WO2011085155A2

WO2011085155A2 - Formulations and methods for dissolving cerumen

Info

Publication number: WO2011085155A2
Application number: PCT/US2011/020453
Authority: WO
Inventors: Aron M. Shapiro; Peter N. Friedensohn; Leo P. Menard; Stephanie K. Lynch; George E. Minno; Jacquelyn M. Nice
Original assignee: Ora Inc
Current assignee: Ora Inc
Priority date: 2010-01-07
Filing date: 2011-01-07
Publication date: 2011-07-14
Anticipated expiration: 2012-07-07
Also published as: WO2011085155A3

Abstract

Formulations, kits, and methods are described herein for relieving symptoms and complications from excessive or impacted cerumen. The formulations comprise effective amounts of limonene, one or more bile salts, and/or sodium bicarbonate.

Description

FORMULATIONS AND METHODS FOR DISSOLVING CERUMEN

RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 61/292,926, filed January 7, 2010.

FIELD OF THE DISCLOSURE

[0002] Embodiments of the present disclosure are related to formulations, kits, and methods for dissolving cerumen.

BACKGROUND OF THE DISCLOSURE

[0003] Cerumen, or ear wax, has a dual function. It prevents microbes from entering the ear and also clears dead skin cells from the ear canal. Cerumen forms when dead skin cells from inside the ear canal mix with the ear canal's glandular secretions. Cerumen impaction may occur because of changes in consistency of cerumen, aberrations in its migration process, or due to the insertion of a foreign object (e.g. cotton swab) into the ear canal. In a symptomatic patient population, cerumen becomes abnormally impacted within the ear canal and can cause significant discomfort and hearing loss. These patients undergo over 8 million cerumen removal procedures in the U.S annually. Impaction causes a range of complications, including pain, decreased hearing, itching, sensation of otic fullness, ringing in the ears, infection, bad odor, otic drainage, cough, and dizziness. Researchers estimate that excessive or impacted cerumen is present in 5% of adults, 10% of children, and more than 30% of geriatric and developmentally delayed populations.

[0004] Cerumen impaction is especially problematic for patients using hearing aids. Hearing aids as well as protective ear plugs are known to stimulate cerumen/sebaceous gland secretions that lead to excess excretion, impaction and hearing loss.

[0005] The most common non-pharmaceutical treatments for impacted cerumen are either mechanical removal or aural irrigation, both of which must be performed by a physician or nurse during an office visit. During aural irrigation, warm tap water is flushed into the ear canal with a syringe. The warm water loosens and removes the cerumen. Irrigation may be an unpleasant experience even though it is performed by a medical professional. The manual cerumen removal procedure may be also uncomfortable.

[0006] One study demonstrated that 38% of all types of cerumen removals performed by general practitioners either resulted in complications (i.e., otitis externa, eardrum perforation, damage to the external ear canal) or failed to remove the cerumen entirely. In the most difficult cases, where a primary care physician is unable to remove the cerumen, patients are referred to otolaryngologists. This additional office visit increases the cost, time, and complexity of removing impacted cerumen.

[0007] Currently available products for treating cerumen impaction have not been shown to be more effective than saline solution. These products are minimally effective because they fail to fully dissolve cerumen. Peroxide -based compounds, for example, only soften cerumen by causing it to foam. A need exists for a product that both dissolves human cerumen effectively and promises to be commercially viable. The present invention meets this need.

[0008] Throughout this description, including the foregoing description of related art, any and all publicly available documents described herein, including any and all U.S. patents, are specifically incorporated by reference herein in their entireties. The foregoing description of related art is not intended in any way as an admission that any of the documents described therein, including pending United States patent applications, are prior art to embodiments of the present disclosure. Moreover, the description herein of any disadvantages associated with the described products, methods, and/or apparatus, is not intended to limit the disclosed

embodiments. Indeed, embodiments of the present disclosure may include certain features of the described products, methods, and/or apparatus without suffering from their described disadvantages.

SUMMARY OF THE DISCLOSURE

[0009] The present invention provides for compositions and methods for providing relief from the discomfort and complications associated with impacted cerumen. According to some embodiments, the present invention provides for cerumenolytic compositions, kits, and methods for dissolving and/or removing cerumen from the ear canal.

[0010] The present invention provides for topical formulations and methods for relieving symptoms and complications caused by excessive or impacted cerumen. According to some embodiments, the formulations comprise effective amounts of limonene, bile salts, and/or sodium bicarbonate.

[0011] According to some embodiments, there are provided cerumenolytic compositions in the form of a solution, suspension, foam, or gel wherein the composition comprises limonene. According to some embodiments, there are provided cerumenolytic compositions in the form of a solution, suspension, foam, or gel wherein the composition comprises one or more bile salts. According to some embodiments, there are provided cerumenolytic compositions in the form of a solution, suspension, foam, or gel wherein the composition comprises sodium bicarbonate. A vial or device containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

[0012] The cerumenolytic compositions may additionally comprise one or more otologically acceptable carriers selected from the group consisting of preservatives, surfactants, foaming agents, viscosity enhancers, penetration enhancers, buffers, sodium chloride or other salts, solubilizers, stabilizers, pH adjusters, tonicity agents, fillers, demulcents, and water, and any combination or mixture thereof.

[0013] The cerumenolytic compositions may additionally be one or more of the agents selected from the group consisting of: olive oil; almond oil; mineral oil; glycerol; carbamide peroxide; sodium bicarbonate; glycerine; arachis oil; turpentine; dichlorobenzene;

Triethanolamine; polypeptides; oleate-condensate; urea; hydrogen peroxide; glycerine; Docusate sodium; combinations thereof; and mixtures thereof. [0014] In some embodiments, the concentration of limonene in the cerumenolytic

composition is from about 10% to 30% w/v. In some embodiments, the concentration of limonene in the cerumenolytic composition is from about 0.001 % to 10% w/v.

[0015] In some embodiments, the concentration of bile salts in the cerumenolytic composition may be from about 10% to the limits of its solubility. In some embodiments, the concentration of bile salts in the cerumenolytic composition may be from about 0.001% to 10% w/v.

[0016] In some embodiments, the concentration of sodium bicarbonate in the cerumenolytic composition is from about 10% to the limits of its solubility. In some embodiments, the concentration of sodium bicarbonate in the cerumenolytic composition is from about 0.001 % to 10% w/v.

[0017] The present invention details the development of a cerumen removal product.

According to some embodiments, the cerumen removal product comprises a cerumenolytically effective amount of limonene, one or more bile salts, and/or sodium bicarbonate. According to some embodiments, the cerumen removal product is one component of a kit featuring a cerumenolytically effective amount of limonene and a device, such as a bulb syringe, intended to be used for irrigating the external ear canal. According to some embodiments, the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation.

[0018] According to some embodiments, the cerumen removal product is one component of a kit featuring a cerumenolytically effective amount of one or more bile salts and a device, such as a bulb syringe, intended to be used for irrigating the external ear canal. According to some embodiments, the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation.

[0019] According to some embodiments, the cerumen removal product is one component of a kit featuring a cerumenolytically effective amount of sodium bicarbonate and a device, such as a bulb syringe, intended to be used for irrigating the external ear canal. According to some embodiments, the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation. [0020] According to some embodiments, the cerumen removal product is one component of a kit featuring a cerumenolytically effective amount of any combination of limonene, one or more bile salts, and/or sodium bicarbonate (e.g., limonene and one or more bile salts; limonene and sodium bicarbonate; limonene, one or more bile salts, and sodium bicarbonate; one or more bile salts and sodium bicarbonate) and a device, such as a bulb syringe, intended to be used for irrigating the external ear canal. According to some embodiments, the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation.

[0021] The compositions of the present invention may be used in methods to prophylactically prevent cerumen impaction or to proactive ly remove and/or dissolve existing cerumen.

[0022] The compositions of the present invention may be used in methods to effectively treat the signs (e.g., occlusion of the ear canal) and symptoms (e.g. , pain, decreased hearing, itching, otic fullness, ringing in the ears) of problematic cerumen.

[0023] The present invention details the development of a cerumen removal kit. According to some embodiments, the cerumen removal kit comprises a cerumenolytic agent able to dissolve and/or soften cerumen and an amount of saline solution to irrigate the cerumen from the ear canal. The effective cerumen solvent and a saline irrigation component may be contained in a single package.

[0024] The cerumenolytic compositions of the present embodiments may be packaged in a vial or device containing a ready-to-administer cerumenolytic composition of the present embodiments. In some embodiments, the device allows the cerumenolytic composition to be administered by drops, by foam, or by spray. In some embodiments, the device is a syringe, a dropper, a plastic bottle, an aerosol or other foam-dispensing bottle, or a spray bottle.

[0025] According to some embodiments kits are provided comprising the vial or device according to the present embodiments and a bulb syringe, vial, or other device for irrigation of the external ear canal. In some embodiments, the device for irrigation of the external ear canal contains no liquid, but, for example, can be filled with tap water at the time of use. In some embodiments, the kit comprises an irrigation solution of sterilized and/or distilled water, or a saline solution, packaged with or within the device for irrigation of the external ear canal. In some embodiments, the kit comprises a bulb syringe, vial, or other device to allow the irrigation solution to be administered by drops, by a stream of liquid, or by spray.

[0026] According to some embodiments, methods are provided for removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising limonene in an amount effective to assist in the removal of human cerumen.

[0027] According to some embodiments, methods are provided for removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising bile salts in an amount effective to assist in the removal of human cerumen.

[0028] According to some embodiments, methods are provided for removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising sodium bicarbonate in an amount effective to assist in the removal of human cerumen.

[0029] According to some embodiments, methods are provided for removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

[0030] According to some embodiments, methods are provided for removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition of the present embodiments. The cerumenolytic composition may be administered by spraying or by instillation, in the form of drops, foam, or gel, into the external ear canal. In some

embodiments, the cerumenolytic composition is applied for a sufficient time period for the composition to bathe the external ear canal and to dissolve, dislodge, break-up, and/or digest cerumen in the ear canal.

[0031] According to some embodiments, methods are provided for treating a sign, symptom or complication of excessive or impacted cerumen comprising administering to the external ear canal a cerumenolytic composition of the present embodiments to assist in the removal of human cerumen. [0032] According to some embodiments, methods for treating a sign, symptom or

complication of excessive or impacted cerumen comprises administering to the external ear canal a cerumenolytic composition comprising limonene in an amount effective to assist in the removal of human cerumen.

[0033] In some embodiments a method is provided for treating of treating a sign, symptom or complication of excessive or impacted cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising one or more bile salts in an amount effective to assist in the removal of human cerumen.

[0034] In some embodiments a method is provided for treating a sign, symptom or complication of excessive or impacted cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition of the present invention comprising sodium bicarbonate in an amount effective to assist in the removal of human cerumen.

[0035] In some embodiments a method is provided for removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

[0036] The sign, symptom or complication includes, but is not limited to, occlusion of the ear canal; pain; decreased hearing; itching; otic fullness; ringing in the ears; hearing aid faults; otitis externa; vertigo; and tinnitus. The cerumenolytic composition may be administered by spraying or by instillation, in the form of drops, foam, or gel, into the external ear canal. In some embodiments, the cerumenolytic composition is applied for a sufficient time period for the composition to bathe the external ear canal and to dissolve, dislodge, break-up, and/or digest cerumen in the ear canal.

[0037] According to some embodiments, a dropper is provided containing a ready-to- administer cerumenolytic composition according to the present embodiments in the form of a solution, suspension, foam, or gel. [0038] According to some embodiments, an aerosol, pump-action, or spray bottle is provided containing a ready-to-administer cerumenolytic composition according to the present embodiments in the form of a solution, suspension, foam, or gel.

[0039] In some embodiments, an aerosol, pump-action, or spray bottle is provided containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises bile salts. In some embodiments, an aerosol, pump- action, or spray bottle is provided containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises sodium bicarbonate. In some embodiments, an aerosol, pump-action, or spray bottle is provided containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

[0040] In some embodiments, a dropper is provided containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises one or more bile salts. In some embodiments, a dropper is provided containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises sodium bicarbonate. In some embodiments, a dropper is provided containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises one or more bile salts. In some embodiments, a dropper is provided containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1. Disintegration of human cerumen sample after soaking in D-limonene solution compared with carbamide peroxide. Pictures were taken at 1 minute and at 15 minutes after the cerumen samples were placed into the solutions. [0042] Figure 2. Disintegration of human cerumen sample after soaking in bile salts solution. Pictures were taken at 1 minute and at 15 minutes after the cerumen samples were placed into the solution.

[0043] Figure 3. Disintegration of human cerumen sample after soaking in sodium

bicarbonate solution. Pictures were taken at 1 minute and at 15 minutes after the cerumen samples were placed into the solution.

DETAILED DESCRIPTION OF THE INVENTION

Limonene

[0044] According to some embodiments, the cerumenolytic used in the compositions of the present invention is limonene (i.e., D-limonene, L-limonene, D,L-limonene), and preferably D- limonene. D-limonene is a cyclic terpene hydrocarbon with the chemical formula CioHi₆ (IUPAC name: 4-isopropenyl-l -methylcyclohexene). Due to its lipophilic and hydrophobic nature, D-limonene will dissolve or separate the lipid components of impacted cerumen into smaller particles. D-limonene, L-limonene or D, L-limonene, limonene oxide, 1 ,8-cineole, nerolidol, methone, methol, carvone, carvacrol, linalool, a-terpineol, fenchone, thymol, pinene oxide, and pulegeon may be used to substitute limonene in the embodiments disclosed herein.

[0045] The limonene formulations of the present invention may be used to dissolve cerumen, such as impacted cerumen, thereby providing relief from the discomfort of excessive or impacted cerumen and may improve disorders of the ear, such as improving hearing in individuals with hearing loss associated with the impaction. Based on initial tolerability testing, this symptomatic relief is not expected to cause any irritation to the skin of the ear canal.

[0046] In certain embodiments, the formulations comprise an effective amount of limonene, preferably from about 0.001% to about 30% limonene mixed in a compatible vehicle or solvent. This includes, but is not limited to from about 0.001 % to about 10% limonene; from about 0.001% to about 15% limonene; from about 0.001 % to about 20% limonene; from about 0.001% to about 25% limonene; from about 0.001 % to about 30% limonene; from about 0.001 % to about 35% limonene; from about 0.001 % to about 40% limonene; from about 0.001% to about 45% limonene; from about 5% to about 10% limonene; from about 5% to about 15% limonene; from about 5% to about 20% Hmonene; from about 5% to about 25% Hmonene; from about 5% to about 30% Hmonene; from about 5% to about 35% Hmonene; from about 5% to about 40% Hmonene; from about 5% to about 50% Hmonene; from about 0.001% to about 5% Hmonene; from about 3% to about 8% Hmonene; from about 4% to about 10% Hmonene; from about 6% to about 10% Hmonene; from about 10% to about 15% Hmonene; from about 10% to about 20% Hmonene; from about 10% to about 25% Hmonene; from about 10% to about 30% Hmonene; from about 10% to about 35% Hmonene; from about 10% to about 40% Hmonene; from about 10% to about 50% Hmonene; from about 15% to about 20% Hmonene; from about 15% to about 25% Hmonene; from about 15% to about 30% Hmonene; from about 15% to about 35%

Hmonene; from about 15% to about 40% Hmonene; and from about 15% to about 50% Hmonene.

[0047] In certain embodiments, the formulations comprise an effective amount of Hmonene, preferably from about 0.001% to about 30% Hmonene mixed in a compatible vehicle or solvent. This includes, but is not limited to from about 0.001% to about 10% Hmonene; from about 0.001% to about 15% Hmonene; from about 0.001% to about 20% Hmonene; from about 0.001% to about 25% Hmonene; from about 0.001% to about 30% Hmonene; from about 0.001% to about 35% Hmonene; from about 0.001% to about 40% Hmonene; from about 0.001% to about 45% Hmonene; from about 1% to about 10% Hmonene; from about 1% to about 15% Hmonene; from about 1% to about 20% Hmonene; from about 1% to about 25% Hmonene; from about 1% to about 30% Hmonene; from about 1% to about 35% Hmonene; from about 1% to about 40% Hmonene; from about 1% to about 45% Hmonene; from about 5% to about 10% Hmonene; from about 5% to about 15% Hmonene; from about 5% to about 20% Hmonene; from about 5% to about 25% Hmonene; from about 5% to about 30% Hmonene; from about 5% to about 35% Hmonene; from about 5% to about 40% Hmonene; from about 5% to about 50% Hmonene; from about 0.001% to about 5% Hmonene; from about 3% to about 8% Hmonene; from about 4% to about 10% Hmonene; from about 6% to about 10% Hmonene; from about 10% to about 15% Hmonene; from about 10% to about 20% Hmonene; from about 10% to about 25% Hmonene; from about 10% to about 30% Hmonene; from about 10% to about 35% Hmonene; from about 10% to about 40% Hmonene; from about 10% to about 50% Hmonene; from about 15% to about 20% Hmonene; from about 15% to about 25% Hmonene; from about 15% to about 30%

Hmonene; from about 15% to about 35% Hmonene; from about 15% to about 40% Hmonene; and from about 15% to about 50% Hmonene. [0048] According to some embodiments, limonene is the sole active ingredient. Thus, the formulations of the present invention include cerumenolytic compositions consisting essentially of limonene. According to some embodiments, there is provided a cerumenolytic composition consisting essentially of limonene in solution. According to some embodiments, there is provided a cerumenolytic composition consisting of limonene in solution.

[0049] According to some embodiments, there is provided a cerumenolytic composition consisting essentially of limonene in solvent or in suspension. According to some embodiments, there is provided a cerumenolytic composition consisting of limonene in solvent or in suspension.

[0050] According to some embodiments, there is provided a cerumenolytic composition consisting essentially of limonene formulated as a foam or gel. According to some embodiments, there is provided a cerumenolytic composition consisting of limonene formulated as a foam or gel.

[0051] According to some embodiments, there is provided a cerumenolytic composition comprising limonene, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, ...) bile salts, and/or sodium bicarbonate in solvent or in suspension. According to some embodiments, there is provided a cerumenolytic composition comprising limonene, one or more bile salts, and sodium bicarbonate in solvent or in suspension. According to some embodiments, there is provided a cerumenolytic composition comprising limonene and one or more bile salts in solvent or in suspension.

According to some embodiments, there is provided a cerumenolytic composition comprising limonene and sodium bicarbonate in solvent or in suspension. According to some embodiments, there is provided a cerumenolytic composition comprising one or more bile salts and sodium bicarbonate in solvent or in suspension. According to some embodiments, there is provided a cerumenolytic composition comprising limonene in solvent or in suspension. According to some embodiments, there is provided a cerumenolytic composition comprising one or more bile salts in solvent or in suspension. According to some embodiments, there is provided a cerumenolytic composition comprising sodium bicarbonate in solvent or in suspension.

[0052] According to some embodiments, there is provided a cerumenolytic composition comprising limonene, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, ...) bile salts, and/or sodium bicarbonate formulated as a foam or gel. According to some embodiments, there is provided a cerumenolytic composition comprising limonene, one or more bile salts, and sodium bicarbonate formulated as a foam or gel. According to some embodiments, there is provided a cerumenolytic composition comprising limonene and one or more bile salts formulated as a foam or gel.

According to some embodiments, there is provided a cerumenolytic composition comprising limonene and sodium bicarbonate formulated as a foam or gel. According to some

embodiments, there is provided a cerumenolytic composition comprising one or more bile salts and sodium bicarbonate formulated as a foam or gel. According to some embodiments, there is provided a cerumenolytic composition comprising limonene formulated as a foam or gel.

According to some embodiments, there is provided a cerumenolytic composition comprising one or more bile salts formulated as a foam or gel. According to some embodiments, there is provided a cerumenolytic composition comprising sodium bicarbonate formulated as a foam or gel.

[0053] According to some embodiments, the purity of limonene (i.e., free from other citrus oil compounds or other impurities) used in the present formulations is at least about 90% limonene. This includes, but is not limited to, at least about 91% limonene, at least about 92% limonene, at least about 93% limonene, at least about 94% limonene, at least about 95% limonene, at least about 96% limonene, at least about 97% limonene, at least about 98% limonene, and at least about 99% limonene. The limonene may then be added to a suitable carrier or buffered carrier. Carriers may include sterilized and/or distilled water, isotonic saline solution, or isosmotic saline solution.

[0054] The limonene may be purified by known distillation techniques, such as that described in U.S. Pat. No. 6,420,435, which is incorporated herein by reference in its entirety.

[0055] In some embodiments, the cerumenolytic formulations of the present embodiments may further contain one or more additional compounds or agents that have cerumenolytic properties. In some embodiments, the limonene formulations of the present embodiments may further contain one or more of the following: olive oil; almond oil; mineral oil; glycerol; carbamide peroxide; sodium bicarbonate; glycerine; arachis oil; turpentine; dichlorobenzene; triethanolamine; polypeptides; oleate-condensate; urea; hydrogen peroxide; glycerine; docusate sodium; combinations thereof; and mixtures thereof.

[0056] In some embodiments, limonene may be combined with sodium bicarbonate or sodium sesquicarbonate. In some embodiments, limonene may be combined with enzymes other than methyl trypsin, combined with sodium bicarbonate or sodium sesquicarbonate. In some embodiments, limonene may be combined with sodium borate or docusate sodium, and further combined with sodium bicarbonate or sodium sesquicarbonate.

Bile Salts

[0057] According to some embodiments, the cerumenolytic used in the compositions of the present invention is a bile salt. A bile salt is classified as a salt of taurocholic acid, glycocholic acid (derivatives of cholic acid), chenodeoxycholic acid, deoxycholic acid and lithocholic acid. The composition which includes, but is not limited to, single salts or mixtures of salts. The chemical formula for cholic acid is C24H40O5 (IUPAC name: 3,7,12-trihydroxy-10,13- dimethylhexadecahydro-lH-cyclopenta[ ]phenanthren-17-yl)pentanoic acid), for glycocholic acid C₂₆H₄₃N0₆ ( -Choloylglycine;N-[(3alpha,5beta,7alpha,12alpha)-3,7,12-trihydroxy-24- oxocholan-24-yl]glycine;glycine,N-[(3alpha,5beta,7alpha,12alpha)-3,7,12-trihydroxy-24- oxocholan-24-yl]-), and for taurocholic acid C₂₆H₄₅ O₇S (2-{[(3a,5 ,7a,12a)-3,7,12-trihydroxy- 24-oxocholan-24-yl] amino } ethanesulfonic acid). The main function of bile acid is to facilitate the formation of micelles in an aqueous solution to aggregate with the hydrophilic regions in contact with surrounding solvent, sequestering the hydrophobic single tail regions. Due to these lipophilic and hydrophobic nature, bile salts will dissolve or separate the lipid components of impacted cerumen into smaller particles.

[0058] In certain embodiments, the formulations comprise an effective amount of bile salts, preferably from about 1% to the limits of its solubility. Solubility may be measured at a temperature between 10 °C and 37 °C (e.g., 10 °C, 15 °C, 18°C, 20°C, 22 °C, 25 °C, 27 °C, 29 °C, or 30 °C), preferably between 20 °C and 27 °C.

[0059] The formulations of the present embodiments comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, ...) bile salts may be used to dissolve cerumen, such as impacted cerumen, thereby providing relief from the discomfort of excessive or impacted cerumen and may improve disorders of the ear, such as improving hearing in individuals with hearing loss associated with the impaction. Based on initial tolerability testing, this symptomatic relief is not expected to cause any irritation to the skin of the ear canal.

[0060] In certain embodiments, the formulations comprise an effective amount of one or more bile salts, preferably from about 0.001% to about 90% one or more bile salts mixed in a compatible vehicle or solvent. This includes, but is not limited to from about 0.001% to about 10% one or more bile salts; from about 0.001% to about 15% one or more bile salts; from about 0.001% to about 20% one or more bile salts; from about 0.001 % to about 25% one or more bile salts; from about 0.001% to about 30% one or more bile salts; from about 0.001% to about 35% one or more bile salts; from about 0.001 % to about 40% one or more bile salts; from about 0.001% to about 45% one or more bile salts; from about % to about 10% one or more bile salts; from about 1% to about 15% one or more bile salts; from about 1% to about 20% one or more bile salts; from about 1% to about 25% one or more bile salts; from about 1 % to about 30% one or more bile salts; from about 1 % to about 35% one or more bile salts; from about 1% to about 40% one or more bile salts; from about 1% to about 45% one or more bile salts; from about 5% to about 10% one or more bile salts; from about 5% to about 15% one or more bile salts; from about 5% to about 20% one or more bile salts; from about 5% to about 25% one or more bile salts; from about 5% to about 30% one or more bile salts; from about 5% to about 35% one or more bile salts; from about 5% to about 40% one or more bile salts; from about 5% to about 50% one or more bile salts; from about 1% to about 5% one or more bile salts; from about 3% to about 8% one or more bile salts; from about 4% to about 10% one or more bile salts; from about 6% to about 10% one or more bile salts; from about 10% to about 15% one or more bile salts; from about 10% to about 20% one or more bile salts; from about 10% to about 25% one or more bile salts; from about 10% to about 30% one or more bile salts; from about 10% to about 35% one or more bile salts; from about 10% to about 40% one or more bile salts; from about 10% to about 50% one or more bile salts; from about 15% to about 20% one or more bile salts; from about 15% to about 25% one or more bile salts; from about 15% to about 30% one or more bile salts; from about 15% to about 35% one or more bile salts; from about 15% to about 40% one or more bile salts; from about 15% to about 50% one or more bile salts; from about 50% to about 90% one or more bile salts; from about 60% to about 90% one or more bile salts; from about 70% to about 90% one or more bile salts; from about 80% to about 90% one or more bile salts.

[0061] In certain embodiments, the formulations comprise an effective amount of one or more bile salts in a compatible vehicle or solvent. According to some embodiments, one or more bile salts is the sole active ingredient. Thus, the formulations of the present invention include cerumeno lytic compositions consisting essentially of one or more bile salts. According to some embodiments, there is provided a cerumenolytic composition consisting essentially of one or more bile salts in solution. According to some embodiments, there is provided a cerumenolytic composition consisting of one or more bile salts in solution formulated as a foam or gel.

[0062] According to some embodiments, there is provided a cerumenolytic composition comprising limonene, one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, ...) bile salts, and/or sodium bicarbonate in solvent or in suspension.

[0063] In some embodiments, the one or more bile salts formulations of the present embodiments may further contain one or more additional compounds or agents that have cerumenolytic properties. In some embodiments, the one or more bile salts formulations of the present embodiments may further contain one or more of the following: olive oil; almond oil; mineral oil; glycerol; carbamide peroxide; sodium bicarbonate; glycerine; arachis oil; turpentine; dichlorobenzene; triethanolamine; polypeptides; oleate-condensate; urea; hydrogen peroxide; glycerine; docusate sodium; combinations thereof; and mixtures thereof.

[0064] In some embodiments, one or more bile salts may be combined with sodium bicarbonate or sodium sesquicarbonate. In some embodiments, one or more bile salts may be combined with enzymes other than methyl trypsin, combined with sodium bicarbonate or sodium sesquicarbonate. In some embodiments, one or more bile salts may be combined with sodium borate or docusate sodium, and further combined with sodium bicarbonate or sodium

sesquicarbonate.

Sodium Bicarbonate

[0065] According to some embodiments, the solution consists of sodium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate, or mixtures thereof are the preferred bicarbonates. The chemical formula for sodium hydrogen carbonate is NaHC0₃. The sodium bicarbonate is used as an effective and gentle exfoliant of dead skin cells in the ear canal.

[0066] In certain embodiments, the formulations comprise an effective amount of sodium bicarbonate, preferably from about 1% to the limits of its solubility. Solubility may be measured at a temperature between 10 °C and 37 °C (e.g., 10 °C, 15 °C, 18°C, 20°C, 22 °C, 25 °C, 27 °C, 29 °C, or 30 °C), preferably between 20 °C and 27 °C.

[0067] The formulations of the present embodiments comprising sodium bicarbonate may be used to dissolve cerumen, such as impacted cerumen, thereby providing relief from the discomfort of excessive or impacted cerumen and may improve disorders of the ear, such as improving hearing in individuals with hearing loss associated with the impaction. Based on initial tolerability testing, this symptomatic relief is not expected to cause any irritation to the skin of the ear canal.

[0068] In certain embodiments, the formulations comprise an effective amount of sodium bicarbonate, preferably from about 0.001% to about 90% sodium bicarbonate mixed in a compatible vehicle or solvent. This includes, but is not limited to from about 0.001% to about 10% sodium bicarbonate; from about 0.001% to about 15% sodium bicarbonate; from about 0.001% to about 20% sodium bicarbonate; from about 0.001% to about 25% sodium

bicarbonate; from about 0.001% to about 30% sodium bicarbonate; from about 0.001% to about 35% sodium bicarbonate; from about 0.001% to about 40% sodium bicarbonate; from about 0.001% to about 45% sodium bicarbonate; from about 1% to about 10% sodium bicarbonate; from about 1% to about 15% sodium bicarbonate; from about 1% to about 20% sodium bicarbonate; from about 1% to about 25% sodium bicarbonate; from about 1% to about 30% sodium bicarbonate; from about 1% to about 35% sodium bicarbonate; from about 1% to about 40% sodium bicarbonate; from about 1% to about 45% sodium bicarbonate; from about 5% to about 10% sodium bicarbonate; from about 5% to about 15% sodium bicarbonate; from about 5% to about 20% sodium bicarbonate; from about 5% to about 25% sodium bicarbonate; from about 5% to about 30% sodium bicarbonate; from about 5% to about 35% sodium bicarbonate; from about 5% to about 40% sodium bicarbonate; from about 5% to about 50% sodium bicarbonate; from about 1% to about 5% sodium bicarbonate; from about 3% to about 8% sodium bicarbonate; from about 4% to about 10% sodium bicarbonate; from about 6% to about 10% sodium bicarbonate; from about 10% to about 15% sodium bicarbonate; from about 10% to about 20% sodium bicarbonate; from about 10% to about 25% sodium bicarbonate; from about 10% to about 30% sodium bicarbonate; from about 10% to about 35% sodium bicarbonate; from about 10% to about 40% sodium bicarbonate; from about 10% to about 50% sodium bicarbonate; from about 15% to about 20% sodium bicarbonate; from about 15% to about 25% sodium bicarbonate; from about 15% to about 30% sodium bicarbonate; from about 15% to about 35% sodium bicarbonate; from about 15% to about 40% sodium bicarbonate; and from about 15% to about 50% sodium bicarbonate; from about 60% to about 90% sodium bicarbonate; from about 70% to about 90% sodium bicarbonate; from about 80% to about 90% sodium bicarbonate.

[0069] In certain embodiments, the formulations comprise an effective amount of sodium bicarbonate in a compatible vehicle or solvent. According to some embodiments, sodium bicarbonate is the sole active ingredient. Thus, the formulations of the present invention include cerumenolytic compositions consisting essentially of sodium bicarbonate. According to some embodiments, there is provided a cerumenolytic composition consisting essentially of sodium bicarbonate in solution. According to some embodiments, there is provided a cerumenolytic composition consisting of sodium bicarbonate in solution formulated as a foam or gel.

According to some embodiments, there is provided a cerumenolytic composition comprising limonene, one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, ...) bile salts, and/or sodium bicarbonate in solvent or in suspension.

[0070] In some embodiments, the sodium bicarbonate formulations of the present

embodiments may further contain one or more additional compounds or agents that have cerumenolytic properties. In some embodiments, the sodium bicarbonate formulations of the present embodiments may further contain one or more of the following: olive oil; almond oil; mineral oil; glycerol; carbamide peroxide; glycerine; arachis oil; turpentine; dichlorobenzene; triethanolamine; polypeptides; oleate-condensate; urea; hydrogen peroxide; glycerine; docusate sodium; combinations thereof; and mixtures thereof.

[0071] In some embodiments, sodium bicarbonate may be combined with sodium

sesquicarbonate. In some embodiments, sodium bicarbonate may be combined with enzymes other than methyl trypsin, combined with sodium sesquicarbonate. In some embodiments, sodium bicarbonate may be combined with sodium borate or docusate sodium, and further combined with sodium sesquicarbonate.

Otologically Acceptable Carriers

[0072] The carrier may be any carrier known in the art. Otologically acceptable carriers may comprise any combination of preservatives, surfactants, foaming agents, viscosity enhancers, penetration enhancers, buffers, sodium chloride or other salts, solubilizers, stabilizers, pH adjusters, tonicity agents, fillers, demulcents, and water.

[0073] Carriers are useful for mixing the constituents, keeping the constituents in solution, and providing an easy method of application to the affected area whether by spray, foam, dropper, or applicator. The carrier may be an aqueous or non-aqueous carrier, foam carrier, liquid or solid carrier. Examples of suitable carriers include, but are not limited to, vitamin E, glycerin, mineral oil, silica, cottonseed oil, coconut oil, vegetable oil, seed oil, fish oil, animal oil, alcohol, talc, corn meal, beeswax, carnauba wax, beta carotene, garlic oil, camphor oil, soluble vitamins, soluble minerals, rape seed oil, nut oils, olive oil, liposomes, or other sterile carriers.

[0074] The preferred preservatives for the compositions of the present invention include, but are not limited to, poly[dimethylimino-2-butene-l ,- 4-diyl] chloride-alpha- [4-tris(2- hydroxyethyl)ammonium]dichloride, which is available from Onyx Chemical Corporation as Polyquarternium 1 or Onamer M™, or from Alcon Laboratories, Inc. as Polyquad^®;

benzalkonium halides such as benzalkonium chloride; alexidine salts; chlorhexidine salts;

hexamethylene biguanimides and their polymers; and mixtures thereof.

[0075] Preservatives may be selected from the classes of : Parabens (methyl-, ethyl-, propyl-, or butyl-), Acids or their salts (benzoic acid, sodium benzoate, sorbic acid, sodium sorbate), Quaternium Ammonium Compounds (cetrimide, Benzalkonium chloride, cetylpyridinium chloride, benzaethonium chloride), alcohols (benzyl alcohol, phenylethyl alcohol), Phenols, Mercurials (phenylmercuric nitrate, thimersal), and Biguanides (chlorhexidine, alexidine, and PHMB). [0076] In some embodiments, the surfactant is nonionic, and may include, but is not limited to, polysorbates, such as polysorbate 20 available from ICI Americas Inc. of Wilmington, Del. under the trademark Tween^® 20; 4-(l ,l ,3,3-tetramethylbutyl)

phenol/poly(oxyethylene)polymers, such as the polymer sold under the trademark Tyloxapol; poly(oxyethylene)-poly(oxypropylene) block copolymers; polyethylene glycol esters of fatty acids, such as coconut, polysorbate, polyoxyethylene, and polyoxypropylene ethers of higher alkanes (C₁₂-C₁₈). Examples of the preferred class include polysorbate 20 polyoxyethylene (23) lauryl ether (Brij^® 35), polyoxyethylene (40) stearate (Myrj^® 52), polyoxyethylene (25) propylene glycol stearate (Atlas^® G2612), Brij^® 35, Myrj^® 52 and Atlas^® G 2612 are trademarks of, and are commercially available from, ICI Americas Inc. Most preferably the nonionic surfactant is selected from poly(oxyethylene)-poly(oxypropylene) block copolymers and mixtures thereof. Such surfactant components can be obtained commercially from the BASF Corporation under the trademarks Pluronic^® and Tetronic^®. Such block copolymers can be generally described as polyoxyethylene/ polyoxypropylene condensation polymers terminated in primary hydroxyl groups.

[0077] In some embodiments, the surfactant may be a foaming agent or foam carrier. Suitable foaming agents may be anionic, cationic, non-ionic or amphoteric surfactants, the choice thereof depending upon a variety of factors such as compatibility with solvents, thickeners, foam stabilizers, foam builders, emollients, preservatives, buffers, emulsifiers and perfume. In some embodiments, the foaming agent is present in an amount of about 5-30% by weight (e.g., 5%, 10%, 15%, 20%, 25%).

[0078] In some embodiments, the foaming agent or foam carriers is selected from one or more of a polyoxyethylene fatty ether, a polyoxyethylene fatty ester, a fatty acid, a sulfated fatty acid surfactant, a phosphated fatty acid surfactant, a sulfosuccinate surfactant, an amphoteric surfactant, a non-ionic poloxamer surfactant, a non-ionic meroxapol surfactant, a petroleum surfactant, an aliphatic amine surfactant, a polysiloxane, and a sorbitan fatty acid ester. Among the suitable non-ionic surfactants may be mentioned ethoxylated fatty acid or alcohols such as ethoxylated lanolin alcohols, ethoxylated alkyl phenols and the ethoxylated sorbitol esters, for example, polyoxyethylene sorbitan monolaurate. Among the suitable anionic foam forming surfactants may be mentioned lauryl sulfates of different cations, such as triethanolamine lauryl sulfate, sodium lauryl sulfate, ammonium lauryl sulfate and nonoethanolamine lauryl sulfate, and analogous cations of lauryl ether sulfate. The cationic surfactants include quaternaries such as N- lauroyl colamino formyl methyl pyridinium chloride. The amphoteric foaming surfactants include carboxylic acid adducts of imidazolinium compounds.

[0079] According to some embodiments, there are pharmaceutically acceptable emulsifiers or surfactants mixed with limonene to create a cerumenolytic composition.

Irrigation Solution

[0080] The cerumenolytic compositions or formulations of the present invention may be packaged together with a solution and/or device for dispensing the solution to form a cerumen removal kit. According to some embodiments, the cerumen removal kit comprises a

cerumenolytic agent able to dissolve and/or soften cerumen and an amount of solution to irrigate the cerumen from the ear canal. The effective cerumen solvent and an irrigation component and/or device may be contained in a single package. Preferably, the effective cerumen solvent and an irrigation component are contained in a single package along with a bulb syringe, vial, or other device to be used in the irrigation.

[0081] The irrigation solution may be any solution acceptable for irrigating the ear canal to remove cerumen debris. Examples of suitable solutions include, but are not limited to, tap water, sterilized and/or distilled water, isotonic saline solution, isosmotic saline solution, bi- or sesqui- carbonate solutions, a peroxide solution (e.g., carbamide peroxide), bile salt solution and docusate sodium.

[0082] According to some embodiments, the irrigation solution consists of saline. The saline solution may be from about 0.8% w/v of NaCl to about 1.0% 0.8% w/v of NaCl. The saline solution may be a solution of about 0.9% w/v of NaCl. The saline solution may be a solution of from about 200 to about 600 mOsm L. The saline solution may be a solution of about 300 mOsm L.

[0083] The saline solution is preferably an isosmotic saline solution. Administration/ Formulations

[0084] According to some embodiments, a cerumenolytic composition comprising limonene, bile salts, and/or sodium bicarbonate, is topically applied to the ear canal to dissolve the problematic cerumen. Limonene may be formulated into an otic solution, suspension, foam, or gel and applied to allow for effective patient removal of their problematic cerumen. This treatment significantly reduces occlusion of the ear canal and relieves symptoms of problematic cerumen, including pain, itching, a sensation of otic fullness, and hearing loss.

[0085] According to some embodiments, the present invention provides a topical

composition, which is administered into the external ear canal by means of a spray, foam, or drops into the external ear canal. The cerumenolytic composition is preferably packaged in a bottle having a syringe or dropper to dispense the composition, or in a plastic bottle that may be squeezed to dispense the composition. In another embodiment, it may be packaged in an aerosol bottle or in any other type of bottle (e.g. , pump-action bottle) that dispenses the composition as a foam.

[0086] According to some embodiments, the cerumenolytic compositions are formulated for administration by spraying or by instillation, in the form of drops, into the external ear canal. In one embodiment, the topical otic formulation will be packaged in a plastic bottle that releases one (1) drop of the solution, suspension, or gel when squeezed gently. The amount of the cerumenolytic composition applied to the ear canal may vary. Suitable dosages include, but are not limited to, 0.02 ml, 0.03 ml, 0.04 ml, 0.05 ml, 0.06 ml, 0.07 ml, 0.08 ml, 0.09 ml, 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1 ml, 1.5 ml, 2 ml, 3 ml etc. Preferably, the limonene effectively dissolves cerumen in a single dose. Other suitable dosages include, but are not limited to, 1 drop, 2 drops, 3 drops, 4 drops, 5 drops, 6 drops, 7 drops, 8 drops, 9 drops, 10 drops, 15 drops, 0.3 ml, 0.5 ml, 1 ml, 1.5 ml, 2 ml, or 3 ml.

[0087] According to some embodiments, the cerumenolytic compositions are formulated for administration by spraying or by instillation, in the form of foam, into the external ear canal. In one embodiment, the topical otic formulation will be packaged in a bottle that releases one (1) metered unit of foam when squeezed or pressed. The amount of the cerumenolytic composition applied to the ear canal may vary. Suitable dosages include, but are not limited to, 0.02 ml, 0.03 ml, 0.04 ml, 0.05 ml, 0.06 ml, 0.07 ml, 0.08 ml, 0.09 ml, 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1 ml, 1.5 ml, 2 ml, etc.

[0088] Applications of the cerumenolytic composition may be repeated, for example on an as needed basis, to treat problematic cerumen. For example, the cerumenolytic composition may be administered at the rate of one or more sprayings or instillations per day {e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). The cerumenolytic composition may be administered over a period of 1 or more days {e.g. , 1 , 2, 3, 4, 5, 6, 7, etc.) This includes from 1 to 4 days, from 3 to 4 days, from 1 to 2 weeks, etc.

[0089] Applications of the cerumenolytic composition may be performed in the absence of problematic cerumen, i.e. for prophylactic measures to prevent the accumulation of problematic cerumen. For example, the cerumenolytic composition may be administered at the rate of one or more sprayings or instillations per day {e.g. , 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) in the absence of problematic cerumen. The cerumenolytic composition may be administered over a period of 1 or more days {e.g., 1 , 2, 3, 4, 5, 6, 7, etc.) in the absence of problematic cerumen. This includes from 1 to 4 days, from 3 to 4 days, from 1 to 2 weeks, etc.

[0090] According to some embodiments, a user may administer the composition by tilting the head toward one shoulder or by assuming a reclined position on his or her side. The user then applies the cerumenolytic composition {e.g. , cerumenolytic composition comprising limonene, bile salts, and/or sodium bicarbonate) to the external ear canal. Approximately 0.02 ml to 2 ml of the composition is typically dosed to the external ear canal. The user keeps the head tilted, or remains in such a reclined position, for a sufficient time period for the composition to bathe the external ear canal and to dissolve, dislodge, break-up, and/or digest cerumen in the ear canal. This time period is preferably from about 30 seconds to 5 minutes, although in certain cases the time period may be shorter or longer. Such times include 1 second, 5 seconds, 10 seconds, 15 seconds, 30 seconds, 45 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, or longer. Preferred ranges include from about 30 seconds to about 1 minutes; from about 1 to about 2 minutes; from about 1 to about 5 minutes; from about 5 to about 10 minutes; etc. [0091] According to some embodiments, a user may administer the composition as a foam by leaving the head upright. The user then applies the foam cerumeno lytic composition (e.g., cerumenolytic composition comprising limonene) to the external ear canal. A metered-dose bottle would be held up to the ear and approximately 0.02 to 2 ml of the composition would be dispensed to the external ear canal. In some embodiments, the user leaves the foam in place for a sufficient time period for the composition to bathe the external ear canal and to dissolve, dislodge, break-up, and/or digest cerumen in the ear canal. This time period is preferably from about fifteen minutes to about 4 hours (e.g., about fifteen minutes to about 3 hours, about fifteen minutes to about 2 hours, about fifteen minutes to about 90 minutes, about fifteen minutes to about 60 minutes, and about fifteen minutes to about thirty minutes), although in certain cases the time period may be shorter or longer. Such times include 1 second, 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, or longer. Preferred ranges include from about 1 to about 5 minutes; from about 2 to about 5 minutes; from about 1 to about 10 minutes; from about 1 to about 2 minutes; from about 1 to about 15 minutes; from about 5 to about 15 minutes; from about 10 to about 20 minutes; etc. In some embodiments, the user leaves the foam in place for an indefinite time period, and does not use any method to remove the foam from the ear canal after a certain time period following application.

[0092] During the incubation period, the user may massage the tragus of the external ear, or any other part of the external ear, to promote the action of the cerumenolytic. This action may be performed preferably from about 5 seconds to about 30 seconds, although in certain cases the time period may be shorter or longer. Such times include 1 second, 2 seconds, 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 1 minute, 2 minutes, or longer.

[0093] After the incubation period, the cerumenolytic composition may optionally be irrigated with water, saline, or other rinsing fluid to complete cerumen removal and to wash away excess product. For example, following the termination of the bathing period, irrigation with an aqueous solution may be performed to facilitate removal of cerumen from the ear canal. Treatment

According to certain embodiments of the invention, the compositions of the present

embodiments are used to alleviate or remedy signs and symptoms associated with excessive or impacted cerumen. Excessive or impacted cerumen may impede the passage of sound in the ear canal and/or may lead to other complications. Symptoms and complications associated with excessive or impacted cerumen include, but are not limited to, the following: pain; decreased hearing; itching; otic fullness; ringing in the ears; hearing aid faults; otitis externa; vertigo; and tinnitus. Signs associated with excessive or impacted cerumen include occlusion of the ear canal and perforation of the ear drum. The compositions, formulations, kits, and methods of the present invention may be used to treat such symptoms and complications associated with excessive or impacted cerumen.

Kits

[0094] The present invention optionally provides for a cerumen removal kit comprising a cerumenolytic composition/solution/suspension/foam/gel and a device for dispensing an irrigation solution. According to some embodiments, the cerumenolytic

composition/solution/suspension/foam/gel contains limonene, preferably limonene, bile salts, and/or sodium bicarbonate. According to some embodiments, the device for dispensing the irrigation solution is a bulb syringe. According to some embodiments, the irrigation solution is saline, preferably an isosmotic saline solution, sterile water, or tap water. According to some embodiments, the irrigation solution may be included in the kit as a vial or device containing the ready-to-administer solution.

[0095] The present invention optionally provides for a cerumen removal kit comprising a cerumenolytic composition/solution/suspension/foam/gel and a device for administering the cerumenolytic composition/solution/suspension/foam/gel. The device may be a dropper, syringe, or bottle that may be squeezed to dispense the composition. The device may be an aerosol bottle, pump-action bottle or other container able to dispense the composition as a foam. The kit may further comprise an irrigation solution. According to some embodiments, the irrigation solution is saline, preferably an isosmotic saline solution, sterile water, or tap water. [0096] The present invention provides for a vial or device containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel suitable for administration by and/or to a patient, wherein the composition comprises limonene. According to some embodiments, the vial may additionally contain otologically acceptable carriers comprising any combination of preservatives, surfactants, foaming agents, viscosity enhancers, penetration enhancers, buffers, sodium chloride or other salts, solubilizers, stabilizers, pH adjusters, tonicity agents, fillers, demulcents, and water.

[0097] The present invention provides for a kit comprising 1) a vial or device containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel suitable for administration by and/or to a patient, wherein the composition comprises limonene; and, optionally, 2) a device (e.g., bulb syringe) for administering an irrigation solution to the external ear canal; and, optionally, 3) a vial or device containing an irrigation solution, preferably a saline solution, sterile water, or tap water.

Definitions

[0098] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims.

[0099] For the purposes of promoting an understanding of the embodiments described herein, reference will be made to preferred embodiments and specific language will be used to describe the same. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. As used throughout this disclosure, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a composition" includes a plurality of such compositions, as well as a single composition, and a reference to "a therapeutic agent" is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth. Thus, for example, a reference to "a host cell" includes a plurality of such host cells, and a reference to "an antibody" is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.

[00100] Unless otherwise indicated, all ingredient concentrations listed as a percentage are in units of volume/volume percent.

[00101] Reference to numeric ranges throughout this specification encompasses all numbers falling within the disclosed ranges. Thus, for example, the recitation of the range of about 1% to about 5% includes 1 %, 2%, 3%, 4%, and 5%, as well as, for example, 2.3%, 3.9%, 4.5%, etc.

[00102] As used herein, the term "bicarbonate" refers to any soluble bicarbonate salt. These salts are most frequently formed with group I metals. Sodium bicarbonate, potassium

bicarbonate, or mixtures thereof are the preferred bicarbonates.

[00103] As used herein, the term "otologically acceptable carrier" refers to any substance or combination of substances that act as a carrier for an active agent or agents and that are suitable for administration to the external ear canal. By way of example, an otologically acceptable vehicle may comprise any combination of preservatives, surfactants, foaming agents, viscosity enhancers, penetration enhancers, buffers, sodium chloride or other salts, solubilizers, stabilizers, pH adjusters, tonicity agents, fillers, demulcents, and water.

Examples

[00104] It is understood that modifications which do not substantially affect the activity of the various embodiments of this invention are also provided within the definition of the invention provided herein. Accordingly, the following examples are intended to illustrate but not limit the present invention. While the claimed invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one of ordinary skill in the art that various changes and modifications can be made to the claimed invention without departing from the spirit and scope thereof. Thus, for example, those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered to be within the scope of this invention, and are covered by the following claims.

Example 1

[00105] In vitro studies were performed showing cerumenolytic efficacy of 4 selected compounds (d-limonene, carbamide peroxide, bile salts, and sodium bicarbonate). Efficacy was assessed by recording the ability of the agents to dissolve a compacted cerumen specimen at 1 , 10, 15, 30, 60 minutes and 24 hours post-application. Limonene, bile salts, and sodium bicarbonate successfully dissolved impacted cerumen compared to carbamide peroxide within 15-minutes time point (Figures 1-3).

[00106] References

[00107] Burton M, Doree C. Ear Drops for the removal of ear wax. Cochrane Database Syst. Rev. 2009 Jan 21 ; (1):CD004326.

[00108] Crandell CC, Roeser RJ. Incidence of excessive/impacted cerumen in individuals with mental retardation: a longitudinal investigation. Am. J. Ment. Retard. 1993; 97:568-574.

[00109] Guest JF, Greener MH, Robinson AC, Smith AF. Impacted cerumen: composition, production, epidemiology and management. QJM 2004; 97:477-488.

[00110] Grossan, M. Cerumen removal— current challenges. Ear Nose Throat. J. 1998; 77(7):541-546,548.

[00111] Igimi H, Tamura R, Toraishi K, Yamamoto F, Kataoka A, Ikejiri Y, Hisatsugu Y, Shimura H. Medical Dissolution of Gallstones Clinical Experience of D-limonene as a Simple, Safe, and Effective Solvent. Dig. Diseases and Sci. 1991; 36 (2): 200-208.

[00112] Jimenez N, Garcia M, Galan J, Vallet A, Owen G, and Wall. Development of a liquid enzyme -based cerumenolytic product. J. Pharm. Sci. 2007; 97(1 1):4970-4982. [00113] Roeser RJ, Ballachanda BB. Physiology, pathophysiology, and anthropology/ epidemiology of human ear canal secretions. J. Am. Acad. Audiol. 1997; 8:391 -400.

[00114] Roland PS, Smith TL, Schwartz SR, Rosenfeld RM, Ballachanda B, Earll JM, Fayad J, Harlor AD, Hirsch BE, Jones SS, Krouse HJ, Magit A, Nelson C, Stutz DR, Wetmore S. Clinical practice guideline: cerumen impaction. Otolaryngol. Head Neck Surg. 2008; 139:S 1 -S21.

[00115] Sharp JF, Wilson JA, Ross L, Barr-Hamilton RM. Ear wax removal: a survey of current practice. Br. Med. J. 1990; 301 : 1251-1253.

Claims

1. A vial or device containing a ready-to-administer cerumeno lytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises limonene.

2. A vial or device containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises one or more bile salts.

3. A vial or device containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises sodium bicarbonate.

4. A vial or device containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises a

therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

5. The vial or device according to any one of claims 1 to 4, wherein the composition

additionally comprises one or more otologically acceptable carriers selected from the group consisting of preservatives, surfactants, foaming agents, viscosity enhancers, penetration enhancers, buffers, sodium chloride or other salts, solubilizers, stabilizers, pH adjusters, tonicity agents, fillers, demulcents, and water, and any combination or mixture thereof.

6. The vial or device according to any one of claims 1 , 4, or 5, wherein the concentration of limonene in the cerumenolytic composition is from about 10% to 30% w/v.

7. The vial or device according to any one of claims 1 , 4, or 5, wherein the concentration of limonene in the cerumenolytic composition is from about 0.001% to 10% w/v.

8. The vial or device according to any one of claims 2, 4 or 5, wherein the concentration of one or more bile salts in the cerumeno lytic composition is from about 10% to the limits of its solubility.

9. The vial or device according to any one of claims 2, 4, or 5, wherein the concentration of one or more bile salts in the cerumeno lytic composition is from about 0.001% to 10% w/v.

10. The vial or device according to any one of claims 3, 4, or 5, wherein the concentration of sodium bicarbonate in the cerumenolytic composition is from about 10% to the limits of its solubility.

11. The vial or device according to any one of claims 3, 4, or 5, wherein the concentration of sodium bicarbonate in the cerumenolytic composition is from about 0.001% to 10% w/v.

12. The vial or device according to any one of claims 1 to 11 , wherein the device allows the cerumenolytic composition to be administered by drops, by foam, or by spray.

13. The vial or device according to any one of claims 1 to 12, wherein the device is a syringe, a dropper, a plastic bottle, an aerosol or other foam-dispensing bottle, or a spray bottle.

14. A kit comprising the vial or device according to any one of claims 1 to 13 and a bulb syringe, vial, or other device for irrigation of the external ear canal.

15. The kit according to claim 14, wherein the device for irrigation of the external ear canal contains no liquid, but can be filled with tap water.

16. The kit according to claim 14, further comprising an irrigation solution of sterilized

and/or distilled water, or a saline solution, packaged with or within the device for irrigation of the external ear canal.

17. The kit according to any one of claims 14 to 16, wherein the bulb syringe, vial, or other device allows the irrigation solution to be administered by drops, by a stream of liquid, or by spray.

18. A method of removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising limonene in an amount effective to assist in the removal of human cerumen.

19. A method of removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising one or more bile salts in an amount effective to assist in the removal of human cerumen.

20. A method of removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising sodium bicarbonate in an amount effective to assist in the removal of human cerumen.

21. A method of removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

22. The method of claim 18 or 21, wherein the concentration of limonene in the

cerumenolytic composition is from about 10% to 30% w/v.

23. The method of claim 18 or 21 , wherein the concentration of limonene in the

cerumenolytic composition is from about 0.001% to 10% w/v.

24. The method of claim 19 or 21, wherein the concentration of one or more bile salts in the cerumenolytic composition is from about 10% to the limits of its solubility.

25. The method of claim 19 or 21 , wherein the concentration of one or more bile salts in the cerumeno lytic composition is from about 0.001% to 10% w/v.

26. The method of claim 20 or 21, wherein the concentration of sodium bicarbonate in the cerumeno lytic composition is from about 10% to the limits of its solubility.

27. The method of claim 20 or 21, wherein the concentration of sodium bicarbonate in the cerumeno lytic composition is from about 0.001% to 10% w/v.

28. The method of any one of claims 18 to 27, wherein the cerumeno lytic composition is administration by spraying or by instillation, in the form of drops, foam, or gel, into the external ear canal.

29. The method of any one of claims 18 to 28, wherein the cerumenolytic composition is applied for a sufficient time period for the composition to bathe the external ear canal and to dissolve, dislodge, break-up, and/or digest cerumen in the ear canal.

30. The method of any one of claims 18 to 29, wherein the cerumenolytic composition is packaged as part of a kit including a bulb syringe, vial, or other device for irrigation of the external ear canal.

31. The method of any one of claims 18 to 30, wherein the kit further comprises an irrigation solution of sterilized and/or distilled water or a saline solution, packaged with or within the device for irrigation of the external ear canal.

32. The method of any one of claims 18 to 31 , wherein the device for irrigation of the

external ear canal contains no liquid, but can be filled with tap water, and used for irrigation of the external ear canal following application of the cerumenolytic composition.

33. A method of treating of treating a sign, symptom or complication of excessive or impacted cerumen, comprising administering to the external ear canal a cerumenolytic composition comprising limonene in an amount effective to assist in the removal of human cerumen.

34. A method of treating of treating a sign, symptom or complication of excessive or

impacted cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising one or more bile salts in an amount effective to assist in the removal of human cerumen.

35. A method of treating of treating a sign, symptom or complication of excessive or

impacted cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising sodium bicarbonate in an amount effective to assist in the removal of human cerumen.

36. A method of removing human cerumen, comprising the step of: administering to the external ear canal a cerumenolytic composition comprising a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

37. The method of claim 33 or 36, wherein the concentration of limonene in the

cerumenolytic composition is from about 10% to 30% w/v.

38. The method of claim 33 or 36, wherein the concentration of limonene in the

cerumenolytic composition is from about 0.001% to 10% w/v.

39. The method of claim 34 or 36, wherein the concentration of one or more bile salts in the cerumenolytic composition is from about 10% to the limits of its solubility.

40. The method of claim 34 or 36, wherein the concentration of one or more bile salts in the cerumeno lytic composition is from about 0.001% to 10% w/v.

41. The method of claim 35 or 36, wherein the concentration of sodium bicarbonate in the cerumeno lytic composition is from about 10% to the limits of its solubility.

42. The method of claim 35 or 36, wherein the concentration of sodium bicarbonate in the cerumeno lytic composition is from about 0.001% to 10% w/v.

43. The method of any one of claims 33 to 42, wherein the sign, symptom or complication is selected from the group consisting of: occlusion of the ear canal; pain; decreased hearing; itching; otic fullness; ringing in the ears; hearing aid faults; otitis externa; vertigo; and tinnitus.

44. The method of any one of claims 33 to 43, wherein the cerumenolytic composition is administration by spraying or by instillation, in the form of drops, foam, or gel, into the external ear canal.

45. The method of any one of claims 33 to 43, wherein the cerumenolytic composition is applied for a sufficient time period for the composition to bathe the external ear canal and to dissolve, dislodge, break-up, and/or digest cerumen in the ear canal.

46. The method of any one of claims 33 to 43, wherein the cerumenolytic composition is packaged as part of a kit including a bulb syringe, vial, or other device for irrigation of the external ear canal.

47. The method of claim 46, wherein the kit further comprises an irrigation solution of

sterilized and/or distilled water, or a saline solution, packaged with or within the device for irrigation of the external ear canal.

48. The method of claim 46, wherein the device for irrigation of the external ear canal contains no liquid, but can be filled with tap water, and used for irrigation of the external ear canal following application of the cerumenolytic composition.

49. A dropper containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises limonene.

50. A dropper containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises one or more bile salts.

51. A dropper containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises sodium

bicarbonate.

52. A dropper containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises one or more bile salts.

53. A dropper containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

54. An aerosol, pump-action, or spray bottle containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises limonene.

55. An aerosol, pump-action, or spray bottle containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises bile salts.

56. An aerosol, pump-action, or spray bottle containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises sodium bicarbonate.

57. An aerosol, pump-action, or spray bottle containing a ready-to-administer cerumenolytic composition in the form of a solution, suspension, foam, or gel wherein the composition comprises a therapeutically effective concentration of any combination or mixture of the compounds selected from the group consisting of limonene, one or more bile salts, and sodium bicarbonate.

58. The vial or device according to any one of claims 1 to 5, wherein the composition

additionally comprises one or more of the agents selected from the group consisting of: olive oil; almond oil; mineral oil; glycerol; carbamide peroxide; sodium bicarbonate; glycerine; arachis oil; turpentine; dichlorobenzene; triethanolamine; polypeptides; oleate- condensate; urea; hydrogen peroxide; glycerine; docusate sodium; combinations thereof; and mixtures thereof.