Otic Formulations, Methods and Devices

Abstract

The present invention relates to formulations and methods for treating ear infections, particularly otomycosis and otitis externa, by administering a one-time treatment containing antibiotics, antifungals, and anti-inflammatory agents in a viscous otic carrier. In one embodiment, the formulation contains therapeutically effective amounts of active ingredients including marbofloxacin, terbinafine and / or clotrimazole, and dexamethasone.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 914,301, filed October 11, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THEINVENTION The present invention relates to antifungal / antibacterial / anti-inflammatory formulations for treating ear infections, particularly chronic otitis, and methods and devices for delivering the formulations. [Background technology]

[0003] Background information Ear infections, especially fungal ear infections, are common ear disorders that often occur in warm, humid climates. Fungal otitis externa is a fungal infection of the external ear canal and associated complications. It has been reported that as many as 30.4% of patients with otitis externa exhibit symptoms of fungal otitis or an inflammatory ear condition.

[0004] Common symptoms of ear fungal infections include ear pain, ear discharge, hearing loss, ear fullness, itching and tinnitus. Some factors that can cause or increase the incidence of fungal infections include humid climates, the presence of earwax that supports fungal growth, the shape of the ear canal, weakened immune function, diabetes, increased use of ENT antibiotics, long-term use of broad-spectrum antibiotics, use of systemic steroids, pregnancy, obstructive hearing aids, trauma and bacterial infections.

[0005] Common fungi causing otitis externa are Aspergillus niger and Candida albicans, and treatment can be tailored to these fungi. Other fungi can also cause otitis externa and can be treated with their respective medications. Whether identification of the pathogen is necessary to determine the preferred treatment is controversial. One school of thought holds that treatment should be based on the susceptibility of the identified species, while others hold that treatment should be based on the efficacy and properties of the drug, regardless of the causative microorganism. Experienced ENT practitioners can now routinely treat fungi without culture, primarily by identifying characteristic fungal elements with the naked eye on exam and applying topical acidifying agents or specific antifungal agents. Thus, practitioners can identify the microorganism or treat possible microorganisms empirically according to best practices, if necessary.

[0006] Currently, there are four major classes of drugs for the treatment of fungal infections: polyenes, triazoles, nucleoside analogs, and echinocandins. The mechanism of action of the polyene and triazole families involves an essential chemical component called ergosterol, which is found in fungal cell membranes. The drugs bind to ergosterol and create polar pores in the fungal membrane, which allow ions and other molecules to leak out of the cell and kill it. Nucleoside analogs interfere with nucleotide synthesis, which prevents proper energy production, metabolism, and signaling in cells. Echinocandins are a new class of antifungal agents that act by interfering with cell wall biosynthesis. However, echinocandins are known to be embryotoxic and require dose adjustments in patients with liver disease.

[0007] Most of the treatments reported to date require solutions, creams, powders, or ointments that are applied topically multiple times over a period of one week to one month. Long-term treatment regimes inconvenience the patient either by requiring multiple visits to the family doctor or otolaryngologist, or, in the case of self-administered medications, by causing secondary fungal or bacterial growths that may further extend the treatment period, as a result of the patient often forgetting to apply the medication as directed. Furthermore, many medications do not have full efficacy against infections caused by combination agents, which may also extend the treatment time. Furthermore, pure liquid medications, such as ear drops, are less desirable for the treatment of chronic otitis externa, especially because the liquid leaves the ear canal very quickly and gravity does not allow the liquid to reach all the infected areas in the ear canal, especially the upper half of the ear canal. In contrast, creams and ointments often remain in the ear and need to be removed by an otolaryngologist.

[0008] US Patent No. 7,220,431 (Non-Patent Document 1) discloses a method for administering a drug to the middle ear of a mammal by applying a formulation to the mammal's tympanic membrane. This method does not show how to treat an infection occurring in the ear canal, such as otitis externa. The formulation is characterized by having a viscosity of less than 100,000 cps, and the formulation forms a gel after application to the tympanic membrane. However, practical application of this patent may be problematic because additional ear drops cannot be introduced once the ear canal is blocked. Furthermore, the solidified gel may become hard and difficult for the patient to remove after the infection symptoms have resolved. If the solidified gel remains in the ear canal for too long after releasing all the active ingredients, fungal or bacterial infections may recur.

[0009] US Patent No. 8,030,297 (Non-Patent Document 2) discloses a method for treating an ear disorder selected from Meniere's disease, autoimmune ear disease, otitis media, acoustic trauma-induced sensorineural hearing loss, drug-induced sensorineural hearing loss, sensorineural hearing loss, idiopathic sensorineural hearing loss, vertigo, and tinnitus. The method requires intratympanic administration of a pharmaceutical composition comprising a thermoreversible aqueous gel having 16% to 21% by weight of polyoxypropylene and polyoxyethylene, and 1 mg / ml to 70 mg / ml of a multiparticulate anti-inflammatory corticosteroid. The "intral tympanic" administration and the target disease make it clear that the patent does not treat otitis externa. Also, the patent does not show the use of antifungal agents to treat fungal infections.

[0010] There are also some veterinary products available for animals. POSATEX OTIC SUSPENSION™ by Intervet® / Schering-Plough Animal Health® contains orbifloxacin, mometasone furoate monohydrate, and posaconazole in a suspension. However, it has limited effectiveness (against Pseudomonas aeruginosa and the yeast Malassezia pachydermatis) and orbifloxacin is only approved for use in dogs. Furthermore, it must be used for 7 consecutive days.

[0011] TRI-OTIC™, manufactured by Med-Pharmex®, contains gentamicin sulfate, betamethasone valerate, and clotrimazole, although this formulation also needs to be applied twice daily into the ear canal for seven consecutive days and has limited efficacy (for bacteria susceptible to Malassezia pachydermatis, formerly Pityrosporum canis, and / or gentamicin).

[0012] A few combinations have been approved for human use, but all have very limited efficacy. CIPRODEX®, manufactured by Alcon®, is a suspension of 0.3% ciprofloxacin and 0.1% dexamethasone (0.3% ciprofloxacin, 0.1% dexamethasone). However, it has no efficacy against fungi and is indicated for use twice daily for seven days. CIPRO HC® is a similar formulation containing ciprofloxacin and hydrocortisone, with the same limitations. CORTISPORIN®, which is commonly available, contains neomycin and polymyxin B sulfate, and hydrocortisone otic solution, with the same limitations, requiring three to four applications per day for up to ten days.

[0013] Thus, there remains a need for medical formulations and methods for treating fungal ear infections, such as otomycosis and otitis externa, that require only a single administration and yet can eradicate the fungal and bacterial infections and areas of concurrent inflammation. There is a particular need for formulations that can retain active medication within the patient's ear canal such that only a single administration of the formulation is required to achieve a high cure rate for otomycosis and otitis externa. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] U.S. Patent No. 7,220,431 [Patent Document 2] U.S. Patent No. 8,030,297 Summary of the Invention

[0015] The present disclosure relates to formulations, methods and devices for treating chronic otitis externa that require only a single administration while retaining high efficacy against a wide range of microorganisms, including fungi and bacteria. The formulations include therapeutically effective amounts of one or more antibacterial agents, one or more antifungal agents, and one or more anti-inflammatory agents, and a viscous base that clears from the ear in less than seven days.

[0016] A preferred embodiment includes marbofloxacin, dexamethasone, and either or both of terbinafine and clotrimazole. Together, these constitute the active ingredients that eradicate a wide range of fungal infections, as well as any associated bacterial infections and inflammation. The formulation may also benefit from combination with an anesthetic or analgesic. For example, benzocaine, which is already approved for use in the ear, can provide significant pain relief.

[0017] The single dose formulation of the present invention can be used to eliminate complications due to patient non-compliance in not following dosing instructions. Furthermore, the optimized method of applying the active pharmaceutical ingredient ("API") directly to the infected area reduces resistance of the bacterial community due to the significantly reduced single dose, thereby minimizing bacterial resistance.

[0018] Additionally, the use of a viscous carrier in the formulation allows the formulation to remain in a viscous form when administered into the ear canal and heated by body heat. The high viscosity allows the entire therapeutic formulation to remain in contact with the infected ear canal for an extended period of time, allowing the active ingredient to be continuously released for at least 2, 3, 4 or more days.

[0019] In embodiments, the formulation includes:

[0020] [Table A]

[0021] In another aspect of the present invention, the use of the combinations of compounds described herein is to manufacture a medicament for treating ear infections as described herein.

[0022] Another aspect of the invention is a method of producing a therapeutic agent, the method comprising blending a combination of compounds described herein with a viscous carrier to produce one of the therapeutic compositions described herein.

[0023] Another aspect of the present invention is a kit comprising a composition as described herein packaged together with instructions for a single dose use to treat ear infections.

[0024] Another aspect of the present invention is a kit comprising a composition as described herein packaged therein together with instructions for a single dose use to treat ear infections.

[0025] The disposable ear formulation for ear canal includes a viscous carrier. The carrier can be any ontologically acceptable material that has a desired viscosity and achieves the goal of retaining the formulation in the ear canal for an extended period of time, preferably at least 2, 3, 4, 5, 6, 7, 8, 9 days or more. Selecting a different carrier may change the physical properties of the formulation, but not the therapeutic effect. For example, one skilled in the art can select the carrier to produce the formulation in a liquid, foam, cream, ointment, or other ontologically acceptable form.

[0026] The thickener may be completely natural, such as wax, or may be a synthetic or semi-synthetic polymer, including polysaccharides, proteins, alcohols, silicones or waxes, etc. Suitable thickeners may include beeswax, candelilla wax, carnauba wax, paraffin, ozokerite 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, and the like.

[0027] Preferred thickening agents are insoluble or poorly water-soluble in water for a useful period and are not ototoxic. Preferred carriers include a combination of mineral oil and thickening agent, such as a proprietary blend of low density polyethylene known as PCCA Plasticized™ (PCCA US, TX, Catalog No. 30-3211). Even more preferred is a mixture of 10-25%, 15-21%, or about 17% or 18% United States Pharmacopeia (USP) or National Formulary (NF) paraffin combined with USP or NF mineral oil to make 100% by weight.

[0028] In a preferred embodiment for a human or other mammalian patient, the carrier is characterized by remaining a liquid with a viscosity of about 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, or 70,000 cPs after application to the subject's ear canal and warming by body heat at 37° C. Viscosities of at least 10,000, 20,000, 30,000, or 40,000 cPs are desirable, and preferably at least 10,000, 15,000, 20,000, 30,000, 40,000, 45,000, 50,000, 55,000, or 60,000 cPs, although variations are possible. If the formulation is too viscous it will not come out so a formulation above 80,000 cPs is less desirable, preferably below 70,000 cPs. The dynamic A (absolute) viscosity should be checked at 37°C according to ATSM D-2394.

[0029] The formulation is viscous, but remains a flowable liquid that can be applied with an injection unit, e.g., syringe and needle. The viscous liquid remains in the ear canal and in contact with the infected portion of the tissue. This allows for the active ingredients in the formulation to be continuously released for an extended period of time, preferably at least 3 days, more preferably at least 4 days, and ideally 5 days, or 6-7 days, thus continuously treating fungal and bacterial infections, as well as inflammation associated with infections. More importantly, because of the long presence of the viscous liquid, the continuously released active ingredients also prevent fungal and bacterial growth and maintain hygienic conditions within the ear canal. Additionally, the viscous nature of the formulation allows the formulation to gradually exit (or be absorbed) from the ear canal after symptoms have resolved.

[0030] In another embodiment of the present invention, the carrier can be a less viscous liquid formulation and a formulation used to treat acute otitis media using tympanotomy tube (AOMT). This allows the liquid product to pass through the tympanic membrane through the tympanotomy tube in the case of otorrhea. Such carriers are described, for example, in U.S. Patent Nos. 7,220,431 and 8,030,297. However, some drugs suitable for use in the ear canal may not be suitable for use across the membrane, and their compatibility must be tested.

[0031] Another aspect of the invention provides a method for treating an ear infection, comprising the step of applying, usually only once or occasionally twice, a formulation into the ear canal of a mammal, the formulation being as described herein.

[0032] In yet another aspect of the invention, a treatment kit for treating ear infections is provided, the kit comprising an injection unit including a containment compartment in fluid communication with a delivery component, such as a small tube or syringe, and a therapeutic formulation contained within the containment compartment. The therapeutic formulation is as described herein. The device is preferably a disposable device that is discarded after use. In other embodiments, the containment compartment allows for multiple administrations, but the delivery component is disposable. [The present invention 1001] a) i) marbofloxacin, ii) terbinafine, clotrimazole, or a combination thereof, and iii) Corticosteroids A therapeutic agent comprising: b) Carrier and 13. An otic preparation comprising: [The present invention 1002] A formulation of the present invention that can be delivered to the ear canal of a mammal in the form of a flowable liquid. [The present invention 1003] The formulation of claim 1002, wherein the carrier comprises a thickening agent such that, when introduced into the ear canal, the formulation remains in the ear canal for at least 3 days and releases a therapeutic agent. [The present invention 1004] The formulation of the present invention, wherein said carrier comprises about 10 to 90% by weight of said thickening agent. [The present invention 1005] The formulation of the present invention 1004, wherein said carrier comprises about 10-50% by weight of said thickening agent and about 50-90% by weight of mineral oil. [The present invention 1006] The formulation of the present invention, wherein the thickening agent is a wax. [The present invention 1007] 1006. The formulation of claim 10, wherein said carrier comprises about 60-80% by weight of mineral oil and about 10-30% of wax. [The present invention 1008] The formulation of the present invention, wherein the wax is paraffin. [The present invention 1009] The formulation of the present invention, wherein the carrier comprises about 65-75% by weight of mineral oil and about 20-30% by weight of paraffin. [The present invention 1010] about 0.1% to 3% by weight of marbofloxacin, and About 0.1% to 5% by weight of terbinafine, clotrimazole, or a combination thereof 1001. A formulation of the present invention comprising: [The present invention 1011] A formulation of the present invention comprising about 0.01 to 2.5% by weight of a corticosteroid. [The present invention 1012] The formulation of the present invention, wherein the carrier comprises about 65-75% by weight of mineral oil and about 20-30% by weight of paraffin. [The present invention 1013] The formulation of the present invention, wherein the corticosteroid is selected from the group consisting of amcinonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clocortolone pivalate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinonide, fluocinolone acetonide, flurandrenolide, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisolone acetate, triamcinolone acetonide, and combinations thereof. [The present invention 1014] The formulation of the present invention, wherein the corticosteroid is dexamethasone, hydrocortisone, or a combination thereof. [The present invention 1015] A formulation of the present invention comprising about 0.1% to 3% by weight of marbofloxacin, about 0.1% to 5% by weight of terbinafine, about 0.01 to 2.5% by weight of a corticosteroid, about 65 to 75% by weight of mineral oil, and about 20 to 30% by weight of paraffin. [The present invention 1016] The formulation of the present invention, wherein the corticosteroid is dexamethasone, hydrocortisone, or a combination thereof. [The present invention 1017] 1001. The formulation of the present invention having a viscosity of about 10 to 80,000 cPs at 37°C, or about 60,000 to 65,000 cPs at 37°C. [The present invention 1018] a) a therapeutic agent for treating fungal and bacterial infections, i) about 1.5 to 2.0% by weight of marbofloxacin; ii) about 1.0-5.0% by weight of terbinafine, clotrimazole, or a combination thereof; and iii) about 0.1 to 0.3% by weight dexamethasone A therapeutic agent comprising: b) about 20-30% by weight of wax; c) about 65-75% by weight of mineral oil; 13. An otic preparation comprising: [The present invention 1019] A formulation of the present invention comprising about 1.0 to 5.0% by weight of terbinafine. [The present invention 1020] A formulation of the present invention, which after application to the ear canal of a mammal having an ear infection, remains in said ear canal and has a viscosity of about 10 to 80,000 cPs at 37°C, about 10,000 to 80,000 cPs at 37°C, about 20,000 to 80,000 cPs at 37°C, about 30,000 to 80,000 cPs at 37°C, or about 40,000 to 80,000 cPs at 37°C. [The present invention 1021] A formulation of the present invention 1020, which when introduced into the ear canal, remains in the ear canal and releases an active ingredient for 2 to 7 days, after which it is not found in the ear. [The present invention 1022] 1021. A formulation of the present invention comprising about 1.5-2.0% by weight marbofloxacin, about 1.5-3.5% by weight terbinafine, about 0.1-0.3% by weight dexamethasone, about 20-30% by weight wax, and about 65-75% by weight mineral oil. [The present invention 1023] A formulation of the present invention 1022 which is for single treatment and has a clinical cure rate of at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% within 2, 14, or 27 days. [The present invention 1024] comprising marbofloxacin, terbinafine and dexamethasone in an auris-acceptable carrier; The carrier has a molecular weight of about 10 to 80,000 cPs at 37° C., about 10,000 to 80,000 cPs at 37° C., about 20,000 to 80,000 cPs at 37° C., about 30,000 to 80,000 cPs at 37° C., or about 40,000 to 80,000 cPs at 37° C., The carrier retains the active ingredient in the ear for 2 to 7 days, after which it is expelled or absorbed; and The formulation is for single-treatment and has a clinical cure rate of at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% within 2, 14, or 27 days; Otic preparations. [The present invention 1025] 1. An otic preparation comprising 1.5-2.0% by weight marbofloxacin, 2.0-5.0% by weight terbinafine, 0.1-0.3% by weight dexamethasone, 20-30% by weight paraffin, and 65-75% by weight mineral oil. [The present invention 1026] 1. An otic preparation comprising 1.5-2.0% by weight marbofloxacin, 1.5-5.0% by weight clotrimazole, 0.1-0.3% by weight dexamethasone, 20-30% by weight paraffin, and 65-75% by weight mineral oil. [The present invention 1027] A method for treating an infection in the ear canal of a mammal, comprising applying a single dose of any one of the formulations of inventions 1001 to 1026 into the ear canal of a mammal having an ear infection. [The present invention 1028] The method of claim 1027, wherein said ear infection is clinically resolved within 2, 14 or 27 days. [The present invention 1029] The method of claim 1027, wherein the mammal is a human, a dog, or a cat. [The present invention 1030] an injection unit including a receiving compartment in fluid communication with a delivery component; Any one of the preparations of the present inventions 1001 to 1026 contained in the storage compartment. A treatment kit comprising: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The present disclosure provides novel formulations and methods for treating ear fungal infections, particularly otitis externa. The formulations and methods of the present invention allow for the treatment and even eradication of chronic otitis externa by administration of the formulation to the ear canal only once.

[0034] The present disclosure provides a novel formulation for treating fungal ear infections comprising an antifungal agent, an antibiotic, and an anti-inflammatory agent in a viscous base of 10-80,000 cPs at ear or body temperature.

[0035] As used herein, "ear infection" refers to a fungal and / or bacterial infection 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.

[0036] As used herein, "active ingredient" means the substance of a pharmaceutical agent that has a therapeutic effect against the condition being treated.

[0037] As used herein, "corticosteroids" refers to a class of steroids with anti-inflammatory effects, including, but not limited to, amcinonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clocortolone pivalate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinonide, fluocinolone acetonide, flurandrenolide, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisolone acetate, triamcinolone acetonide, and combinations thereof.

[0038] As used herein, "thickening agent" means an optically acceptable additive that increases the viscosity of the formulation. The thickening agent can make the entire formulation a liquid of acceptable viscosity in the ear when the temperature is raised to body temperature. 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. Mineral oil can be added to adjust the viscosity of the thickening agent. The thickening agent of the present invention preferably provides the formulation with a viscosity close to about 10-80,000 cPs at 37°C, about 10,000-80,000 cPs at 37°C, about 20,000-80,000 cPs at 37°C, or about 40,000-80,000 cPs at 37°C, for example, about 50,000-70,000 cPs at 37°C, or about 60,000-62,000 cPs at 37°C.

[0039] As used herein, an "infusion unit" refers to a unit that can store a therapeutic agent and inject or deliver the therapeutic agent to a target area of ​​a patient. Exemplary infusion units include, but are not limited to, a syringe that connects to a needle or tube, for example, by a standard luer lock or luer connector. The needle or tube can be customized as described herein.

[0040] As used herein, "flowable" means a liquid having a viscosity of less than 100,000 cPs at room temperature.

[0041] In the claims or the specification, the use of the words "a" or "an" when used in conjunction with the term "comprising" means one or more, unless the context dictates otherwise.

[0042] The term "about" means the stated value plus or minus the measurement error, or, if the measurement method is not given, plus or minus 10% of the stated value.

[0043] In the claims, use of the term "or" is used to mean "and / or" unless expressly stated to refer only to alternatives or where the alternatives are mutually exclusive.

[0044] The terms "comprise," "have," and "include" (and variations thereof) are open-ended linking verbs that, when used in the claims, may add other elements.

[0045] The phrase "consisting of" is exclusive and excludes all additional elements.

[0046] The phrase "consisting essentially of" excludes additional material elements, but can include non-material elements that do not materially alter the nature of the invention, such as instructions for use, special packaging, preservatives, antioxidants, etc. Active pharmaceutical ingredients are considered materials.

[0047] When a drug is referred to by name herein, all active salts, isomers, and derivatives thereof are intended to be included.

[0048] Unless otherwise indicated, all percentages are by weight.

[0049] In one embodiment, the disclosure provides a formulation for treating an ear infection in a mammal, the formulation comprising 0.01%-5% by weight marbofloxacin, 0.01%-5% by weight terbinafine and / or clotrimazole, 0.01%-2.5% by weight corticosteroid, 10%-70% by weight thickening agent, and 30%-90% by weight mineral oil. Other therapeutically suitable bases may also be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0050] In one embodiment, the disclosure provides a formulation for treating an ear infection in a mammal, the formulation comprising 1% to 3% by weight of marbofloxacin, 1% to 3% by weight of terbinafine and / or clotrimazole, 0.1% to 0.3% by weight of a corticosteroid, 15% to 25% by weight of a thickening agent, and 70% to 90% by weight of a mineral oil. Other therapeutically suitable bases may also be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0051] In one embodiment, the disclosure provides a formulation for treating ear infections in a mammal, the formulation comprising 1% to 2% by weight of marbofloxacin, 1% to 2% by weight of terbinafine and / or clotrimazole, 0.1% to 0.25% by weight of a corticosteroid, 15% to 25% by weight of a thickening agent, and 70% to 90% by weight of a mineral oil. Other therapeutically suitable bases may also be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0052] In one embodiment, the disclosure provides a formulation for treating an ear infection in a mammal, the formulation comprising 1% to 3% by weight of marbofloxacin, 1% to 3% by weight of terbinafine and / or clotrimazole, 0.1% to 0.3% by weight of a corticosteroid, 15% to 20% by weight of a thickening agent, and 75% to 80% by weight of a mineral oil. Other therapeutically suitable bases may also be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0053] In one embodiment, the disclosure provides a formulation for treating an ear infection in a mammal, the formulation comprising 1% to 2% by weight of marbofloxacin, 1% to 2% by weight of terbinafine and / or clotrimazole, 0.1% to 0.25% by weight of a corticosteroid, 15% to 20% by weight of a thickening agent, and 75% to 80% by weight of a mineral oil. Other therapeutically suitable bases may also be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0054] In one embodiment, the disclosure provides a formulation for treating an ear infection in a mammal, the formulation comprising 1% to 3% by weight of marbofloxacin, 1% to 5% by weight of terbinafine, 0.1% to 0.3% by weight of a corticosteroid, 20% to 30% by weight of a thickening agent, and 65% to 80% by weight of a mineral oil. Other therapeutically suitable bases may be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0055] In one embodiment, the disclosure provides a formulation for treating an ear infection in a mammal, the formulation comprising 1% to 3% by weight of marbofloxacin, 2% to 4% by weight of terbinafine, 0.1% to 0.3% by weight of a corticosteroid, 20% to 30% by weight of a thickening agent, and 65% to 80% by weight of a mineral oil. Other therapeutically suitable bases may be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0056] In one embodiment, the disclosure provides a formulation for treating an ear infection in a mammal, the formulation comprising 1% to 3% by weight of marbofloxacin, 2% to 4% by weight of terbinafine, 0.1% to 0.3% by weight of a corticosteroid, 20% to 30% by weight of a thickening agent, and 65% to 75% by weight of a mineral oil. Other therapeutically suitable bases may be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0057] In one embodiment, the present disclosure provides a formulation for treating ear infections in a mammal, the formulation comprising 1% to 3% by weight of marbofloxacin, 2% to 4% by weight of terbinafine, 0.1% to 0.3% by weight of dexamethasone, 20% to 30% by weight of paraffin, and 65% to 75% by weight of mineral oil. Other therapeutically suitable bases may also be utilized in the present invention in place of the thickening agent without affecting the efficacy of the formulation.

[0058] 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, fluocinonide, fluocinolone acetonide, 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 combinations thereof.

[0059] In one embodiment, the carrier comprises a mineral oil and a thickening agent. In one embodiment, the thickening agent is paraffin and the carrier comprises about 11-21% by weight or about 17% or 18% by weight paraffin in mineral oil. In one embodiment, the thickening agent is paraffin and the carrier comprises about 20-30% by weight or about 24% or 25% by weight paraffin in mineral oil. In one embodiment, the thickening agent is paraffin and the carrier comprises about 20-30% by weight or about 24% or 25% by weight paraffin in about 65-80% by weight or about 71% or 72% by weight mineral oil. In one embodiment, the thickening agent is paraffin and the carrier comprises about 22-26% by weight or about 24% or 25% by weight paraffin in about 70-75% by weight or about 71% or 72% by weight mineral oil. In one embodiment, the thickening agent is paraffin and the carrier comprises about 65-80% by weight or about 70%-75% by weight paraffin in mineral oil.

[0060] In one embodiment, the method for treating an ear infection comprises the following: applying a formulation of the present disclosure once into the ear canal of the mammal, the formulation forming a gel after application to the ear canal of the mammal, the gel continuously releasing the active ingredient for at least 2, 3, 4, 5, 6, 7, 8, or 9 days. In some embodiments, the method further comprises debriding the ear canal of infectious and inflammatory debris prior to applying the formulation to the ear canal.

[0061] In another embodiment, the invention is a formulation for treating an ear infection, the formulation comprising one or more antifungal agents, one or more antibiotics, one or more anti-inflammatory agents, and a carrier having a viscosity of about 10-80,000 cPs at 37° C., about 10,000-80,000 cPs at 37° C., about 20,000-80,000 cPs at 37° C., or about 40,000-80,000 cPs at 37° C., wherein the carrier retains the active ingredients in the ear for 2-7 days and is then exported or absorbed.

[0062] In one embodiment, the otic formulation comprises marbofloxacin, terbinafine, and dexamethasone in an auris-acceptable carrier, preferably 0.1-10% marbofloxacin, 0.1-10% terbinafine, and 0.01-5% dexamethasone in a suitable carrier as described herein, most preferably 1.5-2.0% marbofloxacin, 1.5-5.0% terbinafine, and 0.1-0.25% dexamethasone.

[0063] In one embodiment, the otic formulation comprises marbofloxacin, clotrimazole, and dexamethasone in an auris-acceptable carrier, preferably 0.1-10% marbofloxacin, 0.1-10% clotrimazole, and 0.01-5% dexamethasone in a suitable carrier as described herein, most preferably 1.5-2.0% marbofloxacin, 1.0-2.0% clotrimazole, and 0.1-0.25% dexamethasone.

[0064] In one embodiment, suitable mammals that can be treated with the formulations and methods of the present invention include humans, dogs, cats, cows, sheep, pigs, horses, and other mammals that veterinarians regularly treat for ear infections.

[0065] The present disclosure further provides a treatment kit for treating ear infections. In one embodiment, the treatment kit includes an injection unit of a syringe, needle or hollow tube with a storage compartment for containing the formulation described herein. The tube or needle can be bent to any degree suitable for use as long as it does not affect the administration of the therapeutic formulation.

[0066] The entire kit can be disposable, in which case the capacity is small to hold a suitable amount for a single dose, e.g., 1-1.5 ml, to prevent waste. Alternatively, the kit can be used repeatedly until the therapeutic formulation is depleted, in which case the capacity is large to hold multiple doses, e.g., 10-30 ml. If the patient is non-human, e.g., a dog, the volume may vary and more doses may be required.

[0067] Preparation of the formulations of the present invention can be carried out in a variety of formulation methods, so long as the final product has the desired properties, such as, for example, remaining fluid at both room and body temperatures while remaining in the ear canal for an extended period of time and continuously releasing the active ingredient.

[0068] The following ingredients are included in the formulation of one embodiment of the present invention.

[0069] [Table B]

[0070] The following ingredients are included in the formulation of one embodiment of the present invention.

[0071] [Table C]

[0072] The following ingredients are included in the formulation of one embodiment of the present invention.

[0073] [Table D]

[0074] [Table E]

[0075] [Table F]

[0076] In manufacturing, marbofloxacin powder, clotrimazole or terbinafine powder, and dexamethasone powder can be weighed according to their respective weights and placed into a mixing vessel, e.g., a flask.

[0077] Next, the mineral oil can be added and the formulation mixed well. Finally, the thickener and additional mineral oil can be added to the container to form the final formulation and mixed well. Additional mineral oil can be added to adjust the viscosity of the formulation.

[0078] In the methods described herein, a suitable dosage of the active ingredient is usually about 0.01 to about 50 mg / kg, for example, about 0.25 to about 15 mg / kg per day, for example, about 2.0 to about 14 mg / kg per day. Within this range, the dosage of each active ingredient may 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 dosages in between, e.g., 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5 mg / kg, etc.) per dosage form. In this form, the composition need only be administered in a single application once over the entire course of treatment to clinically resolve the infection with up to 100% eradication.

[0079] The formulations of the present disclosure are expected to achieve a healing rate of at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. Patients administered the formulations will demonstrate at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% healing in 2-27 days, with most being clinically healed and having complete clearance of the base from the ear in less than 7, 14, or 27 days. Of course, the percentage of base components will vary depending on the wax selected, with softer waxes requiring higher percentages.

[0080] As used herein, "clinical cure rate" refers to a substantial reduction in symptoms or complete eradication of symptoms.In embodiments, the infection is cleared within a duration of less than 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 administration with an efficacy of more than 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% or up to 100%.

[0081] In most cases, a dosage of 1 ml of the formulation is expected to be sufficient. It should be noted that the volume may vary depending on the type of mammal being treated, and those skilled in the art can easily adjust the amount to suit treatment needs. As can be easily understood by those skilled in the art, various amounts of the formulation can be administered to the ear canal of a mammal.

[0082] After debridement of infectious and / or inflammatory debris from the ear canal, a suitable amount of the formulation can be administered from above into the infected ear canal so that all available space in the outer ear is filled. The formulation can be stored in a syringe or container prior to use and can be stored at room temperature without compromising therapeutic efficacy.

[0083] Application of the formulation is exemplified below: First, the ENT specialist carefully places a hollow tube into the patient's ear canal. By pressing the plunger or reservoir unit, the therapeutic formulation is dispensed into the ear canal and allowed to remain therein. In an embodiment, the tube is flexible and equipped with a rounded tip, allowing the practitioner to minimize possible scratching when applying the therapeutic formulation. The dispensed viscous liquid fills the space within the ear canal, thereby contacting the infected area therein while preventing secondary infection within the ear canal.

[0084] After administration of the formulation, each patient can be examined to ensure that the formulation has remained in the ear canal. A cotton ball can be placed in the ear canal (concha) to catch discharge, but no attempt is made to "block" the ear canal. Follow-up examinations can be performed 7-14 days after the initial treatment. Residues of the formulation are expected to be observed on the 14th day, indicating that the formulation has remained in the ear canal for 14 days. Symptoms are usually expected to abate within 3 days, while hearing is expected to return to normal within 5-7 days after treatment.

[0085] The ideal anti-inflammatory agent for use in the formulation is dexamethasone or hydrocortisone. EXAMPLES

[0086] The following examples are provided to further illustrate the advantages and features of the present invention, but they are not intended to limit the scope of the invention. While the examples are typical of those that might be used, other procedures, methods, or techniques known to those skilled in the art can be used instead.

[0087] Example I Treatment of otitis externa in dogs This study evaluated the efficacy and regional safety of an otic formulation of the present invention for the treatment of otitis externa in dogs over a 30 day period. Twenty-four dogs were enrolled in the study from two study sites, and all 24 were treated with the formulation described in Table B. All 24 dogs were included in the safety evaluation and 21 dogs were included in the efficacy evaluation.

[0088] Dogs enrolled in the study and showing signs of otitis externa were presented to the clinic. On day 0, a physical examination was performed, including hearing and otoscopy, to ensure an intact tympanic membrane, absence of foreign bodies and ear mites, and the study ear was clinically scored based on erythema, exudate, swelling and ulceration. To be included in the study, the minimum clinical score had to be 6 or greater. Hearing tests were performed, ear swabs were taken for bacterial culture and fungal (yeast) identification, and ears were irrigated with saline. Dogs were medicated by administering 1.0 mL of IVP per infected ear. If both ears were infected, the right ear was designated the study ear.

[0089] At the first follow-up visit on day 7 (+2), audiological and otoscopic examinations were performed to evaluate the ears and assign a clinical score, and owners were questioned about any adverse events observed.

[0090] At the second follow-up visit on day 14 (± 2 days), audiological and otoscopic examinations were performed to evaluate the ears and assign a clinical score, and owners were questioned about any adverse events observed.

[0091] At the final follow-up visit on day 30 (+3 days), a physical examination, including audiology and otoscopy, was performed to evaluate the ears and assign a clinical score. Hearing tests were also performed. For a case to be considered clinically cured, a final clinical score of 3 or less was required in addition to no deterioration of any individual clinical scores at the final visit. If clinical cure was not achieved, ear swabs were taken for bacterial culture and fungal (yeast) identification.

[0092] Based on clinical scores, 13 dogs were clinically cured by day 30, with at least 9 showing clinical cure by day 7. The number of clinical cures is expected to increase with the use of the formulations shown in Tables E and F. There were no serious or adverse events directly attributable to administration of the formulation, demonstrating the safety of this formulation.

[0093] While preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only. Various alternatives to the embodiments can optionally be used without departing from the spirit of the invention. The scope of the present invention is defined by the following claims.

Claims

1. a) i) 1% to 3% by weight of marbofloxacin; ii) 1% to 3% by weight of terbinafine or a salt thereof, and iii) 0.1% to 0.3% by weight of dexamethasone A therapeutic agent comprising: b) 70% to 90% by weight of a mineral oil; c) 15% to 25% by weight of paraffin; 13. An otic preparation comprising:

2. 10. The otic formulation of claim 1, having a viscosity of about 10-80,000 cPs at 37°C, or about 60,000-65,000 cPs at 37°C.

3. 3. The otic formulation of claim 2, which after application to the ear canal of a mammal having an ear infection, remains in the ear canal and has a viscosity of about 10-80,000 cPs at 37°C, about 10,000-80,000 cPs at 37°C, about 20,000-80,000 cPs at 37°C, about 30,000-80,000 cPs at 37°C, or about 40,000-80,000 cPs at 37°C.

4. 4. The ear preparation of claim 3, which upon introduction into the ear canal remains in the ear canal and releases the active ingredient for 2 to 7 days, after which it is not found in the ear.

5. 5. The otic preparation of claim 4, comprising about 1.5-1.9% by weight marbofloxacin, about 1.6-2.0% by weight terbinafine, about 0.1-0.25% by weight dexamethasone, about 17-18% by weight wax, and about 78-80% by weight mineral oil.

6. 6. The otic formulation of claim 5, which is for a single treatment and has a clinical cure rate of at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% within 2, 14, or 27 days.

7. comprising marbofloxacin, terbinafine and dexamethasone in an auris-acceptable carrier; the carrier has about 10-80,000 cPs at 37° C., about 10,000-80,000 cPs at 37° C., about 20,000-80,000 cPs at 37° C., about 30,000-80,000 cPs at 37° C., or about 40,000-80,000 cPs at 37° C.; The carrier retains the active ingredient in the ear for 2-7 days, after which it is expelled or absorbed; and the otic formulation is for single treatment and has a clinical cure rate of at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% within 2, 14, or 27 days; The otic preparation of claim 1.

8. 1. An otic formulation comprising 1.5-2.0% by weight marbofloxacin, 2.0-5.0% by weight terbinafine, 0.1-0.3% by weight dexamethasone, 20-30% by weight paraffin, and 65-75% by weight mineral oil.

9. 9. The otic formulation of any one of claims 1 to 8 for use in a method for treating an infection in the ear canal of a mammal, said method comprising applying a single dose of the otic formulation into the ear canal of a mammal having an ear infection.

10. 10. The otic formulation of claim 9, wherein the ear infection is clinically resolved within 2, 14 or 27 days.

11. The ear formulation of claim 9, wherein the mammal is a human, a dog or a cat.

12. an injection unit including a receiving compartment in fluid communication with a delivery component; The ear preparation according to any one of claims 1 to 11 contained in the containing compartment; A treatment kit comprising:

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