as the positive control; all studies included a saline group as a negative control, as well as either MCT or 16% Poloxamer 407 solution group as the vehicle control for COMPOSITION A and OTO-311, respectively.

Table 3: Summary of Studies Assessing the Potential of OTO-311 and Gacyclidine to Induce Olney’s Lesions

[00219] Overall, the findings were as follows:

[00220] MK-801, the active control in all studies, administered subcutaneously to males and females resulted in microscopic changes in the cingulate gyrus/retrosplenial cortex and also sporadically in other regions of the brain (piriform cortex and dentate gyrus) in all animals. All males and females treated with MK-801 were affected and these findings were associated with severe behavioral changes (decreased locomotion, sedation, tonic/clonic convulsions and tremors) observed immediately following administration in both males and females gradually improving over time, and completely disappearing in males by Day 3, but not in females by study termination (Day 4).

[00221] Gacyclidine administered IV to males and females at 10 mg/kg resulted in microscopic changes that were significantly less frequent and less severe than the changes associated with the administration of MK-801. Gacyclidine administered IV to males and females at 5 mg/kg, 2 mg/kg and 1 mg/kg did not result in any microscopic changes. However, all doses administered IV resulted in behavioral changes that were observed immediately following injection, but were completely resolved by Day 1. [00222] Saline administered IV or IT to males and females did not result in any microscopic or behavioral changes. MCT administered IT to males and females did not result in any microscopic or behavioral changes. Poloxamer 407 administered IT to males and females did not result in any microscopic or behavioral changes.

[00223] COMPOSITION A administered IT to males and females at 5%, 1.5%, and 0.5% (20 pL of each dose strength) did not result in any behavioral changes. COMPOSITION A administered IT to males at 5%, 1.5%, and 0.5% (20 pL of each dose strength) and females at 5% and 0.5% did not result in any microscopic changes. A low incidence and minimal severity of neuronal necrosis was observed in females dosed with 1.5% COMPOSITION A

[00224] OTO-311 administered IT to males at 10%, 9%, 8%, 7%, and 6% (20 pL of each dose strength) did not result in any microscopic or behavioral changes. OTO-311 administered IT to females at 10%, 9%, 8%, 7%, 6%, 5%, 3%, 1%, and 0.75% (20 pL of each dose strength) did result in microscopic changes that decreased with decreasing dose. These changes were significantly less frequent and less severe than changes associated with the administration of MK-801. However, no behavioral changes were noted at any dose.

Example 5 — Clinical Trial of Gacyclidine MCT Formulations

[00225] In Example 2, single dose nonclinical toxicology studies in rats and cats have been conducted and the results support the clinical investigation of COMPOSITION A in the current study. Additionally, pharmacokinetic assessments have been conducted in these species that provides a complete profile of exposure of COMPOSITION A to the inner ear compartment after intratympanic administration of COMPOSITION A, with negligible systemic exposure.

1. OBJECTIVES

1.1. Primary objective

• To determine the efficacy of COMPOSITION A in subjects with unilateral tinnitus by comparing the proportion of subjects achieving response using the TFI relative to placebo.

1.2. Secondary objectives

• To determine the effect of COMPOSITION A across additional secondary measures of efficacy (tinnitus loudness and annoyance NRS, PGIC, SF- 12) relative to placebo.

• To determine the safety and tolerability of COMPOSITION A in subjects with unilateral tinnitus.

2. OVERVIEW OF STUDY DESIGN This study will be conducted at approximately 55 sites globally.

The duration for each subject will be approximately 18-22 weeks, including an up-to 4-week Screening period, a 2-week Lead-in assessment period, and a 16-week Follow-up period.

After signing informed consent, subjects will complete the TFI at the Screening visit. Subjects must have an overall score of > 32 on the TFI at both Screening and Baseline. After Screening, potential subjects will begin a 2-week Lead-in assessment period. During this time, subjects will enter daily tinnitus annoyance and tinnitus loudness severity into a diary using the appropriate Numeric Rating Scales (NRS) for each symptom. Subjects must have completed the tinnitus diary on at least 5 of the last 7 days of the 14-day Lead-in period for eligibility. The additional +5 days of the Lead-in period will not be used for eligibility.

At the Baseline (Day 1) visit, approximately 140 eligible subjects will be randomized to COMPOSITION A or placebo using a 1: 1 allocation ratio. Randomization is stratified by study site, duration of tinnitus (>2 to <6 months and >6 to < 12 months since onset) and by the average of the TFI score at Screening and Baseline (>32 to <53 points, >54 to <100 points).

After a single intratympanic injection with 0.32 mg COMPOSITION A or placebo to the affected (study) ear on Day 1, subjects will continue to record their tinnitus annoyance and tinnitus loudness on a daily basis using the diary during the 16-week Follow-up period. Subjects will complete the TFI at study visits at Week 4, Week 8, Week 12, and Week 16. Additional efficacy and/or safety assessments will also be completed at Baseline (Day 1), Week 4, Week 8, Week 12, and Week 16 or upon early termination from the study. An independent Safety Review Committee will review accumulated individual subject safety data to ensure appropriate safety and tolerability of COMPOSITION A or placebo.

Study Design Schematic

3. STUDY POPULATION

3.1. General Considerations

Approximately 140 subjects will be enrolled at approximately 55 sites globally. Subjects will be eligible if they meet all of the following inclusion criteria and none of the exclusion criteria.

3.2. Inclusion Criteria

To be eligible for this study, each of the following criteria must be satisfied with a “YES” answer (unless not applicable):

1. Subject is a male or female aged 18 to 75 years, inclusive.

2. Subject has subjective unilateral tinnitus and is consistently aware of their tinnitus throughout much of the waking day.

3. Subject’s tinnitus is likely of cochlear origin, e.g., associated with sensorineural hearing loss; acute hearing loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma); age-related hearing loss; resolved otitis media; ototoxic drug exposure.

4. Subject’s self-reported duration of tinnitus is between 2 months and 12 months (>60 to <365 days) prior to signing informed consent.

5. Subject has an overall score of > 32 on the TFI at both Screening and Baseline visits.

6. Subject has audiometrically-defmed normal hearing or up to moderately severe hearing impairment in the affected ear (study ear) as characterized by pure tone average of < 70 dB at 1000, 2000, and 4000 Hz at Screening.

7. Subject is able to use the diary to complete their daily tinnitus ratings and has completed at least 5 of the last 7 days of diary entries during the 14-day Lead-in period.

8. Female subjects of childbearing potential [i.e., not surgically sterile and/or not post-menopausal (>12 months since last menstrual period without an alternative medical cause)] must have a negative urine pregnancy test at Baseline. Women of childbearing potential who are not abstinent from sex with male partners must use highly effective methods of contraception for the duration of the study including: established use of oral, injected, or implanted hormonal methods of contraception; or placement of an intrauterine device or intrauterine system. Female subjects of childbearing potential must also refrain from egg donation or retrieval for the duration of the study.

9. Male subjects (unless surgically sterile) who are not abstinent from sex with female partners of childbearing potential must agree to use an effective contraceptive method (as detailed for Inclusion Criteria 8) for the duration of the study. Male subjects must refrain from sperm donation for the duration of the study.

Note: Abstinence (male or female subjects) is acceptable if this is the usual lifestyle and preferred contraception for the subject. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable.

10. Subject is willing to comply with the protocol and attend all study visits.

11. Subject is able to provide written informed consent, including agreement to privacy language compliant with country and/or local requirements, after the scope and nature of the investigation have been explained, and before the initiation of any study- related procedures.

3.3. Exclusion Criteria

To be eligible for this study, each of the following criteria must be satisfied with a “NO” answer: (unless not applicable):

1 . Subject has pulsatile tinnitus, temporomandibular joint disease associated with tinnitus perception, tinnitus resulting from traumatic head or neck injury, or tinnitus resulting from a tumor or stroke.

2. Subject has active middle ear disease (including but not limited to: chronic otitis media, acute otitis media, middle ear effusions, middle ear atelectasis, otosclerosis, Eustachian tube dysfunction, or cholesteatoma), Meniere’s disease as outlined by the American Academy of Otolaryngology-Head and Neck Surgery Equilibrium Committee in 2015 (Goebel 2016), concurrent vestibular pathology, or vestibular schwannoma.

3. Subject has recently (< 1 month of Screening) initiated new treatment for tinnitus (e.g., noise or sound generators, hearing aids, behavioral therapy, non-conventional therapy, medications or over-the-counter supplements, transcranial magnetic stimulation); only stable tinnitus treatments (i.e., initiated at least 1 month prior to Screening) are allowed during the study and no new treatments should be introduced during the course of the Study.

4. Subject is not able to accurately localize, identify, and report their tinnitus per Investigator’s opinion. 5. Subject has an abnormality of the tympanic membrane in the affected (study) ear that would increase the risk associated with intratympanic injection, including but not limited to monomeric tympanic membrane.

6. Subject has evidence of perforation or lack of closure of the tympanic membrane, or a myringotomy tube in affected ear at Screening or Baseline visits.

7. Subject is receiving any ongoing therapy known as potentially tinnitus-inducing (e.g., aminoglycosides, ototoxic chemotherapeutic drugs, high doses of intravenous loop diuretics, quinine, high doses of aspirin or other nonsteroidal anti-inflammatory drugs). Usage of low doses of aspirin (e.g., daily doses of 81 mg) or low doses of other nonsteroidal anti-inflammatory drugs for intermittent pain relief may be permitted at the Investigator’s discretion (see Section 7.1).

8. Subject answered “Yes” to Question 4 or 5 regarding active suicidal ideation on the

C-SSRS administered at Screening or Baseline visits. In addition, subjects deemed by the Investigator to be at significant risk of suicidal behavior should be excluded.

9. Subject has severe or untreated depression or anxiety that, in the Investigator’s opinion, would likely reduce the safety of study participation. Antidepressant and antianxiety medications are allowed only if administered at stable doses and frequency for > 1 month prior to Screening with the expectation that the stable daily dose will continue for the duration of the study.

10. Subject is pregnant, lactating, or undergoing fertility treatment.

11 . Subject has a history of serious substance abuse (e.g., cocaine, heroin) within 6 months prior to Screening.

12. Subject has received or is receiving concomitant treatment with any other NMDA receptor antagonist (e.g., memantine, dextromethorphan) within 30 days prior to the Baseline visit. Note, occasional use of dextromethorphan for cough suppression is allowed except between 7 days prior to Baseline and 7 days after injection of the investigational product.

13. Subject has a history of any use of intratympanic gentamicin in the affected ear.

14. Subject has received systemic or intratympanic steroids (including dexamethasone) within 6 weeks prior to the Screening visit.

15. Subject has previously participated in a clinical study with COMPOSITION A or OTO-311.

16. Subject has used moderate or strong inducers of CYP2B6 (e.g., carbamazepine, efavirenz, rifampin, or ritonavir) within 30 days prior to Baseline visit. 17. Subject has used an investigational drug or device within 30 days prior to Screening.

18. Subject has other clinically significant illness, medical condition or medical history at Screening or Baseline that, in the Investigator’s opinion, would likely reduce the safety of study participation or compliance with study procedures.

4. RANDOMIZATION AND BLINDING

4.1. Overview

Approximately 140 eligible subjects will be assigned randomly to 0.32 mg COMPOSITION A or placebo using a 1: 1 allocation ratio, based on a computer-generated randomization schedule.

• 0.32 mg COMPOSITION A; single (0.2 mL volume) intratympanic injection to the affected (study) ear

• Placebo (vehicle); single (0.2 mL volume) intratympanic injection to the affected (study) ear

COMPOSITION A and placebo solutions are identical in appearance.

4.2. Enrollment Procedures

4.2.1. Assignment of Subject Identification Numbers

At the Screening visit (Visit 1), subjects who have signed the informed consent will be assigned a sequential subject identification number by the site. Once assigned, the subject identification number will not be re-assigned and should not be changed. This number will be used to identify the subject throughout the study, including the Screening and Lead-in periods. Any subject that is re-screened will be assigned a new subject identification number. Subjects will be considered enrolled into the study once they complete the informed consent process.

The subject identification number will consist of 9 digits separated by 2 hyphens (e.g., 201-XXX- YYY). The first 3 digits are the study number (201) followed by a hyphen. The second 3 digits are the site number followed by a hyphen. The final 3 digits are the subject number.

4.2.2. Treatment Assignment

After a subject has met all prerequisites for randomization on Day 1 (Baseline/Visit 2), study sites will execute each randomization via the Interactive Response Technology (IRT) randomization system. All study site personnel are blinded to treatment assignment. Study sites will receive a randomization notification indicating the kit number (packaged investigational product), and the date and time of randomization for each subject. Once assigned, kit numbers cannot be re- assigned.

Study sites will provide the information contained in the IRT randomization notification to the person responsible for preparation of the syringe containing investigational product (COMPOSITION A or placebo). The unique kit number provided by IRT will correspond to a kit of packaged investigational product labeled with the identical kit number. The syringe will be prepared from the contents of the investigational product package corresponding to the IRT kit number according to the instructions in the study Pharmacy Manual. The subject identification number and kit number both must be recorded in the subject’s record.

4.2.3. Randomization Algorithm

Subjects will be randomized in a 1 : 1 ratio (COMPOSITION A:placebo) of treatment groups using a permuted block randomization algorithm. Randomization is stratified by study site, duration of tinnitus (>2 to <6 months and >6 to < 12 months since onset) and by the average of the TFI score at Screening and Baseline (>32 to <53 points, >54 to <100 points).

The randomization process will be deployed via IRT which is accessible 24 hours a day to authorized users. The subject’s randomization number will determine the randomized treatment assignment. Investigational product kits will be labeled with a unique kit number using a separate and independent randomization algorithm. Numbered kits will be dispensed based on the treatment assignment.

4.3. Blinding

The study will be double -blinded. Each treatment syringe will be prepared according to the detailed instructions in the Pharmacy Manual.

In case of emergency, the blind should be broken for site personnel only if knowing the subject’s treatment allocation would facilitate specific medical treatment. In all cases, the Investigator should consult with the medical monitor prior to unblinding, and if not possible as soon as it is practical after unblinding has occurred and treatment initiated.

If the blind is broken, the subject will continue to be followed and evaluated per-protocol. The date, time, and reason for the unblinding must be documented on the appropriate page of the eCRF.

The randomization schedule or blocking factor(s) will not be revealed to study subjects, Investigators, clinical staff, site managers or the Sponsor until all subjects have completed the study and the database has been finalized by the Sponsor.

5. DOSAGE AND ADMINISTRATION 5.1. Investigational Product Administration

COMPOSITION A or placebo is provided in individual Investigational Product kits. All kits must be stored at 2-8°C until use.

Syringes containing COMPOSITION A or placebo are prepared in a clean location at room temperature. Refer to the Pharmacy Manual for instructions on COMPOSITION A and placebo preparation instructions.

COMPOSITION A or placebo will be administered as a single (0.2 mb volume) intratympanic injection to an affected (study) ear. Only a physician may perform the intratympanic injection.

COMPOSITION A or placebo should be prepared with a 1 mb luer-lock sterile syringe only. Luer slip tip syringes are not acceptable for use due to the viscosity of COMPOSITION A.

Recommended needles are 25, 26, or 27 gauge and typically range from 1.5 to 3.5 inches in length.

The recommended injection procedure for intratympanic administration of COMPOSITION A or placebo in subjects is as follows. A ventilation hole in the tympanic membrane is not needed due to the small injection volume.

1 . Place the subject in a recumbent position with the affected (study) ear upwards.

2. Prior to COMPOSITION A or placebo administration, confirm the ear to be treated is the affected (study) ear.

3. Anesthetize the tympanic membrane by covering the external surface of the inferior-posterior quadrant with topical lidocaine or lidocaine/prilocaine cream (e.g., EMLA® cream or lidocaine spray or solution) until the tympanic membrane is numb. If applicable, suction away any excess topical preparation. Use of phenol is prohibited for anesthetizing the tympanic membrane (Section 7.1).

4. Using the prepared syringe, insert the needle (bevel facing) into the inferiorposterior quadrant of the tympanic membrane at the level of the round window, taking care not to insert the needle further than necessary.

5. With the needle bevel facing in the inferior-posterior direction, inject 0.2 mb of COMPOSITION A or placebo towards the round window.

6. Have the subject remain recumbent for 15 minutes following the injection.

5.2. Compliance

COMPOSITION A or placebo will be administered by a physician as a single, intratympanic injection at Day 1.

The site will maintain a log of all investigational product received, dispensed, and returned. Investigational product supplies for each subject will be inventoried and accounted for in the study.

6. PRIOR, CONCOMITANT AND SUBSEQUENT THERAPY

Use of all concomitant medications will be recorded in the subject’s eCRF. This will include all symptomatic relief medications for tinnitus symptoms, prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications taken within 30 days before Screening, which will be considered prior therapy. COVID- 19 vaccination at any time prior to Screening or during the study will also be recorded.

At the discretion of the Investigator, any medication deemed necessary for the welfare of the subject may be continued at stable doses during the study, except forthose medications listed in Section 6.1. Any changes in concomitant medications will be recorded in the subject’s eCRF.

6.1. Prohibited Therapy During the Study Period

The following therapies are prohibited during the study:

• Phenol for use in anesthetizing the tympanic membrane

• Intratympanic injection other than that outlined in the current study

• Systemic corticosteroids (inhaled and nasal steroids are permitted)

• Other investigational drug(s) or device(s)

• Other NMDA receptor antagonists (e.g., memantine, dextromethorphan). Note, occasional use of dextromethorphan for cough suppression is allowed except during the period 7 days prior to Baseline and 7 days after the injection of the investigational product.

• Medications known as potentially tinnitus-inducing (e.g., aminoglycosides, ototoxic chemotherapeutic drugs, high doses of intravenous loop diuretics, quinine, high doses of aspirin or other non-steroidal anti-inflammatory drugs). Usage of low doses of aspirin (e.g., daily doses of 81 mg) or low doses of other non-steroidal antiinflammatory drugs for intermittent pain relief may be permitted at the Investigator’s discretion.

• Medications that are considered moderate or strong inducers of CYP2B6 (e.g., carbamazepine, efavirenz, rifampin, and ritonavir)

Use of any of these prohibited therapies will be considered a protocol deviation.

6.2. Other Medications and Therapies It is recognized that during the study subjects may require use of certain medications for relief of symptoms related to tinnitus or other disease (e.g., worsening depression). Use of the following medication and therapies are permitted during the study:

• Stable doses (taken for > 1 month prior to Screening) of antidepressant and antianxiety medications are allowed during the study, and

• Stable prior use (> 1 month prior to Screening) of over-the-counter supplements, medications for tinnitus (e.g., Gingko biloba, melatonin), nonconventional therapy, and transcranial magnetic stimulation for tinnitus.

No new medications, over-the-counter supplements, or other therapies for tinnitus may be introduced during the study.

Any changes reported by the subjects in concomitant medications, including changes in dose or frequency of dosing, while not considered a protocol deviation, should be recorded in the subject’s eCRF.

No new hearing aids, sound/noise therapy devices, or behavioral therapy for tinnitus may be introduced during the study. However, patients using devices or behavioral therapy pre-study are permitted to continue stable use.

• Stable prior use (> 1 month prior to Screening) of hearing aids, noise generators, and/or sound therapy devices is allowed and, if utilized, these devices should be used consistently throughout the duration of study.

• Similarly, any behavioral therapy for tinnitus should also be stable (> 1 month prior to Screening) and continue throughout the duration of the study.

Any changes in the concurrent use of these devices or behavioral therapy for tinnitus, while not considered a protocol deviation, should be recorded in the subject’s eCRF.

7. STUDY EVALUATIONS

7.1. Study Procedures by Visit

7.1.1. Screening Period: Up to 28 days prior to Lead-In

The following assessments, as listed in the Time and Events Schedule (Table 1), will be performed during the screening period: obtain documented informed consent, review and confirm eligibility criteria, medical history, demographics, prior and concomitant medications, vital signs, height and weight measurements, serum pregnancy test (for female subjects of childbearing potential only), clinical laboratory tests, TFI assessment, otoscopy, tympanometry, audiometry, and C-SSRS assessment: Baseline version. The modified Tinnitus Sample Case History Questionnaire (TSCHQ) will be completed at Screening as part of medical history to capture tinnitus-specific medical history. Each subject will also view a short educational video on clinical research participation entitled “What It Means to Take Part in Clinical Research Studies”. Viewing of the video will be completed after informed consent but prior to the TFI at the screening visit.

7.1.2. Lead-In Period: Day -14 to Day -1 (+ 5 days)

The subject will record their tinnitus loudness and tinnitus annoyance each day, using the NRS for each symptom, in a diary during the 14-day Lead-In assessment period. Subjects must have completed the tinnitus diary on at least 5 of the last 7 days of the 14-day Lead-in period for eligibility. The additional +5 days of the Lead-in period will not be used for eligibility.

7.1.3. Baseline/Investigational Product Administration: Day 1

The purpose of the Day 1 Baseline visit is to confirm subject eligibility, capture baseline efficacy and safety data, and administer the investigational product.

Once the Lead-in period is complete and the subject has met the eligibility criteria for tinnitus diary compliance, the Day 1 Baseline assessments are performed. Results from the prior and concomitant medications review, urine pregnancy test (for female subjects of childbearing potential), and C-SSRS (“Since Last Visit” version) must be available and reviewed by the Investigator to confirm the subject’s eligibility before randomization.

In addition, the following assessments are to be performed on all subjects prior to dosing to establish Baseline status: medical history (with particular attention to any untoward medical occurrences that would meet the definition of a serious outcome - See Section 9.1 Serious Adverse Event), vital signs, clinical laboratory tests, TFI (overall score of > 32 on the TFI at Screening and Baseline visits is required for eligibility), SF-12, otoscopy, tympanometry, and audiometry. Once eligibility status is confirmed and the subject is randomized, the investigational product is administered and the remaining Day 1 assessments (i.e., AE monitoring) are completed.

If the subject is no longer eligible, the subject will not be randomized and should be recorded as a screen failure (documentation for screen failures will be limited specifically to end of study reason, demographic information, TSCHQ, reason for screen failure, and inclusion/exclusion criteria). Re-screening of subjects may be permitted after discussion with the medical monitor and sponsor.

All assessments as listed in the Time and Events Schedule (Error! Reference source not found.) are to be performed at this visit.

7.1.4. Week 4 (Day 29 ± 2 days): Follow Up

The primary purpose of the Week 4 visit is to capture efficacy and safety data. Efficacy assessments include the TFI and PGIC. Safety assessments include concomitant medications, vital signs, otoscopy, tympanometry, audiometry, C-SSRS, and AE monitoring. Compliance for completing the daily NRS diary will be reviewed with the subject.

All Week 4 efficacy and safety assessments as listed in the Time and Events Schedule (Error! Reference source not found.) are to be performed.

7.1.5. Week 8 (Day 57 ± 3 days): Follow Up

The primary purpose of the Week 8 visit is to capture efficacy and safety data. Efficacy assessments include the TFI, PGIC, and SF-12. Safety assessments include concomitant medications, vital signs, clinical laboratory tests, otoscopy, tympanometry, audiometry, C-SSRS, and AE monitoring. Compliance for completing the daily NRS diary will be reviewed with the subject.

All Week 8 efficacy and safety assessments as listed in the Time and Events Schedule (Error! Reference source not found.) are to be performed. In the event that a subject terminates early prior to Week 8, a clinical laboratory test should be conducted.

7.1.6. Week 12 (Day 85 ± 4 days): Follow Up

The primary purpose of the Week 12 visit is to capture efficacy and safety data. Efficacy assessments include the TFI and PGIC. Safety assessments include concomitant medications, vital signs, C-SSRS, and AE monitoring. Compliance for completing the daily NRS diary will be reviewed with the subject.

All Week 12 efficacy and safety assessments as listed in the Time and Events Schedule (Error! Reference source not found.) are to be performed.

7.1.7. Week 16 (Day 113 ± 4 days): End of Study/Early Termination

The primary purpose of the Week 16 visit is to capture final efficacy and safety data. Efficacy assessments include the TFI, PGIC, and SF-12. Safety assessments include concomitant medications, weight, vital signs, urine pregnancy test for women of childbearing potential, otoscopy, tympanometry, audiometry, C-SSRS, and AE monitoring.

All Week 16 efficacy and safety assessments as listed in the Time and Events Schedule (Error! Reference source not found.) are to be performed. In the event that a subject terminates prior to Week 8, a clinical laboratory test should be conducted.

7.1.8. Unscheduled Visit

Unscheduled Visits may occur in the event of safety-related issues. Appropriate safety assessments (e.g., otoscopy, vital signs, clinical laboratory tests) may be conducted at the Investigator’s discretion at Unscheduled Visits. 7.2. Medical History and Demographics

The medical history will be obtained from medical records and/or via subject interview at the Screening visit, and includes general medical history, medication history, reproductive history, and history of COVID-19 infection. In addition, if subject has any untoward medical occurrences that would meet the definition of a serious event (see Section 9. 1 Serious Adverse Event) prior to investigational product administration, this information is to be recorded in medical history and immediately discussed with the Medical Monitor to evaluate whether the subject should be excluded from randomization/treatment. Serious medical events that occur prior to investigational product administration should be recorded on the Pre-Dose Serious Medical Occurrences report form.

Tinnitus-specific medical history information is also obtained by having potential subjects complete the modified TSCHQ at Screening. Medical history, conditions, and procedures that occurred prior to Screening may be added throughout the study (if identified later).

Demographic information will also be obtained at the Screening visit and will include age; sex; race; ethnicity; height, without shoes; weight, without shoes. Weight will also be obtained at Week 16.

7.3. Video for Subjects on Clinical Research Participation

Subjects will view an educational video on clinical research participation entitled “What It Means to Take Part in Clinical Research Studies”. This 7-minute video provides general information, in lay terms, on the purpose of blinded, controlled clinical research studies and the roles and responsibilities of a subject in a clinical research study. Viewing of the video will be completed after informed consent but prior to any efficacy assessments (e.g., TFI) at the screening visit.

7.4. Efficacy Evaluations

Efficacy assessments include:

• Tinnitus Functional Index (TFI)

• Daily Tinnitus Annoyance NRS

• Daily Tinnitus Loudness NRS

• Patient Global Impression of Change (PGIC)

• Short Form 12 (SF-12) Health Survey

Subjects who use hearing aids, noise generators, and/or sound therapy devices should continue to do so during the study and should complete the tinnitus assessments and ratings (i.e., TFI, daily tinnitus annoyance NRS, daily tinnitus loudness NRS, PGIC, and SF-12) based on their tinnitus experience with the devices in use. Only stable tinnitus treatments (i.e., started at least 1 month prior to Screening) are allowed during the study and no new treatments should be introduced.

The TFI should be completed at the beginning of each visit prior to other study assessments. The recommended order in which study questionnaire assessments are conducted is: TFI, PGIC, SF-12, and C-SSRS (the C-SSRS is administered after all efficacy questionnaires have been completed). The daily tinnitus loudness and annoyance NRS should be completed at home on the study visit days.

7.4.1. Tinnitus Functional Index (TFI)

The TFI is a validated, 25-item questionnaire that can be used to scale overall severity of tinnitus and to assess treatment-related change in tinnitus (Meikle et al.. 2012; Henry et al.. 2015). The 25 items of the TFI represent 8 subscales covering multiple domains of tinnitus severity: 1) Intrusive, 2) Sense of Control, 3) Cognitive, 4) Sleep, 5) Auditory, 6) Relaxation, 7) Quality of Life, and 8) Emotional. Subjects answer each TFI question by rating their experience over the past week.

Completing the TFI provides an index score from 0 to 100, with higher scores representing a greater problem with tinnitus. A reduction in the TFI index score of 13 points or more is considered clinically meaningful improvement in tinnitus (Meikle et al., 2012).

Subjects will complete the TFI at Screening, Baseline (pre-dose), and Weeks 4, 8, 12 and 16. The TFI should completed at the beginning of each study visit.

7.4.2. Daily Tinnitus Annoyance Numeric Rating Scale (NRS)

Subjects will record their tinnitus annoyance using a tinnitus NRS diary. Numeric rating scales have been widely used to assess tinnitus severity and have demonstrated good test-retest reliability and concordance with other subjective measures of tinnitus (Meikle et al. 2008). Subjects rate their tinnitus annoyance over the past 24 hours. Subjects respond to the following question by selecting the box on the NRS scale corresponding to their degree of tinnitus annoyance on a scale of 0 (Not annoying) to 10 (Extremely annoying): “In the past 24 hours, how annoying was your tinnitus?”.

Subjects eligible at screening will begin using the tinnitus NRS diary at the start of the 14-day Lead-in period to record their tinnitus annoyance every day and will continue to record their tinnitus annoyance once per day through the 16-week Follow Up period. Subjects will be able to record missed diary entries for 1 day after a missed entry. Compliance with the tinnitus NRS diary will be monitored throughout the study with re-training, as necessary.

7.4.3. Daily Tinnitus Loudness Numeric Rating Scale (NRS)

Subjects will record their tinnitus loudness using a tinnitus NRS diary. Subjects rate their tinnitus loudness over the past 24 hours. Subjects respond to the following question by selecting the box on the NRS scale corresponding to the degree of tinnitus loudness on a scale of 0 (No tinnitus) to 10 (Extremely loud tinnitus): “In the past 24 hours, how would you rate the loudness of your tinnitus at its worst?”.

Subjects eligible at screening will begin using the tinnitus NRS diary at the start of the 14-day Lead-in period to record their tinnitus loudness every day and will continue to record their tinnitus loudness once per day through the 16-week Follow Up period. Subjects will be able to record missed diary entries for 1 day after a missed entry. Compliance with the tinnitus NRS diary will be monitored throughout the study with re-training, as necessary.

7.4.4. Patient Global Impression of Change (PGIC)

The PGIC is a patient-reported outcome that evaluates the change in overall “global” tinnitus status as perceived by the subject (Adamchic et al. 2012; van de Heyning et al. 2014). The subject is asked: “Since the beginning of the clinical study, how would you rate your tinnitus?”. The beginning of the clinical study in this context is the time prior to investigational product administration. The 7 response categories (and point scores) for the PGIC are:

• Very much improved = 3

• Much improved = 2

• Minimally improved = 1

• Unchanged = 0

• Minimally worse = -1

• Much worse = -2

• Very much worse = -3

Subjects will complete the PGIC at Weeks 4, 8, 12 and 16.

7.4.5. Short Form 12 (SF-12) Health Survey

The SF-12 is a validated, multipurpose short form survey of 12 questions, all selected from the SF- 36 Health Survey (Ware et al. 1996). The questions are weighted and scored to create two subscales, physical and mental health composite scores, as well as an overall health-related quality of life score.

Subjects will complete the SF-12 at Baseline (pre-dose), Week 8, and Week 16.

7.5. Safety Evaluations

Safety assessments include: Adverse events (see Section 8)

• Concomitant Medications

• Vital Signs

• Clinical Laboratory Tests (Hematology, Serum Chemistry, and Urinalysis)

• Otoscopy

• Audiometry

• Tympanometry

• C-SSRS Assessment

7.5.1. Vital Signs and Height/Weight Measurements

Vital signs measurements (including systolic and diastolic blood pressure, pulse rate, body temperature, and respiratory rate) will be collected at Screening, Baseline (pre-dose), Week 4, Week 8, Week 12, and Week 16.

Vital signs will be measured after subjects have been seated for 5 minutes and while subjects are in a sitting position.

7.5.2. Clinical Laboratory Tests

All clinical laboratory tests (except for urine pregnancy) will be processed by a Central Laboratory.

Non-fasting blood samples and urine samples for hematology, serum chemistry, urinalysis, and pregnancy tests will be prepared using standard procedures.

Clinical laboratory testing will be completed at Screening, Baseline (pre-dose) and Week 8. In addition, female subjects of childbearing potential will have serum pregnancy test for human chorionic gonadotropin (hCG) at Screening and a urine pregnancy test (hCG) at Baseline (predose) and Week 16. The urine pregnancy tests will be performed locally at the site, so results are available that day.

The blood and urine samples will be used for the following tests:

Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and platelet count.

Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl-transpeptidase, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total bilirubin, and total protein.

Urinalysis: appearance, color, pH, specific gravity, protein, glucose, ketones, nitrite, leukocyte esterase, urobilinogen, and microscopic sediment examination.

7.5.3. Otoscopy

Otoscopic exams will be used to assess the auditory canal, the appearance of the tympanic membrane, and the healing of the intratympanic injection site. Presence and size of tympanic membrane perforations will be recorded. Perforations of the tympanic membrane will be captured as AEs if the perforation does not resolve by the end of the study or increases in size.

Otoscopic examinations will be performed by the physician or qualified healthcare professional in both ears at Screening and Baseline (pre-dose) and in study ear only at Weeks 4, 8, 12 and 16.

7.5.4. Tympanometry

Tympanometry assessments will be used to assess the mobility and compliance of the tympanic membrane, pressure and volume in the outer ear canal, and function of the tympanic membrane, ossicles and Eustachian tube.

Tympanograms will be completed in both ears at Screening and Baseline (pre-dose) and in study ear only at Weeks 4, 8, 12 and 16, unless the examiner determines there is a contraindication to performing the procedure.

7.5.5. Audiometry

Audiometric assessments must be conducted in accordance with American-Speech-Language- Hearing Association Guidelines (ASHA, 2005). Equipment calibration must be current and documented. The audiometric assessments must be conducted by a licensed or certified audiologist or a qualified assistant with appropriate training under the direct supervision of a licensed or certified audiologist.

Audiograms are conducted at 250, 500, 1000, 2000, 4000, 6000, and 8000 Hz for air conduction and at 1000, 2000, and 4000 Hz for bone conduction at all study visits. Both air and bone conduction thresholds will be assessed. Subjects wearing hearing aids should be instructed not to wear their hearing aids during the audiogram.

Audiometry will be used to assess hearing function in both ears at Screening and Baseline (predose) and in study ear only at Weeks 4, 8, 12 and 16.

7.5.6. C-SSRS Assessment

The rater-administered Columbia Suicide Severity Rating Scale (C-SSRS) is a scale that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period (Posner 2011). Otologic conditions are sometimes associated with anxiety or depression, requiring prospective assessment of suicidal ideation to ensure patient safety. This is true whether or not a particular product is known or suspected to be associated with treatment- emergent suicidal ideation and/or behavior.

The C-SSRS scale includes questions to solicit the type of information needed to determine if a suicide-related thought or behavior occurred. The C-SSRS must be administered by appropriately trained and certified personnel.

The C-SSRS assessment will be administered at Screening, Baseline (pre-dose) and Weeks 4, 8, 12, and 16.

• The “Baseline” version of the C-SSRS will be used at Screening.

• The “Since Last Visit” version will be used at Baseline (pre-dose), and Weeks 4, 8, 12 and 16 or premature termination.

At Screening or Baseline (Day 1) visits, subjects are to be excluded (per Exclusion Criterion 8) if:

• subject answered “Yes” to Question 4 or 5 regarding active suicidal ideation,

• subject was deemed by the Investigator to be at significant risk of suicidal behavior, or

• subject had a positive score or report of new suicidal ideation or suicidal behavior on the “Since Last Visit” version.

The Investigator should record medical history of suicidal ideation or non-suicidal self-injurious behavior at Screening or Baseline (Day 1) visits if:

• subject has a post-Screening score of 1-3 for Ideation (i.e., a “yes” answer to Questions 1, 2, or 3), or

• subject has responded “yes” to the Non-Suicidal Self-Injurious Behavior question and the score is higher than the Screening C-SSRS score.

At post-dose visits (Weeks 4, 8, 12, and 16), the Investigator is to record an AE and assess use and dose of concomitant antidepressant medication (Section 7.2) if:

• subject has a positive score or report of new suicidal ideation or suicidal behavior,

• subject has a C-SSRS score of 1-3 for Ideation (i.e., a “yes” answer to Questions 1, 2, or 3),

• subject has a “yes” response to the Non-Suicidal Self-Injurious Behavior question and the score is higher than the “Baseline” C-SSRS score.

At post-dose visits (Weeks 4, 8, 12, and 16) the Investigator is to record a Serious Adverse Event (SAE) and assess use and dose of concomitant antidepressant medication (Section 7.2) if:

• subject has any post-Baseline C-SSRS score of 4 or 5 for Ideation (i.e., a “yes” answer to question 4 or 5), and/or

• any questions answered yes for Suicidal Behavior (with the exception of a “yes” response to the Non-Suicidal Self-Injurious Behavior question), and this was not observed at pre-dose testing.

SAE information is reported as indicated in Section 7.2

Subjects reporting new suicidal ideation or behavior can be managed by concomitant antidepressants and may continue in the study or may be discontinued, at the discretion of the Investigator. It is advised that subjects be referred to trained specialists for the treatment of depression, at the discretion of the Investigator.

Suicidality information is to be reported using the following possible AE terms: suicidal plans, suicidal ideation, suicidal tendency, suicidal behavior, suicidal intention, suicidal depression, active suicidal ideation, passive suicidal ideation, self-injurious behavior without suicidal intent.

8. ADVERSE EVENT REPORTING

Timely, accurate, and complete reporting and analysis of safety information from clinical trials will be conducted in accordance with Good Clinical Practice.

Adverse events will be monitored and documented starting during and after administration of investigational product until study participation is complete.

All AEs and serious adverse events (SAEs) that are reported or observed during or after dosing with the investigational product will be recorded on the AE page of the eCRF for all enrolled subjects.

Information to be collected includes description of event, affected ear (for ear-related events only), date of onset, Investigator-specified assessment of the severity and relationship to investigational product, relationship to the intratympanic injection, date of resolution of the event, seriousness, any required treatment or evaluations, and outcome. Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, or progression of disease states must also be reported. Perforations of the tympanic membrane will be captured as AEs if the perforation does not resolve by the end of the study or increases in size.

If the existing medical condition worsens at any time after the injection (e.g., requires intervention or treatment), it should be recorded as an AE (e.g., worsening tinnitus [identify L, R, or both ears]).

Wherever possible, a specific disease or syndrome rather than individual associated signs and symptoms should be identified by the Investigator and recorded on the eCRF using medical terminology. However, if an observed or reported sign or symptom is not considered a component of a specific disease or syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.

Laboratory abnormalities are not considered AEs unless they are associated with clinical signs, symptoms or require medical intervention. Laboratory values considered to be clinically significant may be more extreme than values that are simply outside normal ranges. A clinically significant finding on an examination (e.g., vital signs) or laboratory abnormality (e.g. detected on clinical chemistry or hematology), present at screening and significantly worsens, and requires medical or surgical intervention, or leads to study drug interruption or discontinuation - should be reported as an AE. Any abnormal test that is determined to be an error does not require reporting as an adverse event.

8.1. Adverse Event Classification Definitions

Adverse Event:

An AE is any unfavorable and unintended diagnosis, symptom, sign, syndrome, or disease which occurs after administration of investigational product, having been absent at baseline, or, if present at baseline, appears to worsen.

This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition, including abnormal results of diagnostic procedures and/or laboratory test abnormalities, which are considered AEs if they:

• result in discontinuation from the study

• require treatment or any other therapeutic intervention

• require further diagnostic evaluation (excluding a repetition of the same procedure to confirm the abnormality)

• are associated with clinical signs or symptoms judged by the Investigator to have a significant clinical impact

Serious Adverse Event (SAE):

An SAE is defined as any untoward medical occurrence that:

• results in death, is life-threatening (Note: the term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event rather than to an event which hypothetically might have caused death if it were more severe.),

• requires in-patient hospitalization or prolongation of existing hospitalization,

• results in persistent or significant disability /incapacity, or

• is a congenital anomaly/birth defect.

Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately lifethreatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the above definition. These events should be considered serious.

9. SUBJECT COMPLETION

9.1. Completion

Study subject participation is complete after Week 16 (Visit 6). Subjects who discontinue the study before completion of Week 16 (Visit 6) will not be considered to have completed the study.

9.2. Study Discontinuation

All subjects have the right to withdraw from study evaluations at any time, for any reason, without prejudice; nonetheless, Investigators should attempt to encourage subjects to complete the protocol so that continued observation and follow-up measurements may be obtained.

Subjects may be discontinued from the study for any of the following:

• Withdrawal of consent

• Lost to Follow-up

• Adverse Event

• Principal Investigator decision

• Sponsor decision

• Protocol deviation

• Other

At any point, the Investigator may discontinue the subject’s study participation at the discretion of the Investigator or at the request of the subject, and ensure the subject receives appropriate medical care; the Investigator may also consult the medical monitor to discuss out-of-range test results. 9.2.1. Handling of Withdrawals

Subjects will be free to withdraw from the study, including discontinuing investigational product administration, and further follow-up of the study at any time.

Should a request for early withdrawal from the study with no further follow-up be made, the subject should be encouraged to return to the study site for a last follow up visit and undergo all End-of-Study/Early-Termination assessments.

When a subject withdraws from the study prior to completing the End-of-Study Visit, the reason for withdrawal is to be documented on the eCRFs and in the source document.

9.2.2. Replacements

Subjects who discontinue participation in the study for any reason after dosing will not be replaced. The sample size was estimated to account for an assumed discontinuation rate of 15% by Week 8.

10. STATISTICAL METHODS

10.1. Introduction

Detailed methodology for summary and statistical analyses of the data collected in this study will be documented in a Statistical Analysis Plan (SAP). The SAP may appropriately modify the analyses specified in the protocol, as necessary.

10.2. Analysis Sets

The all enrolled set will include all subjects who sign an informed consent form.

The full analysis set (FAS) includes all randomized subjects, and they will be included in the group to which they were randomized.

The per-protocol analysis set (PP) includes all subjects in the full analysis set that provide TFI data at Weeks 4 and 8, and do not have any protocol deviations that may impact the outcome of the TFI overall score.

The safety analysis set includes all subjects who receive study treatment, and they will be included in the treatment group based on the treatment received.

The FAS and PP sets will be used for efficacy analyses. The safety analysis set will be used for all safety analyses.

10.3. Study Endpoints

10.3.1. Efficacy Endpoints The primary endpoint for this study is the percentage of subjects achieving response, where response is defined as achieving at least a 13-point reduction from baseline in the TFI overall score at both Weeks 4 and 8.

Secondary endpoints include the following:

• Change from Baseline in the NRS ratings of tinnitus annoyance

• Change from Baseline in the NRS ratings of tinnitus loudness

• Change from Baseline in TFI total score

• Change from baseline in TFI subscale scores (Intrusiveness, Sense of Control,

Cognitive, Sleep, Auditory, Relaxation, Quality of Life, Emotional)

• PGIC score

• Change from Baseline in SF-12 scores

10.3.2. Safety Endpoints

The safety endpoints include:

• Incidence of treatment-emergent adverse events

• Change from Baseline in tympanometry

• Change from Baseline in otoscopy

• Change from Baseline in audiometry

• Change from Baseline in suicidal ideation or behavior

• Incidence of concomitant medications

• Change from Baseline in vital signs and weight

10.4. Statistical Analyses

10.4.1. General

There will be two sets of analyses. The Primary analyses will be conducted after all subjects complete Week 8 of the study, with all planned analyses to be conducted with all data collected in the database at time of database freeze. There will be a final analysis conducted once all subjects complete Week 16 of the study, to include all data collected from all subjects across all time points.

All data collected will be summarized descriptively. Descriptive statistics for continuous data are number of subjects, mean, standard deviation, median, minimum, and maximum values. Descriptive statistics for categorical variables will include number of observations and percentages. 10.4.2. Efficacy Analyses

All efficacy endpoints will be summarized descriptively and analyzed using FAS. The primary endpoint will also be summarized descriptively and analyzed using PP.

10.4.2.1. Primary Analyses

The primary endpoint is the percent of responders at Week 8, where subjects will be classified as responders if they achieve at least a 13-point reduction from baseline in the TFI overall score at both Weeks 4 and 8. The primary endpoint will be summarized descriptively by treatment group. The percentage of responders will be analyzed using the common risk difference between treatment groups and will be tested using a Mantel-Haenszel test controlling for study site, duration of tinnitus, and baseline TFI overall score. Specifically, comparison between COMPOSITION A and placebo will be made by testing the following hypothesis:

The primary analysis will be conducted for the comparison of COMPOSITION A and placebo, using a 2-sided test and an alpha level of 5%. The 95% confidence intervals (CI) around the common risk difference will also be provided.

Missing data for the primary endpoint will be imputed using a multiple imputation technique that will be described in detail in the SAP.

10.4.2.2. Secondary Analyses

Secondary endpoints of the change from baseline in NRS Annoyance score, NRS Loudness score, TFI overall score, TFI subscale scores, PGIC, and SF-12 will be summarized descriptively by treatment group and visit.

There will be no adjustment of multiplicity across secondary endpoints.

10.4.2.2.1. Additional Responder Analyses

The following additional responder definitions will also be derived for Weeks 12 and 16:

• Week 12 responder #1: achieving at least a 13-point reduction from baseline in the TFI overall score at Weeks 8 and 12

• Week 12 responder #2: achieving at least a 13-point reduction from baseline in the TFI overall score at Weeks 4, 8, and 12

• Week 16 responder #1: achieving at least a 13-point reduction from baseline in the TFI overall score at Weeks 12 and 16

• Week 16 responder #2: achieving at least a 13-point reduction from baseline in the TFI overall score at Weeks 8, 12, and 16 • Week 16 responder #3: achieving at least a 13-point reduction from baseline in the TFI overall score at Weeks 4, 8, 12 and 16

These additional responder secondary endpoints will be analyzed in the same manner as the primary analysis as described in Section 11.4.2.1.

10.4.2.2.2. Continuous Endpoint Analyses

The change from baseline in NRS Loudness, NRS Annoyance, TFI Total score, each TFI subscale score, and SF-12 will each be analyzed using a linear mixed-effects model with treatment, study day, treatment-by-study day interaction, study site, baseline TFI overall score, and duration of tinnitus as fixed effects. The unstructured covariance model will be used. Least-square adjusted means, the estimated difference in adjusted means between treatment groups and associated 95% Cis will be provided.

10.4.2.2.3. Categorical Endpoint Analyses

The results of the PGIC will be analyzed using a Cochrane-Mantel-Haenszel mean score test controlling for study site, baseline TFI score, and duration of tinnitus. This will be done to compare COMPOSITION A with placebo.

10.4.3. Safety Analyses

All safety endpoints will be summarized descriptively using the safety analysis set. If descriptive summaries warrant further exploration of comparisons between treatment groups, then additional safety analyses may be conducted in an ad hoc manner.

10.4.3.1. Adverse Events

The primary analysis of AEs will consider only treatment-emergent adverse events (TEAEs), events occurring for the first time, or worsening during or after the first dose of investigational product. Subject incidence of TEAEs and SAEs will be tabulated by Preferred Terms (PTs) and System Organ Class (SOC). Severity and relationship to investigational product will also be presented. For summary tables, a subject who experiences the same coded event more than once is counted only one time for that coded event at the highest severity level. AEs will be presented by descending order of frequency in MedDRA SOC and PT.

Listings of all SAEs, AEs leading to study withdrawal, and deaths on-study will also be included. Duration and outcome of each AE will be reported in subject listings.

10.4.3.2. Tympanometry, Otoscopic, and Audiometry

The tympanometry category (A, B-small volume and/or normal, B-large volume, or C) will be summarized by treatment group and study visit. Observations recorded during the conduct of otoscopic exams will be descriptive in nature. The number and percent of subjects presenting with each otoscopic classification will be provided by treatment group and study visit. Where relevant, the number and proportion of subjects with changes in their otoscopic classification from Baseline to the endpoint visit will also be provided for each treatment group. Presence and absence of tympanic membrane perforations will be summarized by treatment group and study visit; the size of any tympanic membrane perforation will be classified as follows: pinhole; <25% of tympanic membrane; 25% to <50% of tympanic membrane; >50% of tympanic membrane.

Descriptive summary statistics for audiometric assessments of air and bone conduction thresholds at each frequency will be provided by treatment group and study visit. All audiometry assessments will be tabulated separately for the treated and untreated ear.

10.4.3.3. Columbia-Suicide Severity Rating Scale (C-SSRS)

The C-SSRS will be administered at each visit using the appropriate version i.e., “Baseline” or “Since Last Visit”.

The “Baseline” version of the C-SSRS captures both suicidal ideation and suicide behavior (lifetime). There are 5 suicidal ideation questions, each captured as yes/no for the subject’s lifetime. There are 4 suicidal behavior questions, each captured as yes/no for the subject’s lifetime. An additional question asks if suicidal behavior is present during the visit. All suicidal ideation and behavioral variables as outlined here will be tabulated overall and by treatment group.

The C-SSRS version used at visits subsequent to the Baseline Visit will be a modified version of the “Baseline” C-SSRS. This “Since Last Visit” version uses the same individual variables for suicidal ideation and behavior assessed at Baseline to capture changes, if any, from previous assessments. In addition, overall suicidality (yes/no) will be defined as any suicidal ideation or behavior since the last visit.

All suicidal ideation and behavior variables will be tabulated overall and by treatment group using a shift table for interpretation of changes in C-SSRS results between baseline and post-baseline assessments. All C-SSRS data will be included in data listings.

10.4.4. Concomitant Medications

Incidence of concomitant medications of interest will be provided for each treatment group. The list of concomitant medications of interest will be provided in the SAP.

10.4.5. Laboratory Parameters, Vital Signs and Weight

The analysis of laboratory parameters and vital signs will include descriptive statistics for the change from baseline to the endpoint visit, change from Baseline for each visit (vital signs only). Where appropriate, analyses will also include shifts from Baseline to the endpoint visit. For laboratory values, the normal ranges will be used to determine the classifications. Values below the normal range will be classified as low, values above the normal range will be classified as high, and values within the normal range will be classified as normal.

10.5. Sample Size

The primary endpoint is the percentage of responders, where response is defined as achieving at least a 13 -point reduction from baseline in the TFI total score at both Weeks 4 and 8. It was observed from the previous study (Example 5) that the response rate for COMPOSITION A (0.32 mg) was 43% and 13% for placebo. Based on these results, the assumed rate of response for COMPOSITION A is 43% and 18% for placebo, which is the 13% observed response rate in previous study plus 5% inflation for potential placebo response.

Assuming a 2-sided test and level of significance of 0.05, 60 subjects in the placebo arm and 60 subjects in each of the COMPOSITION A arms will provide approximately 85% power to detect a treatment difference in favor of COMPOSITION A. It is also assumed that an observed discontinuation rate of 15% will be observed, hence the total sample size is planned to be 140 subjects, 70 subjects per arm. These sample size calculations were conducted using EASTv6.5 software with a test for a difference in proportions between two groups.

11. INVESTIGATIONAL PRODUCT INFORMATION

11.1. Physical Description of Investigational Product

The investigational product administered to subjects will be COMPOSITION A and placebo. COMPOSITION A is supplied as a 1 mL sterile solution (1.6 mg/mL [0.16%] gacyclidine in medium-chain triglycerides) in a vial. Placebo is provided as a 1 mL sterile solution of 100% medium-chain triglycerides in a vial. The vials are provided as kits, and all kits must be stored at 2-8°C until use.

11.2. Directions for Use

COMPOSITION A and placebo syringes will be prepared in a clean, secure location at room temperature. Please refer to the Pharmacy Manual for detailed investigational product preparation instructions.

11.3. Packaging and Labeling

11.3.1. Packaging

All investigational product kits will be labeled with information that will meet the applicable regulatory requirements. 11.3.2. Labels and Labeling Instructions

A label will be affixed to each kit box indicating kit number and storage instructions. A label will be affixed to the COMPOSITION A and placebo vials indicating contents and storage instructions.

11.4. Management of Clinical Supplies

The clinical supplies will be managed by the IRT system; instructions will be provided to all sites. The IRT will create shipment requests that will be generated based on inventory thresholds that are set for each site. A shipment request will be generated by IRT and sent to the clinical supply vendor. Upon shipment and receipt of the clinical study material, the site personnel will acknowledge the shipment and identify any damaged, missing, or unusable kits so they will not be dispensed.

11.4.1. Storage of Kits

All kits will be stored in accordance with instructions on the investigational product label. All temperature excursions of the investigational product must be documented in the investigational product accountability log. Any excursions within the allowable temperature range and conditions should be documented, but the investigational product is still acceptable for use and dispensing to subjects. If any excursions are outside of these conditions, the investigational product should not be used to treat subjects. If this occurs, the individual preparing the investigational product should immediately quarantine the product and report the kit(s) as unacceptable for dispensing to IRT to remove it from inventory.

[00226] A total of 35 patients were randomized (FIG. 8). Thirty -one patients in were randomized and completed at least one postbaseline TFI assessment (evaluable set). Overall, treatment groups were similar with respect to demographic and baseline characteristics (Table 1). Based on audiometry, patients exhibited a wide range of hearing thresholds and most patients had slight or mild hearing loss (based on PTA; 16-25 dB and 26- 40 dB, respectively). The use of hearing aids as well as psychoactive medications including those for symptoms related to tinnitus (e.g., antidepressants, medications for anxiety and insomnia) was comparable for COMPOSITION A and placebo groups and therefore unlikely to have an impact on COMPOSITION A results in this study. Of the COMPOSITION A treated patients, three of six responders were on stable doses of antidepressant and anti-anxiety medications compared with three of eight non-responders, hence the use rate of these medications was similar between responders and non-responders.

[00227] A single intratympanic injection of COMPOSITION A was well-tolerated and patients who received COMPOSITION A had a lower incidence of adverse events than placebo (FIG. 15). There were no adverse events that led to withdrawal, and a very low incidence of tympanic membrane perforation (one) which resolved by the end of the study. There was one serious adverse event (stress cardiomyopathy), but it was not considered related to study drug. Most adverse events were ear- or injection site-related, were mild to moderate in intensity, and resolved by the end of the study. There were no meaningful changes from baseline in tympanometry, otoscopy, or audiometry. There were no notable changes in clinical laboratory tests, vital signs, or assessment of suicidality. Plasma concentrations of gacyclidine were below the limit of assay quantitation (0.1 ng/mL) for both dose levels at all timepoints confirming limited systemic exposure.

[00228] The mean TFI overall score, NRS loudness, and NRS annoyance reduction from baseline trended in favor of COMPOSITION A at each visit (FIG. 9 and 14). Subgroup analyses were performed and showed differences in favor of COMPOSITION A for different subgroups, including: age less than or equal to median age (57 years) at baseline, tinnitus etiology of sensorineural hearing loss and age-related hearing loss, 3 to 6 months tinnitus duration, 76 to 100 (or 40-100) baseline TFI overall score, change in TFI auditory subscale questions at Day 57, and 41 to 70 dB hearing loss at baseline (FIGs. 11-13).

[00229] A clinically meaningful, 13 -point improvement on the TFI was observed in 43% (6/14) of COMPOSITION A patients at both Week 4 and Week 8 versus 13% (2/16) of placebo patients (ad hoc p-value for difference in response rates was 0.026) (FIG. 10). The higher responder rate for COMPOSITION A versus placebo was maintained for all TFI improvement levels of 15, 20, 25, and 30 points.

[00230] All TFI subscales showed numerical improvement in the COMPOSITION A group versus placebo. The auditory subscale score displayed the greatest difference between COMPOSITION A and placebo, in favor of COMPOSITION A. Mean change from baseline in TFI auditory subscale questions for the ability to hear clearly, understand people, and follow conversations for responders showed numerical improvement overtime in patients who received COMPOSITION A compared with those who received placebo. Additionally, quality of life, emotional, and sense of control subscales displayed a mean change from baseline in TFI subscale score of at least 13 -points.

[00231] Treatment with COMPOSITION A led to numerical reductions in the daily ratings of tinnitus loudness and annoyance. The 7-day average tinnitus loudness and annoyance NRS decreased overtime in favor of COMPOSITION A compared with placebo, with a decrease from baseline for the COMPOSITION A group as early as Week 2 and the largest decrease at Week 8. For the six COMPOSITION A patients who were TFI responders, the mean decrease in tinnitus loudness was -1.7 (1.9) at Week 4 and -2.5 (2.2) at Week 8, and in tinnitus annoyance was -1.9 (1.9) at Week 4, and -2.4 (2.0) at Week 8.

[00232] All responders had an improved or unchanged PGIC response category at Week 8. Correlations existed when assessing the relationship for change from baseline in TFI overall score versus each of PGIC (-0.75), change from baseline in tinnitus annoyance NRS (0.74), and change from baseline in tinnitus loudness NRS (0.79) across all evaluable patients. These correlations were very strong when assessing COMPOSITION A responders (-0.79, 0.85, 0.90, respectively).

Notably, correlation coefficient between improvement in TFI and improvement in tinnitus loudness and annoyance levels as well as PGIC > 0.8 (considered “very strong” relationship

Example 6 — Additional Clinical Trial of Gacyclidine MCT Formulations

[00233] In Example 2, single dose nonclinical toxicology studies in rats and cats have been conducted and the results support the clinical investigation of COMPOSITION A in the current study. Additionally, pharmacokinetic assessments have been conducted in these species that provides a complete profile of exposure of COMPOSITION A to the inner ear compartment after intratympanic administration of COMPOSITION A, with negligible systemic exposure.

1. OBJECTIVES

1.1. Primary objective

• To evaluate the safety and tolerability of a single-dose of COMPOSITION A in subjects with subjective tinnitus (unilateral and/or bilateral).

1.2. Secondary objective

• To assess the plasma PK of gacyclidine including (+) and (-) enantiomers of gacyclidine (and possibly its metabolites).

1.3. Tertiary objective

• To assess the activity of COMPOSITION A using the Tinnitus Functional Index (TFI), Patient Global Impression of Severity (PGIS), and Patient Global Impression of Change (PGIC).

2. OVERVIEW OF STUDY DESIGN

This study will be conducted at 1-2 sites in the United States and will involve one overnight stay in the Phase 1 unit. The in-patient portion of the study will last a minimum of 24 hours from the time of intratympanic injection to allow for pharmacokinetic collection and safety assessment. The total study duration for each subject will be approximately 4-7 weeks, including an up to 3-week Screening period and a 4-week follow-up period post-intratympanic injection.

Cohort 1 will evaluate 0.64 mg COMPOSITION A or placebo administered as a single-dose by intraympanic injection to a single (study) ear (unilateral injection), Cohort 2 will evaluate 0.32 mg of COMPOSITION A or placebo administered as a single-dose by intratympanic injection to each ear (bilateral injection), and Cohort 3 will evaluate 0.64 mg COMPOSITION A or placebo administered as a single-dose by intratympanic injection to each ear (bilateral injection). After signing informed consent and completing Screening, eligible subjects will be randomized to COMPOSITION A or placebo at the Baseline visit (Day 1). For each of these cohorts, approximately 8-12 subjects will receive intratympanic injection(s) of either COMPOSITION A or placebo in a 3: 1 randomization ratio. Plasma samples for PK analysis will be obtained on Day 1 (pre-dose, 0.5, 1, 2, 4, 8, and 12 hours post-administration), Day 2 (24 hours postadministration), and Day 8 (168 hours post-administration]. Subjects will remain overnight in the Phase 1 unit on Day 1 and will be discharged on Day 2 after a minimum 24-hour in-patient stay. Follow-up visits for safety and activity assessments will be conducted on Week 1 (Day 8), Week 2, and Week 4 (end of study) or upon early termination from the study. Activity assessments include the TFI completed at Screening, Baseline (pre-dose on Day 1) and Week 4, the PGIS assessed at Baseline (pre-dose on Day 1) and Week 4, and the PGIC which will be completed at Week 4. There are no restrictions for conducting Cohorts 1 and 2 in parallel.

2.1. Dose escalation and safety data review

Standard safety data reviews are conducted prior to escalating to the next higher dose-level cohort.

Study Design Schematic

3. STUDY POPULATION

3.1. General Considerations

Approximately 24-36 subjects will be enrolled at approximately 1-2 Phase 1 study sites in the United States. Subjects will be eligible if they meet all of the following inclusion criteria and none of the exclusion criteria.

3.2. Inclusion Criteria

1. Cohort 1 only: Subject has subjective unilateral or bilateral tinnitus and is consistently aware of their tinnitus throughout much of the waking day.

2. Cohorts 2 and 3: Subject has subjective bilateral tinnitus and is consistently aware of their tinnitus throughout much of the waking day.

3. Subject is a male or female aged 18 to 70 years, inclusive.

4. Subject’s tinnitus is likely of cochlear origin, e.g., associated with sensorineural hearing loss; acute hearing loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma); age-related hearing loss; resolved otitis media; ototoxic drug exposure.

5. Subject has audiometrically-defmed normal hearing or up to severe hearing impairment in the affected ear(s) to be injected as charterized by pure tone average of < 90 dB at 1000, 2000, and 4000 Hz at Screening.

6. Female subjects of childbearing potential [i.e., not surgically sterile and/or not post-menopausal (>12 months since last menstrual period with no alternative medical cause)] must have a negative urine pregnancy test at Baseline (Day 1). Women of childbearing potential who are not abstinent from sex with male partners must use highly effective methods of contraception for the duration of the study including: established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system. Female subjects of childbearing potential must also refrain from egg donation or retrieval for the duration of the study.

7. Male subjects (unless surgically sterile) who are not abstinent from sex with female partners of childbearing potential must agree to use a highly effective contraceptive method (as detailed for Inclusion Criteria 6). Male subjects must refrain from sperm donation for the duration of the study.

Note: Abstinence (male or female subjects) is acceptable if this in the usual lifestyle and preferred contraception for the subject. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptableSubject is willing to comply with the protocol and attend all study visits.

8. Subjet is willing to comply with the protocol and attend all study visits.

9. Subject is able to provide written informed consent after the scope and nature of the investigation have been explained, and before the initiation of any study-related procedures.

3.3. Exclusion Criteria

1. Subject has pulsatile tinnitus, tinnitus resulting from traumatic head or neck injury, tinnitus resulting from a tumor or stroke, or tinnitus resulting from COVID-19 infection or vaccination.

2. Subject has active middle ear disease (including but not limited to: chronic otitis media, acute otitis media, middle ear effusions, middle ear atelectasis, or cholesteatoma), Meniere’s disease as outlined by the American Academy of Otolaryngology-Head and Neck Surgery Equilibrium Committee in 2015 (Goebel 2016), concurrent vestibular pathology, or vestibular schwannoma at the Investigator’s discretion.

3. Subj ect is not able to accurately identify and report their tinnitus per Investigator’ s opinion.

4. Subject has an abnormality of the tympanic membrane in the study ear that would increase the risk associated with intratympanic injection, including but not limited to monomeric tympanic membrane.

5. Subject has evidence of perforation or lack of closure of the tympanic membrane at Screening or Baseline (Day 1) visits.

6. Subject is receiving any ongoing therapy known as potentially tinnitus-inducing (e.g. aminoglycosides, ototoxic chemotherapeutic drugs, loop diuretics, quinine, high doses of aspirin or other nonsteroidal anti-inflammatory drugs). Usage of low doses of aspirin (e.g., daily doses of 81 mg) or other non-steroidal anti-inflammatory drugs may be permitted at the Investigator’s discretion.

7. Subject answered “Yes” to Question 4 or 5 regarding active suicidal ideation on the C-SSRS administered at Screening or Baseline (Day 1) visits. In addition, subjects deemed by the Investigator to be at significant risk of suicidal behavior should be excluded.

8. Subject has moderate to severe or untreated/uncontrolled depression or anxiety that, in the Investigator’s opinion, would likely reduce the safety of study participation or compliance with study procedures. Only stable doses (taken for > 1 month prior to Screening) of antidepressant and anti-anxiety medications are allowed during the study.

9. Subject is pregnant, lactating, or undergoing fertility treatment.

10. Subject has a history of substance abuse or addiction (e.g., cocaine, heroin) within the preceding 12 months prior to Screening or tests positive for selected drugs of abuse at Screening or Baseline (Day 1) visits.

11. Subject has received or is receiving concomitant treatment with any other NMDA receptor antagonist (e.g., memantine, dextromethorphan) within 30 days prior to the Baseline visit. Note, occasional use of dextromethorphan for cough suppression is allowed except between 7 days prior to Baseline and 7 days after injection of the investigational product.

12. Subject has a history of previous use of intratympanic gentamicin in the study ear.

13. Subject has received systemic or intratympanic steroids (including dexamethasone) within 6 weeks prior to the Screening visit.

14. Subject has previously participated in a study with COMPOSITION A or OTO- 311.

15. Subject has used moderate or strong inducers of CYP2B6 (e.g. carbamazepine, efavirenz, rifampin, or ritonavir) within 30 days prior to Screening.

16. Subject has used an investigational drug or device within 30 days prior to Screening.

17. Subject has other clinically significant illness, medical condition or medical history at Screening or Baseline (Day 1) that, in the Investigator’s opinion, would likely reduce the safety of study participation or compliance with study procedures.

4. RANDOMIZATION AND BLINDING

4.1. Overview

A single-dose of 0.64 mg COMPOSITION A administered by unilateral intratympanic injection and single-doses of 0.32 mg and 0.64 mg COMPOSITION A administered by bilateral intratympanic injection are planned to be tested in this study. Enrolled subjects will be assigned randomly to either COMPOSITION A or placebo using a 3: 1 allocation ratio (COMPOSITION A:placebo), based on a computer-generated randomization schedule.

4.2. Enrollment Procedures

4.2.1. Assignment of Subj ect Identification Numbers

At the Screening visit (Visit 1), subjects signing the informed consent will be assigned a sequential subject identification number by the site. Once assigned, the subject identification number will not be re-assigned and should not be changed. This number will be used to identify the subject throughout the study, including the Screening period. Subjects will be considered enrolled into the study once they are randomized.

4.2.2. Treatment Assignment

After a subject has met all prerequisites for randomization on Day 1 (Baseline/Visit 2), study sites will execute each randomization via the interactive web randomization system (IWR). Study site personnel, who are blinded to treatment assignment, will receive a randomization notification indicating the kit number (packaged investigational product), and the date and time of randomization for each subject. Once assigned, kit numbers cannot be re-assigned. Subjects will be considered enrolled into the study once they are randomized.

Study sites will provide the information contained in the IWR randomization notification to the person responsible for preparation of the syringe containing investigational product (COMPOSITION A or placebo). The unique kit number provided by IWR will correspond to a kit of packaged investigational product labeled with the identical kit number. The syringe will be prepared from the contents of the investigational product package corresponding to the kit number according to the instructions in the study Pharmacy Manual. The subject identification number and kit number both must be recorded in the subject’s record.

4.2.3. Randomization Algorithm

Subjects will be randomized in a 3: 1 ratio (COMPOSITION A:placebo) of treatment groups using a permuted block randomization algorithm.

The randomization process will be deployed via IWR which is accessible 24 hours a day to authorized users. The subject’s randomization number will determine the randomized treatment assignment. Investigational product kits will be labeled with a unique kit number using a separate and independent randomization algorithm. Numbered kits will be dispensed based on the treatment assignment.

4.3. Blinding

The blind should be broken for site personnel only if knowing the subject’s treatment allocation would facilitate specific medical treatment. In all cases, the Investigator should consult with the medical monitor prior to unblinding, if possible, and must contact the medical monitor as soon as it is practical after unblinding has occurred and treatment initiated.

5. DOSAGE AND ADMINISTRATION

5.1. Investigational Product Administration

COMPOSITION A or placebo will be administered as a single (0.2 mb volume) intratympanic injection to an affected ear for unilateral administration or to each ear for bilateral administration. Only a physician may perform the intratympanic injection.

Recommended needles may be 25, 26, or 27 gauge and typically range from 1.5 to 3.5 inches in length.

7. Place the subject in a recumbent position with the ear to be injected upwards.

8. Prior to COMPOSITION A or placebo administration, confirm the ear to be treated.

9. Anesthetize the tympanic membrane by covering the external surface of the inferior-posterior quadrant with topical preparation containing lidocaine, prilocaine, or other related anesthetic (e.g. EMLA® cream or lidocaine spray or solution) until the tympanic membrane is numb. If necessary, suction away excess topical preparation. Phenol should not be used to anesthetize the tympanic membrane.

10. Using the prepared syringe, insert the needle into the inferior-posterior quadrant of the tympanic membrane at the level of the round window, taking care not to insert the needle further than necessary.

11 . With the needle bevel facing in the inferior-posterior direction, inject 0.2 mL of COMPOSITION A or placebo towards the round window.

12. For unilateral injection (Cohort 1), have the subject remain recumbent for at least 15 minutes following the injection. For bilateral administration (Cohorts 2 and 3), have the subject remain recumbent for at least 15 minutes following the first ear injection and perform the second ear injection at least 15 minutes but no later than 90 minutes after the first ear injection. After dosing the second ear, have the subject remain recumbent for at least 15 minutes.

5.2. Compliance

COMPOSITION A or placebo will be administered by a physician as a single-dose, intratympanic injection at Day 1. Cohort 1 will receive a single unilateral injection to one ear, while Cohorts 2 and 3 will receive a single injection to each ear (bilateral). Any deviations in administration will be documented in the source documents and the eCRF.

The site will maintain a log of all investigational product dispensed and returned. Investigational product supplies for each subject will be inventoried and accounted for in the study.

6. PRIOR, CONCOMITANT AND SUBSEQUENT THERAPY

Use of all concomitant medications will be recorded in the subject’s eCRF. This will include all symptomatic relief medications for tinnitus symptoms, prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications taken within 30 days before randomization, which will be considered prior therapy. COVID- 19 vaccination at any time prior to Screening or during the study will also be recorded.

At the discretion of the Investigator, any concomitant medication deemed necessary for the welfare of the subject may be continued at stable doses during the study, except for those medications listed in Section 6. 1 . Any changes in concomitant medications will be recorded in the subject’s eCRF.

6.1. Prohibited Therapy During the Study Period

The following therapies are prohibited during the study:

• Phenol for use in anesthetizing the tympanic membrane.

• Intratympanic injection other than that outlined in the current study.

• Systemic corticosteroids (inhaled and nasal steroids are permitted). Other investigational drug(s) or device(s).

• Other NMDA receptor antagonists (e.g. memantine, dextromethorphan). Note, occasional use of dextromethorphan for cough suppression is allowed except between 7 days prior to Baseline and 7 days after injection of the investigational product.

• Medications known as potentially tinnitus-inducing (e.g. aminoglycosides, ototoxic chemotherapeutic drugs, high doses of intravenous loop diuretics, quinine, high doses of aspirin or other non-steroidal anti-inflammatory drugs). Usage of low doses of aspirin (e.g., daily doses of 81 mg) or low doses of other non-steroidal antiinflammatory drugs for intermittent pain relief may be permitted at the Investigator’s discretion.

• Medications that are considered moderate or strong inducers of CYP2B6 (e.g. carbamazepine, efavirenz, rifampin, and ritonavir).

6.2. Symptomatic Relief Medications and Therapies

It is recognized that subjects may at times use certain medications, devices (hearing aids, sound/noise therapy devices), and behavioral therapy for relief of symptoms related to tinnitus during the study. Only stable doses (taken for > 1 month prior to Screening) of antidepressant and anti-anxiety medications are allowed during the study.

Subjects who use hearing aids, noise generators, and/or sound therapy devices should continue to do so during the study and should complete the tinnitus assessments (i.e., TFI, PGIS, and PGIC) based on their tinnitus experience with the devices in use.

Any changes reported by the subject for tinnitus-specific treatments and therapies should be recorded in the subject’s eCRF.

7. STUDY EVALUATIONS

7.1. Study Procedures by Visit

7.1.1. Screening Period: Up to 21 days prior to Baseline

The following assessments, as listed in the Time and Events Schedule (Table 1), will be performed during the screening period: informed consent, review and confirm eligibility criteria, medical history (including history of COVID- 19 infection), demographics, concomitant medications (including COVID-19 vaccination), vital signs, height and weight measurements, serum pregnancy test (for female subjects of childbearing potential only), clinical laboratory tests, tympanometry, audiometry, otoscopy, TFI assessment, and C-SSRS assessment: Baseline version. The modified Tinnitus Sample Case History Questionnaire (TSCHQ) will be completed at Screening as part of medical history to capture tinnitus-specific medical history.

7.1.2. Check-in to Research Unit/Baseline/Investigational Product Administration: Day 1

Once a subject has signed consent, completed the Screening assessments, and met all study eligibility criteria, the subject will check into the Research Unit for an overnight stay. Results from the concomitant medications review, urine pregnancy test (for female subjects of childbearing potential), and C-SSRS (“Since Last Visit” version) must be available and reviewed by the Investigator to confirm the subject’s eligibility before randomization. In addition, the following assessments are to be performed on all subjects prior to dosing to establish Baseline status: medical history, vital signs, clinical laboratory tests, tympanometry, audiometry, otoscopy, TFI, PGIS, and pre-dose PK sample. Tympanometry and audiometry at Day 1 may be completed at Day 1 (pre-dose) or up to 5 days prior to Day 1, and there must be at least a 5-day interval between the Screening and Day 1 assessments.

If the subject is no longer eligible, the subject will not be randomized and should be recorded as a screen failure. Information related to specific inclusion/exclusion criteria will be documented. Once eligibility status is confirmed and the subject is randomized, the investigational product is administered and the remaining Day 1 assessments (i.e., PK sampling at 0.5, 1, 2, 4, 8, and 12 hours [± 15 minutes at each timepoint] post-dose, AE monitoring) are completed.

7.1.3. Discharge from Research Unit: Day 2

Prior to discharge from the research unit on Day 2, the following assessments are to be performed: concomitant medications, vital signs, AE collection, and the plasma PK sample at 24 [± 1 hour] hours post-administration.

7.1.4. Week 1 (Day 8): Follow Up

The primary purpose of Week 1 (Day 8) visit is to capture safety and PK data. Safety assessments include concomitant medications, vital signs, clinical laboratory tests, tympanometry, audiometry, otoscopy, C-SSRS, and AE collection. A final PK sample will be obtained at this visit at 168 [± 6 hours] hours post-administration.

7.1.5. Week 2 (Day 15 [± 2 days]): Follow Up The primary purpose of Week 2 (Day 15) visit is to capture safety data. Safety assessments include concomitant medications, vital signs, tympanometry, audiometry, otoscopy, C-SSRS, and AE monitoring.

7.1.6. Week 4 (Day 29 [± 2 days]): End of Study /Early Termination

The primary purpose of Week 4 (Day 29) visit is to capture final safety and activity data. Safety assessments include concomitant medications, weight, vital signs, urine pregnancy test for women of childbearing potential, clinical laboratory tests, tympanometry, audiometry, otoscopy, C-SSRS, and AE monitoring. Activity assessments include the TFI, PGIS, and PGIC.

If a subject terminates from the study prior to Week 4 (Early-Termination), every attempt should be made to perform all assessments as listed for Week 4.

7.1.7. Unscheduled Visit

Unscheduled Visits may occur in the event of safety-related issues. Appropriate safety assessments (e.g., otoscopy, vital signs, clinical laboratory tests) may be conducted at the Investigator’s discretion at Unscheduled Visits.

7.2. Medical History and Demographics

The medical history will be obtained from medical records and/or via subject interview at the Screening visit, and includes general medical history, medication history including COVID-19 vaccination), and history of COVID-19 infection. Tinnitus-specific medical history information is also obtained by having potential subjects complete the modified TSCHQ at Screening. Medical history, conditions, and procedures that occurred prior to Screening may be added throughout the study (if identified later).

Demographic information will also be obtained at the Screening visit and will include: age; sex; race; height, without shoes (cm); body weight, without shoes (kg); and highest level of education completed.

7.3. Activity Evaluations

Activity assessments include:

Tinnitus Functional Index (TFI)

Patient Global Impression of Severity (PGIS)

Patient Global Impression of Change (PGIC) Subjects who use hearing aids, noise generators, and/or sound therapy devices should continue to do so during the study and should complete the tinnitus assessments (i.e., TFI, PGIS, and PGIC) based on their tinnitus experience with the devices in use.

The recommended order in which study questionnaire assessments are conducted is: TFI, PGIS, PGIC, and C-SSRS.

7.3.1. Tinnitus Functional Index (TFI)

Subjects will complete the TFI at Screening, Day 1 (pre-dose), and Week 4.

7.3.2. Patient Global Impression Scales (PGIS and PGIC)

The global assessment tools, Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC), evaluate the subject’s overall perception of their condition, in this case tinnitus. Both are l-item questionnaires using balanced Likert scales that ask the subject to rate the severity of their tinnitus (PGIS, using a single-state 5- point categorical scale) or to rate the perceived change in their tinnitus in response to treatment (PGIC, using a transitional 7-point categorical scale). The PGIC has been used in the validation of the TFI (Meikle et al., 2012) and to assess the change in overall “global” tinnitus status as perceived by the subject (Adam chic et al. 2012; van de Heyning et al. 2014).

For the PGIS, the subject is asked: “Please choose the response below that best describes the severity of your tinnitus over the past 7 days.” The 5 response categories (and point scores) for the PGIS are:

None = 0 Mild =1

• Moderate = 2

• Severe = 3

• Very severe = 4

For the PGIC, the subject is asked: “Since the beginning of the clinical study, how would you rate your tinnitus?”. The beginning of the clinical study in this context is the time prior to investigational product administration. The 7 response categories (and point scores) for the PGIC are:

• Very much improved = 3

• Much improved = 2

• Minimally improved = 1

• Unchanged = 0

• Minimally worse = -1

• Much worse = -2

• Very much worse = -3

Subjects will complete the PGIS on Day 1 (Baseline) and Week 4, and the PGIC at Week 4.

7.4. Blood Sampling for Plasma PK Evaluations

Blood samples for plasma gacyclidine (including (+) and (-) enantiomers of gacyclidine and possibly its metabolites) will be collected from all subjects.

On Day 1 (Baseline), a pre-dose sample will be collected at any time prior to the intratympanic administration and post-dose samples will be collected at 0.5, 1, 2, 4, 8, and 12 hours (± 15 minutes at each timepoint) after intratympanic administration. On Day 2, a 24-hour PK sample will be obtained at 24 hours [±1 hour] post-administration. On Day 8, a final PK sample will be obtained at 168 hours [± 6 hours] post-administration. Timing for post-dose PK samples for bilateral administration (Cohorts 2 and 3) will be based on the time after the second ear has received the intratympanic injection.

Collection, storage, and shipping of plasma PK samples for gacyclidine will be performed as outlined in the Laboratory Manual. Every attempt should be made to collect samples at the protocol-specified times.

Plasma samples will be evaluated for gacyclidine including (+) and (-) enantiomers of gacyclidine and (possibly its metabolites) using validated analytical procedures by a bioanalytical laboratory.

7.5. Safety Evaluations

Safety assessments include:

• Adverse events (see Section 9)

• Vital Signs and Weight Measurements

• Clinical Laboratory Tests (Hematology, Serum Chemistry, and Urinalysis)

• Tympanometry

• Audiometry

• Otoscopy

• C-SSRS Assessment

• Concomitant Medications

7.5.1. Vital Signs and Weight Measurements

Vital signs measurements (including systolic and diastolic blood pressure, pulse rate, body temperature, and respiratory rate) will be collected at Screening visit, Day 1 pre-dose, and approximately 2, 4, 8, and 12 hours post-dose on Day 1, at approximately 24 hours postdose on Day 2, and at Week 1, Week 2, and Week 4 visits.

Vital signs should be measured per standard practice (e.g., after subjects have been seated for 5 minutes and while subjects are in a sitting position).

Weight will only be measured at Screening and at Week 4. Height will only be measured at Screening.

7.5.2. Clinical Laboratory Tests

All clinical laboratory tests, except for urine pregnancy and urine drug screen, will be processed by a Central Laboratory.

Blood and urine samples for hematology, serum chemistry, urinalysis, pregnancy tests, and urine drug screens will be prepared using standard procedures. Clinical laboratory testing will be completed at Screening, Day 1 (pre-dose), Week 1, and Week 4. In addition, female subjects of childbearing potential will have serum pregnancy test at Screening and a urine pregnancy test at Day 1 (pre-dose) and Week 4. Urine drug screens will be completed at Screening and Day 1 (pre-dose). The urine pregnancy tests and urine drug screens will be performed locally at the site, so results are available that day.

The blood samples will be used for the following tests:

The urine samples will be used for the following tests:

Urine drug screen: including but not limited to alcohol (ethanol), amphetamines, barbiturates, benzodiazepines, cocaine, marijuana, methamphetamines, opiates, and phencyclidine.

7.5.3. Tympanometry

Tympanograms will be completed in both ears at Screening, Baseline (Day 1, pre-dose), and Week 1, Week 2, and Week 4 visits, unless the examiner determines there is a contraindication to performing the procedure. Tympanometry at Day 1 may be completed at Day 1 (pre-dose) or up to 5 days prior to Day 1, and there must be at least a 5-day interval between the Screening and Day 1 assessments.

7.5.4. Audiometry

Audiometric assessments must be conducted in accordance with American-Speech- Language-Hearing Association Guidelines (ASHA, 2005). Equipment calibration must be current and documented. The audiometric assessments must be conducted by a licensed or certified audiologist or a qualified assistant with appropriate training under the direct supervision of a licensed or certified audiologist.

Audiometry will be used to assess hearing function in both ears at Screening, Baseline (Day 1, pre-dose), and Week 1, Week 2, and Week 4 visits. Audiometry at Day 1 may be completed at Day 1 (pre-dose) or up to 5 days prior to Day 1, and there must be at least a 5-day interval between the Screening and Day 1 assessments.

7.5.5. Otoscopy

Otoscopic examinations will be performed by the physician in both ears at Screening and Baseline (Day 1, pre-dose) and at Week 1, Week 2, and Week 4 visits.

7.5.6. C-SSRS Assessment

The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicide- related thoughts and behaviors during the assessment period (Posner 2011). Otologic conditions are sometimes associated with anxiety or depression, requiring prospective assessment of suicidal ideation to ensure patient safety. This is true whether or not a particular product is known or suspected to be associated with treatment-emergent suicidal ideation and/or behavior. The C-SSRS must be administered by appropriately trained and certified personnel.

The C-SSRS assessment will be administered at Screening, Day 1 (pre-dose) and Week 1, Week 2, and Week 4 visits. The “Baseline” version of the C-SSRS will be used at Screening. For all other days, the “Since Last Visit” version will be used. At Screening or Baseline (Day 1) visits, subjects are to be excluded (per Exclusion Criterion 7) and should be referred for evaluation by a clinician/mental health professional if:

At Screening or Baseline (Day 1) visits, the Investigator should record medical history of suicidal ideation or non-suicidal self-injurious behavior if:

At post-dose visits (Week 1, Week, 2 and Week 4), the Investigator is to record an AE and assess use and dose of concomitant antidepressant medication (Section 7.2) if:

At post-dose visits (Week 1, Week 2, and Week 4), the Investigator is to record a Serious Adverse Event (SAE) and assess use and dose of concomitant antidepressant medication (Section 7.2) if:

Randomized subjects reporting new suicidal ideation or behavior can be managed by concomitant antidepressants and may continue in the study or may be discontinued, at the discretion of the Investigator. It is advised that subjects be referred to trained specialists for the treatment of depression, at the discretion of the Investigator.

8. ADVERSE EVENT REPORTING

8.1. Adverse Event Classification Definitions

Adverse Event:

• result in discontinuation from the study

• require treatment or any other therapeutic intervention

Serious Adverse Event (SAE):

An SAE is defined as any untoward medical occurrence that: results in death, • is life-threatening (Note: the term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event rather than to an event which hypothetically might have caused death if it were more severe.),

• results in persistent or significant disability/incapacity, or

• is a congenital anomaly/birth defect.

Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the above definition. These events should be considered serious.

9. SUBJECT COMPLETION

9.1. Completion

Study subject participation is complete after the Week 4 visit (Visit 5). Subjects who withdraw their consent to be followed or are lost-to-follow-up before completion of Week 4 will not be considered to have completed the study.

9.2. Study Discontinuation

All subjects have the right to discontinue from study evaluations at any time, for any reason, without prejudice; nonetheless, Investigators should attempt to encourage subjects to complete the protocol so that continued observation and follow-up measurements may be obtained.

Subjects may be discontinued from the study for any of the following:

• Withdrawal of consent (subject decision)

• Lost to Follow-up

• Adverse Event

Principal Investigator decision

Sponsor decision At any point, the Investigator may discontinue the subject’s study participation at the discretion of the Investigator or at the request of the subject, and ensure the subject receives appropriate medical care; the Investigator may also consult the medical monitor to discuss out-of-range test results.

9.2.1. Handling of Study Discontinuations

Subjects will be free to discontinue from the study, including discontinuing investigational product administration, and further follow-up of the study at any time.

Should a request for early discontinuation from the study with no further follow-up be made, the subject should be encouraged to return to the study site for a last follow up visit and undergo all End-of-Study/Early-Termination assessments.

When a subject discontinues from the study prior to completing the End-of-Study Visit, the reason for discontinuation is to be documented on the eCRFs and in the source document.

9.2.2. Replacements

In order to meet the target for evaluable subjects per dose level cohort of COMPOSITION A, subjects who discontinue participation in the study prior to Day 8 assessments for nonsafety related reasons may be replaced.

10. STATISTICAL METHODS

10.1. Sample Size

The sample size for each dose level cohort (approximately 8-12 subjects per cohort) was selected based on clinical judgment and prior experience to ensure that the safety and tolerability will be adequately assessed while minimizing subject exposure. Hence, there is no statistical rationale for the selected sample size.

10.2. Analysis Sets

The safety analysis set includes all subjects who receive study treatment. The safety analysis set will be used for all summaries of safety and activity. In safety and activity, subjects will be included in the treatment group based on the treatment that was received.

10.3. Study Endpoints

10.3.1. Safety Endpoints All safety endpoints will be summarized descriptively using the safety analysis set. If descriptive summaries warrant further exploration of comparisons between treatment groups, then additional safety analyses may be conducted in an ad hoc manner.

10.3.1.1. Adverse events

10.3.1.2. Tympanometry, Otoscopic, and Audiometry

The tympanometry category (A, B-small volume and/or normal, B-large volume, or C) will be summarized by treatment group and study visit.

Observations recorded during the conduct of otoscopic exams will be descriptive in nature. The number and percent of subjects presenting with each otoscopic classification will be provided by treatment group and study visit. Where relevant, the number and proportion of subjects with changes in their otoscopic classification from Baseline to the endpoint visit will also be provided for each treatment group. Presence and absence of tympanic membrane perforations will be summarized by treatment group and study visit; the size of any tympanic membrane perforation will be classified as follows: pinhole; <25% of tympanic membrane; 25% to <50% of tympanic membrane; >50% of tympanic membrane.

10.3.1.3. Columbia-Suicide Severity Rating Scale (C-SSRS)

10.3.1.4. Concomitant Medications

10.3.1.5. Laboratory Parameters, Vital Signs and Weight

10.3.2. Plasma PK Endpoint

The PK endpoint is plasma concentrations of gacyclidine (including (+) and (-) enantiomers of gacyclidine and possibly its metabolites).

10.3.3. Activity Endpoints Activity endpoints are change from Baseline in TFI overall score, PGIS, and PGIC at Week 4. Descriptive statistics will be provided for the observed and change from baseline TFI overall score values and PGIS by visit. The PGIC observed values at Week 4 will also be provided.

11. INVESTIGATIONAL PRODUCT INFORMATION

11.1. Physical Description of Investigational Product

The investigational product administered to subjects will be COMPOSITION A and placebo. COMPOSITION A is supplied as a 1 mL sterile solution (3.2 mg/mL [0.32%] gacyclidine in medium-chain triglycerides for Cohort 1 [0.64 mg unilateral] and Cohort 3 [0.64 mg bilateral]; 1.6 mg/mL [0.16%] gacyclidine in medium-chain triglycerides for Cohort 2 [0.32 mg bilateral]) in a vial. Placebo is provided as 1 mL of sterile 100% medium-chain triglycerides solution in a vial. The vials are provided as kits, and all kits must be stored at 2-8°C until use.

11.2. Directions for Use

11.3. Packaging and Labeling

11.3.1. Packaging

All investigational product kits will be labeled with information that will meet the applicable regulatory requirements.

11.3.2. Labels and Labeling Instructions

11.4. Management of Clinical Supplies

The clinical supplies will be managed by IWR randomization system. IWR will create shipment requests that will be generated based on inventory thresholds that are set for each site. A shipment request will be generated by IWR and sent to the clinical supply vendor. Upon shipment and receipt of the clinical study material, the site personnel will acknowledge the shipment and identify any damaged, missing, or unusable kits so they will not be dispensed.

11.4.1. Storage of Kits

[00234] While preferred embodiments of the present disclosure have been shown and described herein, such embodiments are provided by way of example only. Various alternatives to the embodiments described herein are optionally employed. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:

2. The method of claim 1, wherein the gacyclidine is in free base form.

3. The method of claim 1, wherein the composition comprises from 0.05mg to 0.70mg gacyclidine.

4. The method of claim 1, wherein the composition comprises about 0.1 Img gacyclidine.

5. The method of claim 1, wherein the composition comprises from 0.05mg to 0.25mg gacyclidine.

6. The method of claim 1, wherein the composition comprises about 0.32mg gacyclidine.

7. The method of claim 1, wherein the composition comprises from 0.25mg to 0.40mg gacyclidine.

8. The method of claim 1, wherein the composition comprises about 0.64mg gacyclidine.

9. The method of claim 1, wherein the composition comprises from 0.55mg to 0.70mg gacyclidine.

10. The method of claims 1, wherein the auris acceptable vehicle comprises a triglyceride of a medium chain fatty acid, and wherein the otic formulation comprises least about 50 wt% of the triglyceride.

11. The method of claim 10, wherein the medium chain fatty acid comprises 6 to 12 carbon atoms in the carbon chain.

12. The method of claim 10, wherein the medium chain fatty acid is selected from the group consisting of caproic acid (hexanoic acid), enanthic acid (heptanoic acid), caprylic acid (octanoic acid), pelargonic acid (nonanoic acid), capric acid (decanoic acid), undecylenic acid (undec- 10-enoic acid), lauric acid (dodecanoic acid), or a combination thereof.

13. The method of claim 10, wherein the triglyceride is selected from the group consisting of balassee oil, coconut oil, cohune oil, palm kernel oil, tucum oil, or combinations thereof.

14. The method of claim 10, wherein the otic pharmaceutical formulation comprises between about 90% to about 99.99% by weight of the triglyceride.

15. The method of claim 10, wherein the otic pharmaceutical formulation comprises between about 99.5% to about 99.99% by weight of the triglyceride.

16. The method of claim 10, wherein the otic pharmaceutical formulation is free or substantially free of poloxamer.

17. The method of claim 10, wherein the otic pharmaceutical formulation is free or substantially free of water.

18. The method of claim 1, wherein the otic formulation has an osmolarity from about 100 mOsm/L to about 1000 mOsm/L.

19. The method of claim 1, wherein the gacyclidine is dissolved in the otic formulation.

20. The method of claim 1, wherein the otic pharmaceutical formulation comprises between about 0.01% to about 0.5% by weight of the gacyclidine.

21. The method of claim 1, wherein the otic pharmaceutical formulation comprises between about 0.05% to about 0.35% by weight of the gacyclidine.

22. The method of claim 1, wherein the otic formulation is administered through intratympanic injection.

23. The method of claim 1, wherein the otic formulation is administered through unilateral intratympanic injection.

24. The method of claim 1, wherein the otic formulation is administered through bilateral intratympanic injection.