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 filing date of the original application is October 8, 2020, the application number is 202080068395.2, and the invention title is "Otic preparations, methods, and devices", the entirety of which is incorporated herein by reference.

[0002] Cross-reference to related applications

[0003] This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62 / 914,301, filed on October 11, 2019, the entire content of which is hereby incorporated by reference in its entirety and made a part of the present invention. Technical field

[0004] The present invention relates to antifungal / antibacterial / anti-inflammatory preparations for treating ear infections, particularly chronic otitis, and methods and devices for their delivery. Background art

[0005] Ear infections, particularly fungal ear infections, are common ear diseases that typically occur in warm and humid environments. Otomycosis 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 exhibit symptoms of otomycosis or ear inflammation.

[0006] Common symptoms of fungal ear infections include ear pain, ear discharge, deafness, ear fullness, ear itching, and tinnitus. Several factors that may cause or increase the rate of fungal infections include: humid climate, the presence of cerumen (earwax) that supports fungal growth, ear canal structure, weakened immune function, diabetes, overuse of topical ear antibiotics, long-term use of broad-spectrum antibiotics, use of systemic steroids, pregnancy, occlusion of hearing aids by mold, trauma, and bacterial infections.

[0007] Common fungi that cause otitis externa include Aspergillus niger and Candida albicans, and targeted treatment can be carried out against these fungi. Other fungi may also cause otitis externa and can be treated with corresponding therapeutic agents. A controversial issue is whether it is necessary to identify the causative agent when determining the appropriate therapy. Some people believe that treatment should be based on the sensitivity after identifying the fungal species, while others believe that regardless of the causative microorganism, treatment should be based on the efficacy and characteristics of the drug. Experienced otolaryngologists (ENT) can now roughly determine typical fungal elements through examination without culturing the fungi and can routinely handle the fungi in most cases, and then apply topical acidifying agents or specific antifungal agents. Therefore, as needed, practitioners can determine the fungal species or handle the possible fungi based on experience in accordance with best practices.

[0008] Currently, there are mainly four types of drugs available for the treatment of fungal infections, including polyenes, triazoles, nucleoside analogs, and echinocandins. The mechanisms of action of the polyene and triazole families involve a basic chemical component found in the fungal cell membrane, called ergosterol. The drug binds to ergosterol, forming polar pores in the fungal membrane, which causes ions and other molecules to leak out of the cell, thereby killing the cell. Nucleoside analogs interfere with nucleotide synthesis, thus preventing normal energy production, metabolism, and signal transduction in the cell. Echinocandins are a new class of antifungal agents that act by interfering with cell wall biosynthesis, but are known to be embryotoxic and require dose adjustment when used in patients with liver disease.

[0009] To date, the most common treatment is multiple topical applications of solutions, creams, powders, or ointments, with the treatment lasting from one week to one month. Long-term treatment regimens are inconvenient for patients because they either have to visit a primary care physician or an otolaryngologist multiple times, or often forget to take the medication as prescribed when using self-administered medications, resulting in secondary proliferation of fungi and bacteria, which may further prolong the treatment period. In addition, many drugs do not achieve the full efficacy of multiple agents against the infection, which may also prolong the treatment time. Moreover, drugs in pure liquid dosage forms such as ear drops are not very effective for chronic otitis externa, mainly because the liquid drains out of the ear canal quickly and, under the influence of gravity, the liquid cannot reach all the infected areas in the ear canal, especially the upper part of the ear canal. Creams and ointments usually remain in the ear and must subsequently be removed by an otolaryngologist.

[0010] U.S. Patent No. 7,220,431 discloses a method of administering a preparation to the middle ear of a mammal by applying the preparation to the tympanic membrane of the mammal. The method does not provide guidance on how to treat infections occurring in the ear canal, such as otitis externa. This preparation is characterized by a viscosity of less than 100,000 cps and forms a gel after being applied to the tympanic membrane. However, there may be problems with the practical application of this patent because once the ear canal is blocked, it is no longer possible to instill ear drops. In addition, it is difficult for patients to remove the solidified gel after the infection symptoms have subsided. If the solidified gel remains in the ear canal for too long after releasing all its 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 deafness induced by acoustic trauma, sensorineural deafness induced by drugs, sensorineural deafness, idiopathic sensorineural deafness, vertigo, and tinnitus. Such a method requires the intratympanic administration of a pharmaceutical composition containing a thermoreversible hydrogel containing 16%-21% (by weight) of polyoxypropylene and polyoxyethylene and 1 mg / ml - 70 mg / ml of a multi-particle anti-inflammatory corticosteroid. The "intratympanic" administration route and the targeting of the disease indicate that this patent cannot treat otitis externa. This patent also does not provide guidance on how to use any antifungal agent to treat fungal infections.

[0012] There are also several veterinary drug products available for animals. Animal 's POSATEX OTIC SUSPENSION TM is a suspension containing orbifloxacin, mometasone furoate monohydrate, and posaconazole. However, its efficacy is limited (only applicable to Pseudomonas aeruginosa and Malassezia pachydermatis in yeast form), and orbifloxacin is only approved for use in dogs. In addition, it needs to be used daily for 7 days.

[0013] 's TRI-OTIC TM contains gentamicin sulfate, betamethasone valerate, and clotrimazole. However, this formulation needs to be applied to the ear canal twice a day for 7 days, and its efficacy is limited (only applicable to Malassezia pachydermatis, formerly known as Malassezia furfur in dogs, and / or bacteria sensitive to gentamicin).

[0014] There are also some compositions approved for human use, but their efficacies are all very limited. 's 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 a day for seven days. is a similar preparation containing ciprofloxacin and hydrocortisone, which also has limitations. Can be used in the field of genetics, contains neomycin, polymyxin B sulfate, and hydrocortisone ear solution, but also has limitations and needs to be applied 3 - 4 times a day for no more than 10 days.

[0015] Therefore, there is still a need for a preparation and method for treating ear fungal diseases such as otomycosis and otitis externa that can eradicate a series of fungal and bacterial infections and concurrent inflammations through a single administration. There is an urgent need for a preparation that can keep the active agent in the patient's ear canal to achieve a high cure rate for otomycosis and otitis externa through a single administration. Summary of the Invention

[0016] The present invention relates to a preparation, method and device for treating chronic otitis externa by single administration, and maintaining extremely high efficacy against a wide range of microorganisms including fungi and bacteria. The preparation contains a therapeutically effective amount of one or more antibacterial agents, one or more antifungal agents, one or more anti-inflammatory agents, and a thickened matrix discharged from the ear within 7 days.

[0017] Preferred embodiments contain marbofloxacin, dexamethasone, and terbinafine and / or clotrimazole. Together they constitute the active ingredients for eradicating a wide range of fungal infections and any concurrent bacterial infections and inflammations. The preparation can also be used in combination with an anesthetic or analgesic. For example, benzocaine approved for use in the ear can significantly relieve pain.

[0018] The preparation of the present invention can eliminate complications caused by patients' non-compliance with medication instructions through single administration. In addition, the best method of directly applying the active pharmaceutical ingredient (API) to the infected area can reduce the bacterial community drug resistance by significantly reducing the single dose, thus keeping the bacterial drug resistance at the lowest level.

[0019] In addition, by using a viscous carrier in the preparation, the preparation can maintain a viscous dosage form after entering the ear canal and the temperature rises to body temperature. Due to the high viscosity, the entire therapeutic preparation remains in contact with the infected ear canal for a long time, and can continuously release the active ingredient for at least two days, three days, four days or more days.

[0020] In each embodiment, the preparation contains the following components.

[0021] Table A

[0022]

[0023]

[0024] In another aspect of the present invention, a composition of the compound can be used to prepare a therapeutic agent for treating the ear infection.

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

[0026] In another aspect of the present invention, a kit is also provided, including the packaged composition and instructions for treating ear infections by single administration.

[0027] In another aspect of the present invention, a kit is also provided, including the composition with an inner package and instructions for treating ear infections by single administration.

[0028] The disposable ear preparation for the ear canal contains a viscous carrier. The carrier can be any pharmaceutically acceptable material with the required viscosity that enables the preparation to stay in the ear canal for a long time (preferably at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or longer). Selecting different carriers may change the physical properties of the preparation, but does not change the therapeutic effect. For example, those skilled in the art can select different carriers to make the preparation into a fluid, foam, cream, ointment or other pharmaceutically acceptable dosage forms.

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

[0030] Preferably, the thickening agent is insoluble in water or has low water solubility, has a long-lasting effect, and is non-ototoxic. Preferably, the carrier includes a composition of mineral oil and a thickening agent, such as PCCA Plasticized TM (PCCA US, TX, product number: 30-3211) proprietary low-density polyethylene mixture. A more preferred carrier is a mixture of 10-25%, 15-21% or about 17% or 18% of United States Pharmacopeia (USP) or National Formulary (NF) paraffin wax incorporated into 100% (w / w) USP or NF mineral oil.

[0031] The carrier is characterized in that when it is used in human or other mammalian patients in a preferred embodiment, it enters the ear canal of the subject and remains a viscous fluid after the temperature rises to 37°C body temperature, with a viscosity of about 10,000 cPs, 20,000 cPs, 30,000 cPs, 40,000 cPs, 50,000 cPs, 60,000 cPs or 70,000 cPs. The viscosity needs to reach 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 can be adjusted according to changes. An overly thick preparation cannot be discharged, so the viscosity should not exceed 80,000 cPs, preferably less than 70,000 cPs. The dynamic A (absolute) viscosity should be determined at 37°C according to ATSM D-2394.

[0032] Although the preparation is thick, it is still a flowable fluid that can be applied through injection devices such as syringes and needles. The viscous fluid remains in the ear canal and stays in contact with the infected part of the tissue. In this way, the active ingredients in the preparation can be continuously released for a long time, preferably at least 3 days, more preferably at least 4 days, ideally 5 days, or even 6 - 7 days, so as to continuously treat fungal and bacterial infections and concurrent inflammations. More importantly, due to the long residence time of the thick fluid, the continuously released active ingredients can also maintain the hygiene of the ear canal by preventing the proliferation of fungi and bacteria. In addition, the viscosity of the preparation enables it to gradually drain out (or be absorbed) from the ear canal after the symptoms subside.

[0033] In another embodiment of the present invention, the carrier can be a thinner liquid preparation for treating acute otitis media through a tympanostomy tube (AOMT). In the case of ear drainage, the liquid dosage form product can pass through the tympanic membrane via the tympanostomy tube. For example, such carriers are introduced in U.S. Patent No. 7,220,431 and U.S. Patent No. 8,030,297. However, some drugs suitable for the external ear canal may not be suitable for trans - membrane use, and the applicability of each drug must be tested.

[0034] In another aspect of the present invention, a method for treating ear infections is also provided. The method includes applying the preparation to the ear canal of a mammal, usually with only one or possibly two administrations, wherein the preparation is as described herein.

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

[0036] The present invention provides a novel preparation and method for treating ear fungal infections (especially otitis externa). The preparation and method of the present invention can treat and even eradicate chronic otitis externa by applying the preparation to the ear canal once.

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

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

[0039] As used herein, the "active ingredient" refers to a pharmaceutical substance that has a therapeutic effect on the disease to be treated.

[0040] As used herein, the "corticosteroid" refers to a class of steroids with anti-inflammatory effects, which may include but are not limited to: amcinonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clocortolone pivalate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisolone acetate, triamcinolone acetonide, and combinations thereof.

[0041] As used herein, the "thickening agent" refers to an optically acceptable additive that can increase the viscosity of the preparation. When the temperature rises to body temperature, the thickening agent can make the whole preparation in the form of a viscous fluid acceptable to the ear. Examples of thickening agents that can be used in the present invention include but are not limited to low-density polyethylene, poloxamer, wax, and combinations thereof. The viscosity of the thickening agent can be adjusted by adding mineral oil. The thickening agent in the present invention preferably makes the viscosity of the preparation reach 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), such as about 50,000 - 70,000 cPs (37 °C) or about 60,000 - 62,000 cPs (37 °C).

[0042] As used herein, the "injection unit" refers to a unit that can store a therapeutic agent and inject or deliver the therapeutic agent to the target area of a subject. Typical injection units include but are not limited to syringes connected to a needle or a tube, for example, the connection is achieved through a standard Luer lock or Luer fitting. The needle or tube can be customized as described herein.

[0043] As used herein, "flowable" means that the viscosity of the fluid is less than 100,000 cPs at room temperature.

[0044] Unless the context otherwise requires, the words "a" or "an" used in the claims or the specification, when used in conjunction with the term "comprising", mean one or more.

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

[0046] The term "or" used in the claims means "and / or", unless expressly stated otherwise to refer only to alternatives or mutually exclusive alternatives.

[0047] The terms "comprising", "having", and "including" (and their variants) are open-ended linking verbs that permit the addition of other components when used in claims.

[0048] The phrase "consisting of" is closed-ended and excludes other components.

[0049] The phrase "consisting essentially of" excludes other substantial components, but permits 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 a drug name is mentioned herein, it includes all active salts, isomers, and derivatives of the drug.

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

[0052] In one embodiment, the present invention provides a preparation 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 corticosteroid, 10% - 70% (by weight) of thickening agent, and 30% - 90% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0053] In one embodiment, the present invention provides a preparation for treating ear infections in mammals, comprising 1% - 3% (by weight) of marbofloxacin, 1% - 3% (by weight) of terbinafine and / or clotrimazole, 0.1% - 0.3% (by weight) of corticosteroid, 15% - 25% (by weight) of thickening agent, and 70% - 90% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0054] In one embodiment, the present invention provides a preparation for treating ear infections in mammals, comprising 1% - 2% (by weight) of marbofloxacin, 1% - 2% (by weight) of terbinafine and / or clotrimazole, 0.1% - 0.25% (by weight) of corticosteroid, 15% - 25% (by weight) of thickening agent, and 70% - 90% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0055] In one embodiment, the present invention provides a preparation for treating ear infections in mammals, comprising 1%-3% (by weight) of marbofloxacin, 1%-3% (by weight) of terbinafine and / or clotrimazole, 0.1%-0.3% (by weight) of corticosteroid, 15%-20% (by weight) of thickening agent, and 75%-80% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0056] In one embodiment, the present invention provides a preparation for treating ear infections in mammals, comprising 1%-2% (by weight) of marbofloxacin, 1%-2% (by weight) of terbinafine and / or clotrimazole, 0.1%-0.25% (by weight) of corticosteroid, 15%-20% (by weight) of thickening agent, and 75%-80% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0057] In one embodiment, the present invention provides a preparation 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 corticosteroid, 20%-30% (by weight) of thickening agent, and 65%-80% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0058] In one embodiment, the present invention provides a preparation 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 corticosteroid, 20%-30% (by weight) of thickening agent, and 65%-80% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0059] In one embodiment, the present invention provides a preparation 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 corticosteroid, 20%-30% (by weight) of thickening agent, and 65%-75% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices may also be used in the present invention to replace the thickening agent.

[0060] In one embodiment, the present invention provides a preparation 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 wax, and 65%-75% (by weight) of mineral oil. Without affecting the efficacy of the preparation, other therapeutically suitable matrices can also be used to replace the thickener in the present invention.

[0061] In one embodiment, the corticosteroid is selected from: amcinonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clocortolone pivalate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, 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 a combination 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% of 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% of 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% of paraffin wax added to about 65-80% w / w or about 71% or 72% of the mineral oil. In one embodiment, the thickener is paraffin wax, and the carrier comprises about 22-26% w / w or about 24% or 25% of paraffin wax added to about 70-75% w / w or about 71% or 72% of the 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% of the mineral oil.

[0063] In one embodiment, the method for treating ear infections comprises the following steps: applying the preparation of the present invention to the ear canal of a mammal in one application, wherein the preparation forms a gel after being applied to the ear canal of the mammal, and the gel continuously releases the active ingredient for at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or 9 days. In some embodiments, before applying the preparation to the ear canal, the method further comprises removing infectious and inflammatory debris from the ear canal.

[0064] In another embodiment, the present invention is a preparation 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 causes the active ingredients to remain in the ear for 2 - 7 days and then be excreted or absorbed.

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

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

[0067] In one embodiment, the mammals suitable for treatment with the preparation and method of the present invention include: humans, canines, felines, bovines, ovines, porcines, equines, and other mammals that are typically treated for ear infections 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), which includes a storage chamber for storing the medicament. The tube or needle can be bent to any suitable degree for use as long as it does not affect the dispensing of the treatment preparation.

[0069] The entire kit can be disposable, in which case the storage capacity is very small and only contains the dosage suitable for single administration, such as 1 ml - 1.5 ml, to prevent waste. Alternatively, the kit can be reusable until the treatment preparation is exhausted, in which case the storage capacity is very large and can support multiple administrations, such as 10 ml - 30 ml. If the patient is not human, the capacity may vary. For example, canines may require a larger dose.

[0070] The preparations of the present 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 staying in the ear canal for a long time and continuously releasing the active ingredient.

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

[0072] Table B

[0073] Active ingredient Dosage (% w / w) Marbofloxacin 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 preparation comprises the following components.

[0075] Table C

[0076] Active ingredient Dosage (% w / w) Marbofloxacin 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 preparation comprises the following components.

[0078] Table D

[0079] Active ingredient Dosage (% w / w) Marbofloxacin 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 ingredient Dosage (% w / w) Marbofloxacin 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 ingredient Dosage (% w / w) Marbofloxacin 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, marbofloxacin powder, clotrimazole or terbinafine powder, and dexamethasone powder can be weighed according to the corresponding weights and placed into a mixing container (such as a flask).

[0085] Then mineral oil can be added and the composition can be mixed evenly. Finally, a thickening agent and more mineral oil can be added to the container to reach the final volume and mixed evenly. The viscosity of the preparation can be adjusted by adding more mineral oil.

[0086] Suitable dosage levels of the active ingredient in the method are generally about 0.01 - about 50 mg / kg per day, such as about 0.25 - about 15 mg / kg per day, and again such as about 2.0 - about 14 mg / kg per day. Within this range, the dosage of each active ingredient in the 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 - 5.5 mg / kg, 2.5 - 5.0 mg / kg, 2.5 - 4.0 mg / kg, 2.5 - 3.5 mg / kg (including all intermediate dosages, 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, 3.5 mg / kg). The composition of this formulation only needs to be applied once during the entire treatment course to achieve clinical regression of the infection, with an elimination rate as high as 100%.

[0087] The preparation described in the present invention is expected to achieve a cure rate of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. Patients treated with the preparation are expected to reach a cure rate of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% within 2 days - 27 days, and most patients are clinically cured within 7 days, 14 days or 27 days, and the matrix is completely discharged from the ear. Of course, the percentage of the matrix components may vary depending on the selected wax. The softer the wax, the higher the required percentage.

[0088] As used herein, "clinical cure rate" refers to a significant reduction or complete elimination of symptoms. In the examples, within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days or 27 days after single-dose administration, the infection regresses, and the curative effect is greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and even reaches 100%.

[0089] In most cases, the expected sufficient dose of the preparation is 1 ml. It should be noted that this volume may vary depending on the type of mammal being treated, and a person of ordinary skill in the art can easily adjust the dosage according to the treatment needs. A person skilled in the art should fully understand that different amounts of the preparation can be used in the ear canal of mammals.

[0090] After clearing the infectious and / or inflammatory debris in the ear canal, an appropriate amount of the above preparation can be used in 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 reducing its therapeutic effect.

[0091] The instructions for using the preparation are as follows. First, an otolaryngologist carefully inserts a hollow tube into the patient's ear canal. By pressing the plunger or storage unit, the therapeutic preparation can be dispensed into the ear canal and remain therein. In the examples, the tube is flexible and includes a rounded tip, enabling the doctor to minimize scratching when applying the therapeutic preparation. The viscous fluid is dispensed to fill the space in the ear canal, thereby contacting the infected area therein while preventing secondary infections in the ear canal.

[0092] After administration, each patient can be examined to ensure that the preparation remains in the ear canal. The exit can be blocked with a cotton ball at the outer ear canal (ear pit), but no attempt has been made to "plug" the ear canal with a stopper. A follow-up examination can be conducted 7 to 14 days after the initial treatment. It is expected that the residue of the preparation will be observed on the 14th day, indicating that the preparation can indeed remain in the ear canal for 14 days. It is expected that the symptoms will usually be relieved within three days and the hearing will return to normal within 5 to 7 days after treatment.

[0093] The ideal anti-inflammatory agents that can be used in the preparation are dexamethasone or hydrocortisone.

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

[0095] Example 1

[0096] Treatment of otitis externa in dogs.

[0097] This study evaluated the effectiveness and actual safety of the ear preparation of the present invention in treating otitis externa in dogs within thirty (30) days. Twenty-four (24) dogs from two study sites participated in the study. All 24 dogs were treated with the preparation described in Table B. Safety assessments were conducted on all 24 dogs, and efficacy assessments were conducted on 21 dogs.

[0098] Dogs participating in this study presented for otitis externa. On Day 0, the tympanic membrane was examined for integrity by physical examination, including audiometry and otoscopy, foreign bodies and ear mites were ruled out, and the study ear was clinically scored based on erythema, exudate, swelling, and ulceration. A clinical score of at least 6 was required for inclusion in the study. Audiometry was performed, ear swabs were obtained for bacterial culture and fungal (yeast) identification, and the ear was cleaned with saline. 1.0 mL of IVP was administered to each infected ear of the dog. If both ears were infected, the right ear was designated as the study ear.

[0099] During the first follow-up at Day 7 (+2 days), the ear was evaluated and clinically scored by audiometry and otoscopy, and the owner was questioned about any adverse events observed.

[0100] During the second follow-up at Day 14 (±2 days), the ear was evaluated and clinically scored by audiometry and otoscopy, and the owner was questioned about any adverse events observed.

[0101] During the final follow-up at Day 30 (+3 days), the ear was evaluated and clinically scored by physical examination, including audiometry and otoscopy, and audiometry was performed. A final clinical score of 3 or less was required, and no individual clinical score could have decreased at the final follow-up for the case to be considered clinically cured. If clinical cure was not achieved, ear swabs were obtained for bacterial culture and fungal (yeast) identification.

[0102] Based on the clinical scores, 13 dogs were clinically cured by Day 30, with at least 9 cured by Day 7. An increase in the number of clinical cures was expected with the formulations shown in Tables E and F. No serious adverse events or adverse events directly attributable to the use of the formulations were found, demonstrating the safety of the formulations described.

[0103] Preferred embodiments of the invention are shown and described herein, but these are provided by way of example only. 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) a therapeutic agent, comprising: i) marbofloxacin; ii) terbinafine, clotrimazole or a combination thereof; and iii) a corticosteroid; and b) a carrier.

2. The preparation according to claim 1, wherein The preparation can be delivered to the ear canal of a mammal in a flowable fluid dosage form.

3. The preparation according to claim 2, wherein The carrier comprises a thickening agent, enabling the preparation to remain in the ear canal for at least 3 days after entering the ear canal and release the therapeutic agent.

4. The preparation according to claim 3, wherein The carrier comprises about 10 - 90% w / w of the thickening agent.

5. The preparation according to claim 4, wherein, The carrier comprises about 10 - 50% w / w of the thickening agent and about 50 - 90% w / w of mineral oil.

6. The preparation according to claim 5, wherein, The thickening agent is wax.

7. The preparation according to claim 6, wherein The carrier comprises about 60 - 80% w / w of mineral oil and about 10 - 30% of wax.

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

9. The preparation according to claim 8, wherein The carrier comprises about 65 - 75% w / w of mineral oil and about 20 - 30% w / w of paraffin wax.

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

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