WO2011085155A2 - Formulations et procédés pour la dissolution de cérumen - Google Patents

Formulations et procédés pour la dissolution de cérumen Download PDF

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Publication number
WO2011085155A2
WO2011085155A2 PCT/US2011/020453 US2011020453W WO2011085155A2 WO 2011085155 A2 WO2011085155 A2 WO 2011085155A2 US 2011020453 W US2011020453 W US 2011020453W WO 2011085155 A2 WO2011085155 A2 WO 2011085155A2
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WO
WIPO (PCT)
Prior art keywords
composition
cerumenolytic
ear canal
sodium bicarbonate
limonene
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PCT/US2011/020453
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English (en)
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WO2011085155A3 (fr
Inventor
Aron M. Shapiro
Peter N. Friedensohn
Leo P. Menard
Stephanie K. Lynch
George E. Minno
Jacquelyn M. Nice
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Ora, Inc.
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Publication of WO2011085155A2 publication Critical patent/WO2011085155A2/fr
Publication of WO2011085155A3 publication Critical patent/WO2011085155A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • Embodiments of the present disclosure are related to formulations, kits, and methods for dissolving cerumen.
  • Cerumen or ear wax
  • Cerumen 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.
  • 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.
  • embodiments of the present disclosure may include certain features of the described products, methods, and/or apparatus without suffering from their described disadvantages.
  • 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.
  • the present invention provides for topical formulations and methods for relieving symptoms and complications caused by excessive or impacted cerumen.
  • the formulations comprise effective amounts of limonene, bile salts, and/or sodium bicarbonate.
  • 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.
  • 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.
  • 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.
  • 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;
  • the concentration of limonene in the cerumenolytic composition is from about 0.001 % to 10% w/v.
  • 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.
  • 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.
  • the present invention details the development of a cerumen removal product.
  • the cerumen removal product comprises a cerumenolytically effective amount of limonene, one or more bile salts, and/or sodium bicarbonate.
  • 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.
  • the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation.
  • 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.
  • the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation.
  • 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.
  • the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation.
  • 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.
  • the kit also contains an amount of solution (e.g., saline, water) to be used for the irrigation.
  • 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.
  • 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.
  • signs e.g., occlusion of the ear canal
  • symptoms e.g. , pain, decreased hearing, itching, otic fullness, ringing in the ears
  • 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.
  • 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.
  • the device allows the cerumenolytic composition to be administered by drops, by foam, or by spray.
  • the device is a syringe, a dropper, a plastic bottle, an aerosol or other foam-dispensing bottle, or a spray bottle.
  • kits 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.
  • 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.
  • 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.
  • 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.
  • methods 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.
  • methods 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.
  • methods 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.
  • methods 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.
  • methods 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.
  • 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.
  • methods 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.
  • methods 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.
  • 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.
  • a method 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.
  • a method 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.
  • a method 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 CioHi 6 (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.
  • 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.
  • the formulations comprise an effective amount of limonene, preferably from about 0.001% to about 30% limonene mixed in a compatible vehicle or solvent.
  • 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
  • Hmonene from about 15% to about 40% Hmonene; and from about 15% to about 50% Hmonene.
  • 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 1% to about
  • 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.
  • 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.
  • 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.
  • 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.
  • a cerumenolytic composition comprising limonene, one or more bile salts, and sodium bicarbonate in solvent or in suspension.
  • a cerumenolytic composition comprising limonene and one or more bile salts in solvent or in suspension.
  • 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.
  • 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.
  • a cerumenolytic composition comprising limonene, one or more bile salts, and sodium bicarbonate formulated as a foam or gel.
  • a cerumenolytic composition comprising limonene and one or more bile salts formulated as a foam or gel.
  • a cerumenolytic composition comprising limonene and sodium bicarbonate formulated as a foam or gel.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cerumenolytic formulations of the present embodiments may further contain one or more additional compounds or agents that have cerumenolytic properties.
  • 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.
  • 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.
  • 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.
  • cholic acid is C24H40O5 (IUPAC name: 3,7,12-trihydroxy-10,13- dimethylhexadecahydro-lH-cyclopenta[ ]phenanthren-17-yl)pentanoic acid), for glycocholic acid C 26 H 43 N0 6 ( -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 C 26 H 45 O 7 S (2- ⁇ [(3a,5 ,7a,12a)-3,7,12-trihydroxy- 24-oxocholan-24-yl] amino ⁇ ethanesulfonic acid).
  • bile 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.
  • 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.
  • 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.
  • 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.
  • the formulations comprise an effective amount of one or more bile salts in a compatible vehicle or solvent.
  • one or more bile salts is the sole active ingredient.
  • the formulations of the present invention include cerumeno lytic compositions consisting essentially of one or more bile salts.
  • cerumenolytic composition consisting essentially of one or more bile salts in solution.
  • cerumenolytic composition consisting of one or more bile salts in solution formulated as a foam or gel.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 NaHC0 3 .
  • the sodium bicarbonate is used as an effective and gentle exfoliant of dead skin cells in the ear canal.
  • 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.
  • 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.
  • 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
  • the formulations comprise an effective amount of sodium bicarbonate in a compatible vehicle or solvent.
  • sodium bicarbonate is the sole active ingredient.
  • the formulations of the present invention include cerumenolytic compositions consisting essentially of sodium bicarbonate.
  • cerumenolytic composition consisting essentially of sodium bicarbonate in solution.
  • cerumenolytic composition consisting of sodium bicarbonate in solution formulated as a foam or gel.
  • 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.
  • the sodium bicarbonate formulations of the present invention are sodium bicarbonate formulations of the present.
  • the sodium bicarbonate formulations of the present embodiments may further contain one or more additional compounds or agents that have cerumenolytic properties.
  • 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.
  • sodium bicarbonate may be combined with sodium
  • sodium bicarbonate may be combined with enzymes other than methyl trypsin, combined with sodium sesquicarbonate.
  • sodium bicarbonate may be combined with sodium borate or docusate sodium, and further combined with sodium sesquicarbonate.
  • 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.
  • 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.
  • 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.
  • 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 MTM, 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.
  • 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).
  • Parabens methyl-, ethyl-, propyl-, or butyl-
  • Acids or their salts benzoic acid, sodium benzoate, sorbic acid, sodium sorbate
  • Quaternium Ammonium Compounds cetrimide, Benzalkonium chloride, cetyl
  • 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 (C 12 -C 18 ).
  • 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.
  • 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.
  • the foaming agent is present in an amount of about 5-30% by weight (e.g., 5%, 10%, 15%, 20%, 25%).
  • 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.
  • 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.
  • 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.
  • emulsifiers or surfactants mixed with limonene to create a cerumenolytic composition.
  • 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.
  • the cerumen removal kit comprises a
  • the effective cerumen solvent and an irrigation component and/or device may be contained in a single package.
  • 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.
  • the irrigation solution may be any solution acceptable for irrigating the ear canal to remove cerumen debris.
  • 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.
  • 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.
  • the saline solution is preferably an isosmotic saline solution.
  • 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.
  • the present invention provides a topical
  • 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.
  • the cerumenolytic compositions are formulated for administration by spraying or by instillation, in the form of drops, into the external ear canal.
  • 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.
  • the limonene effectively dissolves cerumen in a single dose.
  • 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.
  • the cerumenolytic compositions are formulated for administration by spraying or by instillation, in the form of foam, into the external ear canal.
  • 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.
  • cerumenolytic compositions may be repeated, for example on an as needed basis, to treat problematic cerumen.
  • 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.
  • cerumenolytic composition may be performed in the absence of problematic cerumen, i.e. for prophylactic measures to prevent the accumulation of problematic cerumen.
  • 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.
  • 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.
  • cerumenolytic composition e.g. , cerumenolytic composition comprising limonene, bile salts, and/or sodium bicarbonate
  • 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.
  • 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.
  • cerumeno lytic composition e.g., cerumenolytic composition comprising limonene
  • 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.
  • 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.
  • 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.
  • 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.
  • the cerumenolytic composition may optionally be irrigated with water, saline, or other rinsing fluid to complete cerumen removal and to wash away excess product.
  • irrigation with an aqueous solution may be performed to facilitate removal of cerumen from the ear canal.
  • compositions of the present invention are provided. According to certain embodiments of the invention, the compositions of the present invention are provided.
  • 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.
  • 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.
  • a cerumenolytic composition/solution/suspension/foam/gel optionally provides for a device for dispensing an irrigation solution.
  • the cerumenolytic composition/solution/suspension/foam/gel optionally provides for a device for dispensing an irrigation solution.
  • composition/solution/suspension/foam/gel contains limonene, preferably limonene, bile salts, and/or sodium bicarbonate.
  • the device for dispensing the irrigation solution is a bulb syringe.
  • the irrigation solution is saline, preferably an isosmotic saline solution, sterile water, or tap water.
  • the irrigation solution may be included in the kit as a vial or device containing the ready-to-administer solution.
  • 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.
  • the irrigation solution is saline, preferably an isosmotic saline solution, sterile water, or tap water.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • an 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.
  • 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.

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Abstract

La présente invention se rapporte à des formulations, des trousses et des procédés pour le soulagement de symptômes et de complications ayant pour origine du cérumen en excès ou un bouchon de cérumen. Les formulations comprennent des quantités efficaces de limonène, un ou plusieurs sels biliaires et/ou du bicarbonate de sodium.
PCT/US2011/020453 2010-01-07 2011-01-07 Formulations et procédés pour la dissolution de cérumen WO2011085155A2 (fr)

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WO2014189478A3 (fr) * 2013-05-23 2015-01-15 Kapar Umut Solution d'hygiène auriculaire applicable sous forme de mousse ou de shampoing
DE202015100655U1 (de) 2015-02-03 2016-02-04 Bio.Lo.Ga. S.R.L. Pharmazeutische Zusammensetzung zur topischen Anwendung im Gehörgang
CN106821782A (zh) * 2017-02-14 2017-06-13 青岛雅各仕生物技术有限公司 宠物用滴耳剂及其制备方法
CN107375325A (zh) * 2017-07-19 2017-11-24 江苏威克斯医疗科技有限公司 一种外耳道冲洗液及其用途
WO2018034910A1 (fr) * 2016-08-14 2018-02-22 Eosera Inc. Nouvelles compositions et procédés d'élimination de cérumen
US10154927B2 (en) 2012-06-14 2018-12-18 Earways Medical Ltd. Ear wax removal device and methods thereof
US10238545B2 (en) 2013-12-03 2019-03-26 Earways Medical Ltd. Ear wax removal device and methods thereof
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US11324635B2 (en) 2012-06-14 2022-05-10 Earways Medical Ltd. Cerumen removal apparatus
US10154927B2 (en) 2012-06-14 2018-12-18 Earways Medical Ltd. Ear wax removal device and methods thereof
WO2014189478A3 (fr) * 2013-05-23 2015-01-15 Kapar Umut Solution d'hygiène auriculaire applicable sous forme de mousse ou de shampoing
US10238545B2 (en) 2013-12-03 2019-03-26 Earways Medical Ltd. Ear wax removal device and methods thereof
US11432964B2 (en) 2013-12-03 2022-09-06 Earways Medical Ltd. Ear wax removal device and methods thereof
DE202015100655U1 (de) 2015-02-03 2016-02-04 Bio.Lo.Ga. S.R.L. Pharmazeutische Zusammensetzung zur topischen Anwendung im Gehörgang
WO2016124408A1 (fr) 2015-02-03 2016-08-11 Bio.Lo.Ga. S.R.L. Composition pour une application topique dans le canal auditif
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WO2018034910A1 (fr) * 2016-08-14 2018-02-22 Eosera Inc. Nouvelles compositions et procédés d'élimination de cérumen
US10596106B2 (en) * 2016-08-14 2020-03-24 Eosera, Inc. Compositions and methods for cerumen removal
CN106821782A (zh) * 2017-02-14 2017-06-13 青岛雅各仕生物技术有限公司 宠物用滴耳剂及其制备方法
US11304850B2 (en) 2017-03-24 2022-04-19 Earways Medical Ltd. Apparatus and method for treating or/and refreshing an ear canal
CN107375325A (zh) * 2017-07-19 2017-11-24 江苏威克斯医疗科技有限公司 一种外耳道冲洗液及其用途

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