Ear formulations, methods and devices

Abstract

The invention relates to otological formulations, methods and devices. The present invention relates to a formulation and a method for treating ear infections, in particular auricular mycosis and otitis externa, by single administration. The formulations comprise an antibiotic, an antifungal agent and an anti-inflammatory agent added to a thick ear carrier. In one embodiment, the formulation comprises a therapeutically effective amount of an active ingredient, including marbofloxacin, terbinafine and / or clotrimazole and dexamethasone.

Description

[0001] This application is a divisional application. The original application was filed on October 8, 2020, with application number 202080068395.2, and the invention title was "Ear Preparations, Methods and Apparatus", the entire contents of which are incorporated herein by reference.

[0002] Cross-references to related applications

[0003] This application claims the benefit of priority under section 119(e) of the U.S. Patent and Trademark Act to U.S. Provisional Patent Application No. 62 / 914,301, filed October 11, 2019, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] This invention relates to antifungal / antibacterial / anti-inflammatory preparations for treating ear infections (especially chronic otitis media) and their delivery methods and devices. Background Technology

[0005] Ear infections, especially fungal infections of the ear, are common ear diseases that typically occur in warm, moist environments. Fungal otitis externa is a fungal infection of the external auditory canal and related complications. It has been reported that up to 30.4% of patients with otitis externa present with symptoms of fungal otitis or ear inflammation.

[0006] Common symptoms of fungal ear infections include ear pain, ear discharge, hearing loss, ear fullness, ear itching, and tinnitus. Several factors that may cause or increase the incidence of fungal infections include: humid climates, the presence of earwax (cerumen) that supports fungal growth, ear canal structure, weakened immune function, diabetes, overuse of topical ear antibiotics, prolonged use of broad-spectrum antibiotics, use of systemic steroids, pregnancy, obliterative fungal growth in hearing aids, trauma, and bacterial infections.

[0007] Common fungi causing otitis externa include Aspergillus niger and Candida albicans, which can be treated with specific antifungal agents. Other fungi can also cause otitis externa and can be treated with appropriate medications. One point of contention is whether it is necessary to identify the causative agent when determining the appropriate treatment. Some believe that treatment should be based on susceptibility after identifying the fungal species, while others believe that treatment should be based on the efficacy and properties of the medication, regardless of the causative microorganism. Experienced otolaryngologists (ENT) now often do not need to culture the fungus; they can roughly identify typical fungal features through examination and routinely treat the fungus in most cases, followed by the application of a topical antacid or specific antifungal agent. Therefore, practitioners can identify the fungus as needed or treat any present fungi based solely on experience and best practices.

[0008] Currently, there are four main classes of drugs used to treat fungal infections: polyenes, triazoles, nucleoside analogs, and echinocandins. The mechanisms of action of polyenes and triazoles involve a fundamental chemical component found in fungal cell membranes called ergosterol. Drugs bind to ergosterol, creating polar pores in the fungal membrane, causing ions and other molecules to leak out of the cell, ultimately killing it. Nucleoside analogs interfere with nucleotide synthesis, thereby preventing normal energy production, metabolism, and signal transduction within the cell. Echinocandins are a new class of antifungal agents that work by interfering with cell wall biosynthesis, but they are known to have embryotoxicity, requiring dosage adjustments for patients with liver disease.

[0009] The most common treatment to date is repeated application of solutions, creams, powders, or ointments, lasting from one week to one month. Long-term treatment can be inconvenient for patients, as they may have to visit their primary care physician or ENT specialist multiple times, or frequently forget to take medications as prescribed, leading to secondary fungal and bacterial growth and potentially prolonging the treatment period. Furthermore, many medications are not effective against all infections, which can also extend the treatment time. Additionally, purely liquid medications such as ear drops are less effective for chronic otitis externa, primarily because the fluid drains quickly from the ear canal, and gravity prevents it from reaching all infected areas, especially the upper part of the ear canal. Creams and ointments, on the other hand, usually remain in the ear and must be removed by an ENT specialist later.

[0010] U.S. Patent No. 7,220,431 discloses a method for administering medication to the middle ear of mammals by applying a formulation to the tympanic membrane. This method does not provide guidance on how to treat infections occurring in the ear canal, such as otitis externa. The formulation is characterized by a viscosity of less than 100,000 cps and forms a gel upon application to the tympanic membrane. However, practical application of this patent may present problems because once the ear canal is blocked, ear drops cannot be instilled. Furthermore, it is difficult for patients to remove the hardened gel after the infection symptoms subside. If the hardened gel remains in the ear canal for too long after releasing all the active ingredients, fungal and bacterial infections are likely to recur.

[0011] U.S. Patent No. 8,030,297 discloses a method for treating ear diseases selected from Meniere's disease, autoimmune ear diseases, otitis media, sensorineural hearing loss induced by acoustic trauma, drug-induced sensorineural hearing loss, sensorineural hearing loss, idiopathic sensorineural hearing loss, vertigo, and tinnitus. This method requires intratympanic administration of a pharmaceutically synthesized compound comprising 16%-21% (by weight) of a thermoreversible hydrogel of polyoxypropylene and polyoxyethylene, and 1 mg / ml-70 mg / ml of a microparticle-based anti-inflammatory corticosteroid. The "intratympanic" administration method and the disease-specific targeting indicate that this patent does not treat otitis externa. This patent also does not provide guidance on the use of any antifungal agents to treat fungal infections.

[0012] There are also several veterinary drug products that can be used on animals. Schering-Plough Animal POSATEX OTIC SUSPENSION TM It is a suspension containing obibixacin, mometasone furoate, and posaconazole. However, its efficacy is limited (only effective against Pseudomonas aeruginosa and Malassezia yeast), and obibixacin is only approved for use in dogs. Furthermore, it needs to be used daily for 7 days.

[0013] TRI-OTIC TM It contains gentamicin sulfate, betamethasone valerate, and clotrimazole. However, this formula needs to be applied to the ear canal twice daily for 7 days, and its effectiveness is limited (only effective against Malassezia furfur, formerly known as Pityrosporum canis, and / or bacteria sensitive to gentamicin).

[0014] Some of these compositions have been approved for human use, but their efficacy is very limited. of It is a suspension containing 0.3% ciprofloxacin and 0.1% dexamethasone (0.3% ciprofloxacin, 0.1% dexamethasone). However, it is ineffective against fungi and needs to be used twice daily for seven days. CIPRO It is a similar formulation containing ciprofloxacin and hydrocortisone, and it also has limitations. It can be used in the field of genetics, containing neomycin and polymyxin B sulfate as well as hydrocortisone ear solution, but it also has limitations, requiring application 3-4 times a day for no more than 10 days.

[0015] Therefore, there remains a need for a formulation and method for treating otomycosis and otitis externa, which can eradicate a range of fungal and bacterial infections and associated inflammations with a single dose. There is an urgent need for a formulation that allows the active agent to remain in the patient's ear canal, thereby achieving a high cure rate for otomycosis and otitis externa with a single dose. Summary of the Invention

[0016] This invention relates to formulations, methods, and apparatus for treating chronic otitis externa with a single dose while maintaining high efficacy against a wide range of microorganisms, including fungi and bacteria. The formulation comprises a therapeutically effective amount of one or more antibacterial agents, one or more antifungal agents, and one or more anti-inflammatory agents, as well as a thickening matrix that is expelled from the ear within 7 days.

[0017] Preferred embodiments include marbofloxacin, dexamethasone, and terbinafine and / or clotrimazole. Together, these constitute the active ingredient for eradicating a wide range of fungal infections and any concurrent bacterial infections and inflammation. The formulation may also be used in combination with anesthetics or analgesics. For example, benzocaine, approved for use in the ear, can significantly relieve pain.

[0018] The formulation of this invention can eliminate complications caused by patients' failure to follow the instructions for use with a single dose. Furthermore, the optimal method of applying the active pharmaceutical ingredient (API) directly to the infected area reduces bacterial community resistance by significantly lowering the single dose, thereby keeping bacterial resistance to a minimum.

[0019] Furthermore, the use of an adhesive carrier in the formulation allows it to maintain its viscous form after entering the ear canal and reaching body temperature. Due to its high viscosity, the entire therapeutic formulation remains in contact with the infected ear canal for an extended period, enabling continuous release of the active ingredient for at least two, three, four, or more days.

[0020] In each embodiment, the formulation comprises the following components.

[0021] Table A

[0022]

[0023]

[0024] In another aspect of the invention, a therapeutic agent for treating the ear infection can be prepared using a composition of the said compounds.

[0025] In another aspect of the invention, a method for preparing a therapeutic agent is also provided, comprising mixing a composition of the compound with a viscous carrier to produce a therapeutic compound.

[0026] In another aspect of the invention, a kit is also provided, comprising the said synthesis packaged with instructions for use regarding the treatment of ear infections by a single dose.

[0027] In another aspect of the invention, a kit is also provided, comprising the said synthesis with inner packaging and instructions for use for treating ear infections by a single dose.

[0028] The single-use otomedicine for the ear canal comprises an adhesive carrier. The carrier can be any bulk-acceptable material having the desired viscosity that allows the formulation to remain in the ear canal for an extended period (preferably at least 2, 3, 4, 5, 6, 7, 8, 9 days or longer). Choosing different carriers may alter the physical properties of the formulation but will not change its therapeutic effect. For example, those skilled in the art can choose different carriers to formulate the formulation as a fluid, foam, cream, ointment, or other bulk-acceptable dosage form.

[0029] Thickeners can be purely natural, such as waxes, or synthetic or semi-synthetic polymers, including polysaccharides, proteins, alcohols, silicones, or waxes. Suitable thickeners may include beeswax, candelilla wax, carnauba wax, paraffin wax, ceresin wax, cetyl alcohol, corn starch, glyceryl stearate, guar gum, gum arabic, xanthan gum, lanolin, microcrystalline wax, acrylate polymers, polyalphaolefins, HE cellulose, PEG-150 distearate, sorbitol, stearic acid, stearyl palmitate, poloxamer 407, etc.

[0030] The preferred thickener is insoluble in water or has low water solubility, provides long-lasting effects, and is non-ototoxic. The preferred carrier comprises a combination of mineral oil and the thickener, such as PCCA Plasticized... TM (PCCA US, TX, Catalog No.: 30-3211) Proprietary low-density polyethylene blend. A more preferred carrier is a blend of 10-25%, 15-21%, or about 17% or 18% of United States Pharmacopeia (USP) or National Formulary (NF) paraffin to 100% (w / w) USP or NF mineral oil.

[0031] The carrier is characterized in that, when used in a preferred embodiment for human or other mammalian patients, it remains a viscous fluid after entering the subject's ear canal and reaching a body temperature of 37°C, with a viscosity of approximately 10,000 cPs, 20,000 cPs, 30,000 cPs, 40,000 cPs, 50,000 cPs, 60,000 cPs, or 70,000 cPs. Viscosities should be at least 10,000 cPs, 20,000 cPs, 30,000 cPs, or 40,000 cPs, preferably at least 10,000 cPs, 15,000 cPs, 20,000 cPs, 30,000 cPs, 40,000 cPs, 45,000 cPs, 50,000 cPs, 55,000 cPs, or 60,000 cPs, but adjustments can be made as needed. Overly viscous formulations cannot be discharged; therefore, viscosities should not exceed 80,000 cPs, and preferably be below 70,000 cPs. The dynamic A (absolute) viscosity should be determined according to ATSM D-2394 at 37°C.

[0032] Although the preparation is viscous, it remains a flowable fluid that can be applied using syringes and needles. The sticky fluid remains in the ear canal, maintaining contact with the infected tissue. This allows the active ingredients in the preparation to be released continuously for a prolonged period, preferably at least 3 days, more preferably at least 4 days, ideally 5 days, or even 6-7 days, thus providing sustained treatment for fungal and bacterial infections and associated inflammation. More importantly, the prolonged residence time of the viscous fluid allows the continuously released active ingredients to maintain hygiene within the ear canal by preventing the proliferation of fungi and bacteria. Furthermore, the viscosity of the preparation allows it to gradually drain (or be absorbed) from the ear canal after symptoms subside.

[0033] In another embodiment of the invention, the carrier can be a thinner liquid formulation for treating acute otitis media via an AOMT (Auricular Osmotic Tube). In cases of ear drainage, the liquid formulation can be passed through the tympanic membrane via the tympanic incision tube. Such carriers are described, for example, in U.S. Patent Nos. 7,220,431 and 8,030,297. However, some medications suitable for the external auditory canal may not be suitable for membrane-penetrating use, and the suitability of each medication must be tested.

[0034] In another aspect of the invention, a method for treating ear infections is also provided. The method includes applying a preparation to the ear canal of a mammal, typically administered once or possibly twice, wherein the preparation is as described herein.

[0035] In another aspect of the invention, a treatment kit for treating ear infections is also provided, comprising an injection unit having a storage chamber in fluid communication with a delivery component such as a tube or syringe; and a therapeutic preparation stored in the storage chamber. The therapeutic preparation is as described herein. The device is preferably designed for single use and is discarded after use. In other embodiments, the storage chamber may be used for multiple administrations, but the delivery component is disposable. Detailed Implementation

[0036] This invention provides a novel formulation and method for treating fungal infections of the ear (especially otitis externa). The formulation and method of this invention can treat or even eradicate chronic otitis externa by applying the formulation to the ear canal in a single application.

[0037] This invention provides a novel formulation for treating fungal ear infections, comprising an antifungal agent, an antibiotic, and an anti-inflammatory agent added to a viscous matrix (viscosity of 10-80,000 cPs at ear or body temperature).

[0038] The term "ear infection" as used herein refers to fungal and / or bacterial infections of the ear. The site of infection is primarily the ear canal. In one embodiment, the term "ear infection" includes otomycosis, chronic and acute otitis externa.

[0039] The "active ingredients" mentioned in this article refer to pharmaceutical substances that have therapeutic effects on the conditions being treated.

[0040] The term "corticosteroids" as used in this article refers to a class of steroids with anti-inflammatory effects, including but not limited to: ancinonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clocotropin neovalerate, desonide, desoxymethasone, dexamethasone sodium phosphate, difluralasone diacetate, fluocinolone acetonide, fluocinolone acetonide, fluticasone propionate, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisolone acetate, triamcinolone acetonide, and combinations thereof.

[0041] The term "thickener" as used herein refers to an optically acceptable additive capable of increasing the viscosity of a formulation. When the temperature rises to body temperature, the thickener can give the entire formulation an ear-acceptably viscous fluid consistency. Examples of thickeners that may be used in this invention include, but are not limited to, low-density polyethylene, poloxamer, waxes, and combinations thereof. The viscosity of the thickener can be adjusted by adding mineral oil. The thickeners of this invention preferably give the formulation a viscosity of approximately the following levels: about 10-80,000 cPs (37°C), about 10,000-80,000 cPs (37°C), about 20,000-80,000 cPs (37°C), or about 40,000-80,000 cPs (37°C), for example, about 50,000-70,000 cPs (37°C) or about 60,000-62,000 cPs (37°C).

[0042] The term "injection unit" as used herein refers to a unit capable of storing and injecting or delivering therapeutic agents to a target area of ​​a subject. Typical injection units include, but are not limited to, syringes connected to a needle or tube, for example, via a standard Luer lock or Luer connector. Needles or tubes may be customized as described herein.

[0043] The term "flowable" as used in this article refers to a fluid with a viscosity of less than 100,000 cPs at room temperature.

[0044] Unless the context otherwise requires, the terms “a” or “an” as used in the claims or description, when used in conjunction with the term “comprising”, refer to one or more.

[0045] The term "about" refers to the stated value plus or minus the measurement error margin, or, if the measurement method is not specified, plus or minus 10%.

[0046] The term "or" as used in the claims means "and / or", unless it is explicitly stated that the term refers only to alternatives or mutually exclusive alternatives.

[0047] The terms “comprising,” “having,” and “including” (and variations thereof) are open-ended copulas that allow for the addition of other components when used in the claims.

[0048] The phrase “composed of” is closed, excluding other components.

[0049] The phrase "mainly composed of..." excludes other substantial components, but allows the inclusion of non-substantial components that do not significantly alter the nature of the invention, such as instructions for use, special packaging, preservatives, antioxidants, etc. Active pharmaceutical ingredients fall within the substantial category.

[0050] When referring to drug names in this article, all active salts, isomers, and derivatives of the drug are included.

[0051] Unless otherwise stated, all percentages are by weight.

[0052] In one embodiment, the present invention provides a formulation for treating ear infections in mammals, comprising 0.01%-5% (by weight) of marbofloxacin, 0.01%-5% (by weight) of terbinafine and / or clotrimazole, 0.01%-2.5% (by weight) of corticosteroids, 10%-70% (by weight) of a thickener, and 30%-90% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0053] In one embodiment, the present invention provides a formulation for treating mammalian ear infections, comprising 1%-3% (by weight) of marbofloxacin, 1%-3% (by weight) of terbinafine and / or clotrimazole, 0.1%-0.3% (by weight) of corticosteroids, 15%-25% (by weight) of a thickener, and 70%-90% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0054] In one embodiment, the present invention provides a formulation for treating mammalian ear infections, comprising 1%-2% (by weight) of marbofloxacin, 1%-2% (by weight) of terbinafine and / or clotrimazole, 0.1%-0.25% (by weight) of corticosteroids, 15%-25% (by weight) of a thickener, and 70%-90% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0055] In one embodiment, the present invention provides a formulation for treating mammalian ear infections, comprising 1%-3% (by weight) of marbofloxacin, 1%-3% (by weight) of terbinafine and / or clotrimazole, 0.1%-0.3% (by weight) of corticosteroids, 15%-20% (by weight) of a thickener, and 75%-80% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0056] In one embodiment, the present invention provides a formulation for treating mammalian ear infections, comprising 1%-2% (by weight) of marbofloxacin, 1%-2% (by weight) of terbinafine and / or clotrimazole, 0.1%-0.25% (by weight) of corticosteroids, 15%-20% (by weight) of a thickener, and 75%-80% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0057] In one embodiment, the present invention provides a formulation for treating ear infections in mammals, comprising 1%-3% (by weight) of marbofloxacin, 1%-5% (by weight) of terbinafine, 0.1%-0.3% (by weight) of corticosteroids, 20%-30% (by weight) of a thickener, and 65%-80% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0058] In one embodiment, the present invention provides a formulation for treating ear infections in mammals, comprising 1%-3% (by weight) of marbofloxacin, 2%-4% (by weight) of terbinafine, 0.1%-0.3% (by weight) of corticosteroids, 20%-30% (by weight) of a thickener, and 65%-80% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0059] In one embodiment, the present invention provides a formulation for treating ear infections in mammals, comprising 1%-3% (by weight) of marbofloxacin, 2%-4% (by weight) of terbinafine, 0.1%-0.3% (by weight) of corticosteroids, 20%-30% (by weight) of a thickener, and 65%-75% (by weight) of mineral oil. Other therapeutically suitable matrices may be used instead of the thickener in the present invention without affecting the efficacy of the formulation.

[0060] In one embodiment, the present invention provides a formulation for treating ear infections in mammals, comprising 1%-3% (by weight) of marbofloxacin, 2%-4% (by weight) of terbinafine, 0.1%-0.3% (by weight) of dexamethasone, 20%-30% (by weight) of paraffin, and 65%-75% (by weight) of mineral oil. Other therapeutically suitable matrices may be used in place of the thickener in the present invention without affecting the efficacy of the formulation.

[0061] In one embodiment, the corticosteroid is selected from: ancinonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clocotropin neovalerate, desonide, desoxymethasone, dexamethasone sodium phosphate, difluralasone diacetate, fluocinolone acetonide, fluocinolone acetonide, fluticasone propionate, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisolone acetate, triamcinolone acetonide, and combinations thereof. More preferably, the corticosteroid is dexamethasone, hydrocortisone, triamcinolone acetonide, or combinations thereof.

[0062] In one embodiment, the carrier comprises mineral oil and a thickener. In one embodiment, the thickener is paraffin wax, and the carrier comprises about 11-21% w / w or about 17% or 18% paraffin wax added to the mineral oil. In one embodiment, the thickener is paraffin wax, and the carrier comprises about 20-30% w / w or about 24% or 25% paraffin wax added to the mineral oil. In one embodiment, the thickener is paraffin wax, and the carrier comprises about 20-30% w / w or about 24% or 25% paraffin wax added to about 65-80% w / w or about 71% or 72% mineral oil. In one embodiment, the thickener is paraffin wax, and the carrier comprises about 22-26% w / w or about 24% or 25% paraffin wax added to about 70-75% w / w or about 71% or 72% mineral oil. In one embodiment, the thickener is paraffin wax, and the carrier comprises paraffin wax added to about 65-80% w / w or about 70-75% mineral oil.

[0063] In one embodiment, the method of treating an ear infection includes the steps of: applying the formulation of the present invention to a mammalian ear canal in a single application, wherein the formulation forms a gel after application to the mammalian ear canal, the gel continuously releasing an active ingredient over at least 2, 3, 4, 5, 6, 7, 8, or 9 days. In some embodiments, the method further includes removing infectious and inflammatory debris from the ear canal before applying the formulation to the ear canal.

[0064] In another embodiment, the present invention is a formulation for treating ear infections, comprising: one or more antifungal agents; one or more antibacterial agents; one or more anti-inflammatory agents; and a carrier having a viscosity of about 10-80,000 cPs (37°C), about 10,000-80,000 cPs (37°C), about 20,000-80,000 cPs (37°C), or about 40,000-80,000 cPs (37°C), wherein the carrier allows the active ingredient to remain in the ear for 2-7 days, and then be expelled or absorbed.

[0065] In one embodiment, the otomedicine comprises marbofloxacin, terbinafine, and dexamethasone added to an ear-acceptable carrier. Preferably, 0.1-10% marbofloxacin, 0.1-10% terbinafine, and 0.01-5% dexamethasone are used; most preferably, 1.5-2.0% marbofloxacin, 1.5-5.0% terbinafine, and 0.1-0.25% dexamethasone are added to the suitable carrier.

[0066] In one embodiment, the otomedicine comprises mabofloxacin, clotrimazole, and dexamethasone added to an ear-acceptable carrier. Preferably, 0.1-10% mabofloxacin, 0.1-10% clotrimazole, and 0.01-5% dexamethasone are used; most preferably, 1.5-2.0% mabofloxacin, 1.0-2.0% clotrimazole, and 0.1-0.25% dexamethasone are added to the suitable carrier.

[0067] In one embodiment, mammals suitable for treatment using the formulations and methods described in this invention include: humans, canines, felines, bovines, sheep, swine, equines, and other mammals whose ear infections are typically treated by veterinarians.

[0068] The present invention further provides a treatment kit for treating ear infections. In one embodiment, the treatment kit includes an injection unit (a syringe, needle, or hollow tube) comprising a storage chamber for storing the medication. The tube or needle can be bent to any suitable degree as long as it does not affect the dispensing of the treatment formulation.

[0069] The entire kit can be disposable, in which case the storage capacity is small, containing only a dose suitable for a single administration, such as 1 ml to 1.5 ml, to prevent waste. Alternatively, the kit can be reused until the therapeutic agent is depleted, in which case the storage capacity is large, supporting multiple administrations, such as 10 ml to 30 ml. The volume may vary if the patient is not human; for example, dogs may require a larger dose.

[0070] The formulations described in this invention can be prepared by various chemical methods, as long as the final product has the desired properties, such as maintaining fluidity at room temperature and body temperature, while remaining in the ear canal for a relatively long time and continuously releasing the active ingredient.

[0071] In one embodiment of the present invention, the formulation comprises the following components.

[0072] Table B

[0073] Active ingredients Dosage (% w / w) Maboxacin 1.5-1.9 Terbinafine 1.6-2.0 Dexamethasone (micronized) 0.1-0.25 mineral oil 78-80 paraffin 17-18 Total 100

[0074] In one embodiment of the present invention, the formulation comprises the following components.

[0075] Table C

[0076] Active ingredients Dosage (% w / w) Maboxacin 1.5-2.0 Clotrimazole 1.0-2.0 Dexamethasone (micronized) 0.1-0.25 mineral oil 78-80 paraffin 17-18 Total 100

[0077] In one embodiment of the present invention, the formulation comprises the following components.

[0078] Table D

[0079] Active ingredients Dosage (% w / w) Maboxacin 1.7-1.8 Terbinafine 1.6-2.0 Dexamethasone (micronized) 0.1-0.25 mineral oil 78-79 paraffin 17-18 Total 100

[0080] Table E

[0081] Active ingredients Dosage (% w / w) Maboxacin 1.5-1.9 Terbinafine 2.7-3.3 Dexamethasone (micronized) 0.1-0.3 mineral oil 70-74 paraffin 22-26 Total 100

[0082] Table F

[0083] Active ingredients Dosage (% w / w) Maboxacin 1.5-1.9 Terbinafine 2.7-3.3 Dexamethasone (micronized) 0.1-0.3 mineral oil 71-72 paraffin 23-24 Total 100

[0084] During preparation, the appropriate weights of marbofloxacin powder, clotrimazole or terbinafine powder and dexamethasone powder can be weighed and placed in a mixing container (e.g., a flask).

[0085] Then mineral oil can be added and the composition mixed thoroughly. Finally, thickener and more mineral oil can be added to the container to reach the final volume, and mixed thoroughly. The viscosity of the formulation can be adjusted by adding more mineral oil.

[0086] The appropriate dosage level of the active ingredient in the method is typically about 0.01-50 mg / kg per day, for example, about 0.25-15 mg / kg per day, or about 2.0-14 mg / kg per day. Within this range, the dosage of each active ingredient in a single-dose formulation can be about 0.25-3.5 mg / kg, 0.25-14 mg / kg, 1.0-10 mg / kg, 1.5-10 mg / kg, 2.0-10 mg / kg, 2.5-8.0 mg / kg, 2.5-8 mg / kg, 2.5-7.0 mg / kg, 2.5-6.5 mg / kg, 2.5-6.0 mg / kg, 2.5-5 mg / kg, etc. Dosage levels are 0.5 mg / kg, 2.5-5.0 mg / kg, 2.5-4.0 mg / kg, and 2.5-3.5 mg / kg (including all intermediate doses, such as 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, and 3.5 mg / kg). This formulation requires only a single application throughout the entire treatment course to achieve clinical resolution of the infection, with an elimination rate of up to 100%.

[0087] The formulations described in this invention are expected to achieve cure rates of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. Patients treated with the formulations are expected to achieve cure rates of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% within 2 to 27 days, with most patients achieving clinical cure within 7, 14, or 27 days, and the matrix being completely expelled from the ear. Of course, the percentage of the matrix component may vary depending on the wax chosen. The softer the wax, the higher the required percentage.

[0088] The "clinical cure rate" mentioned in this article refers to a significant reduction or complete elimination of symptoms. In the examples, infection remission occurred within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 days after a single dose, with efficacy rates greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and even reaching 100%.

[0089] In most cases, the intended adequate dose of the formulation is 1 ml. It should be noted that this volume may vary depending on the type of mammal being treated, and those skilled in the art can easily adjust the dosage as needed. Those skilled in the art will fully understand that different amounts of this formulation can be used in the ear canal of mammals.

[0090] After clearing infectious and / or inflammatory debris from the ear canal, an appropriate amount of the above-described preparation can be applied to the infected ear canal to fill all available space in the outer ear. The preparation can be stored in a syringe or container before use and can be stored at room temperature without diminishing its therapeutic effect.

[0091] The instructions for use of the formulation are as follows. First, an ENT specialist carefully inserts the hollow tube into the patient's ear canal. Pressing the plunger or storage unit dispenses and retains the treatment formulation within the ear canal. In this embodiment, the tube is flexible and includes a rounded tip to minimize scratching when applying the treatment formulation. The viscous fluid is dispensed to fill the space within the ear canal, thereby contacting the infected area while preventing secondary infection within the ear canal.

[0092] After administration, each patient should be examined to ensure the preparation remains in the ear canal. The exit point can be plugged with a cotton ball at the external auditory canal (ear socket), but we have not attempted to "plug" the ear canal with a stopper. Follow-up examinations can be performed 7-14 days after initial treatment. Residue is expected to be observed on day 14, indicating that the preparation can indeed remain in the ear canal for 14 days. Symptoms are expected to usually subside within three days, and hearing is expected to return to normal within 5-7 days after treatment.

[0093] Ideal anti-inflammatory agents that can be used in the formulation are dexamethasone or hydrocortisone.

[0094] The following embodiments are provided to further illustrate the advantages and features of the present invention, and are not intended to limit the scope of the invention. These embodiments are typical available examples, but other procedures, methods, or techniques well known to those skilled in the art may also be used.

[0095] Example 1

[0096] Treatment of canine otitis externa.

[0097] This study evaluated the efficacy and practical safety of the otopathic formulation of the present invention for the treatment of canine otitis externa over thirty (30) days. Twenty-four (24) dogs from two study sites participated in the study. All 24 dogs were treated with the formulation described in Table B. Safety was assessed in all 24 dogs, and efficacy was assessed in 21 dogs.

[0098] Dogs participating in this study presented with symptoms of otitis externa. On day 0, a physical examination, including auditory and otoscopy, was performed to check the tympanic membrane for integrity, confirm the absence of foreign bodies and ear mites, and a clinical score was assigned to the study ear based on erythema, effusion, swelling, and ulceration. A clinical score of at least 6 was required for inclusion in the study. Hearing tests were performed, and ear swabs were obtained for bacterial culture and fungal (yeast) identification. The ears were cleaned with saline solution. 1.0 mILIVP was administered to each infected ear of the dogs. If both ears were infected, the right ear was designated as the study ear.

[0099] During the first follow-up on day 7 (+2 days), ear assessment and clinical scoring were performed by auditory and otoscopy, and the owner was asked about any adverse events observed.

[0100] During the second follow-up on day 14 (±2 days), ear assessment and clinical scoring were performed by auditory and otoscopy, and the owner was asked about any adverse events observed.

[0101] During the final follow-up on day 30 (+3 days), an ear assessment and clinical scoring were performed through physical examination, including auditory and otoscopy, and hearing tests were conducted. A final clinical score of 3 or less, with no individual clinical score decreasing at the final follow-up, was required for clinical cure. If clinical cure was not achieved, an ear swab was obtained for bacterial culture and fungal (yeast) identification.

[0102] Based on clinical scores, 13 dogs achieved clinical cure by day 30, with at least 9 achieving clinical cure by day 7. The number of clinical cures is expected to increase when using the formulations shown in Tables E and F. No serious adverse events or adverse events directly caused by the use of the formulations were observed, demonstrating the safety of the formulations.

[0103] Preferred embodiments of the invention are shown and described herein, but these embodiments are merely illustrative. Various alternatives to the embodiments may be employed without departing from the spirit of the invention. The scope of the invention is defined by the claims.

Claims

1. An ear preparation comprising: a) Therapeutic agents, including: i) Mapofloxacin; ii) Terbinafine, clotrimazole, or combinations thereof; and iii) Corticosteroids; and b) Carrier.

2. The formulation according to claim 1, wherein, The formulation can be delivered into the ear canal of mammals in a flowable fluid formulation.

3. The formulation according to claim 2, wherein, The carrier contains a thickener, which allows the formulation to remain in the ear canal for at least 3 days after entering the ear canal, releasing the therapeutic agent.

4. The formulation according to claim 3, wherein, The carrier contains approximately 10-90% w / w of thickener.

5. The formulation according to claim 4, wherein, The carrier contains approximately 10-50% w / w of thickener and approximately 50-90% w / w of mineral oil.

6. The formulation according to claim 5, wherein, The thickener is wax.

7. The formulation according to claim 6, wherein, The carrier contains approximately 60-80% w / w mineral oil and approximately 10-30% wax.

8. The formulation according to claim 7, wherein, The wax is paraffin wax.

9. The formulation according to claim 8, wherein, The carrier contains approximately 65-75% w / w mineral oil and approximately 20-30% w / w paraffin.

10. The formulation according to claim 1, wherein, The formulation comprises about 0.1%-3% w / w of mabofloxacin and about 0.1%-5% w / w of terbinafine, clotrimazole, or a combination thereof.

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