JP2018070620A - Otitis treating composition and method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compositions and methods for treating ear infection including otitis externa and otitis media.SOLUTION: Provided is a pharmaceutical composition comprising 0.1 to 10% (w/w) of povidone iodine, 30 to 99% (w/w) of dimethyl sulfoxide (DMSO), one or more excipients acceptable for ear, and optionally, a gelling agent. Provided is a method for preventing or treating ear infection using the pharmaceutical composition. A pharmaceutical composition for ear which comprises PEG and/or vaseline and does not comprise steroid is also provided.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part application of U.S. Patent Application Serial No. 15 / 213,289 pending filed July 18, 2016, U.S. Patent Application in the pending, 2012 5 Filed as a national transition application under US Patent Law Section 371 from international application PCT / US2012 / 036942 filed on August 8, issued as US Patent No. 9,408,867 on August 9, 2016 US patent application Ser. No. 14 / 116,360. All of the aforementioned U.S. patent applications are U.S. Provisional Application No. 61 / 518,709, filed May 11, 2011, U.S. Provisional Application No. 61 / 518,689, filed May 11, 2011, 2011. US Provisional Application No. 61 / 518,690, filed May 11, 2011, US Provisional Application No. 61 / 457,699, filed May 16, 2011, US Provisional Application, filed September 19, 2011 No. 61 / 627,148 and US Provisional Application No. 61 / 600,268, filed Feb. 17, 2012, are claimed. All of the aforementioned applications are incorporated herein by reference in their entirety.

  [0001] Millions of patients have infection or inflammation of the ear canal, whether in the outer ear (otitis externa) or middle ear (otitis media). For the main purpose of the present invention, these diseases are collectively referred to as “otitis”. Otitis may be acute or chronic, or may indicate leaching.

[0002] Current treatments for bacterial, fungal / yeast, and viral infections of the ear canal treat only some pathogens of infections and may not be effective. Many current treatments use undesirable ingredients such as steroids and other potentially harmful ingredients.

[0003] For example, US Patent Applications, Publication Nos. 2009/0263345; 2012/0003174; and 2013/0089510 disclose the treatment of otitis with PVP-I and steroids. According to these published patents, otitis externa (outer ear infection) is inflammation of the outer ear and ear canal. It is a common cause of human ear pain, as well as a problem common to dogs, cats, and other mammals. It also occurs in many other species. This disorder includes inflammation of the ear canal skin. This inflammation can be caused by active fungal, viral or bacterial organisms. The ear canal skin is often swollen, painful, and tender. Otitis media (middle ear infection) occurs in the area between the eardrum, including the Eustachian tube, and the inner ear. Otitis media is extremely common in children, with infants on average 2-3 times a year, almost always with a viral upper respiratory infection (URI) and most commonly with a common cold. Accompany. Rhinoviruses and adenoviruses that cause many common cold symptoms can cause swelling and congestion in the inner ear and can permanently damage the middle ear structure. Otitis media is also caused by many types of bacteria and other viruses. In addition, ear infections (especially in children) are one of many diseases that are difficult to treat with conventional antibiotics due to antibiotic-resistant bacteria and antibiotic-resistant microorganisms. Many cases of otitis media are caused, for example, by one of several major pathogens, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Staphylococcus epidermidis, or Pseudomonas aeruginosa.

  [0004] Accordingly, conventional antibiotics or steroids are not used in view of known shortcomings such as antibiotic resistance, potential adverse side effects of steroids that may arise from the use of compositions containing conventional antibiotics or steroids There is an urgent need to develop new approaches to prevent and address these diseases.

[0005] A recent discovery by Capriotti et al. Discloses a composition comprising an iodophor such as povidone iodine (PVP-I) as an active ingredient and dimethyl sulfoxide (DMSO) as a penetration enhancer for the active ingredient. These compositions have been shown to be useful in the treatment of skin and nail fungal infections. See US Publication No. US2014 / 02055559 (Capriotti '559). The patent is hereby incorporated in its entirety by reference. PVP
-I is well known to be a disinfectant with a broad spectrum of activity against viral species, fungal species, bacterial species, and acne mites, and is not known for bacterial resistance, fungal resistance or viral resistance Absent. PVP-I has also been shown to inhibit biofilm formation and remove biofilms that have already been formed.

[0006] Various organic solvents such as dimethyl sulfoxide (DMSO) are known to enhance percutaneous absorption of drugs. Nevertheless, DMSO promotes the penetration of small or low molecular weight (LMW) compounds or pharmaceuticals, but higher molecular weight (HMW) compounds, such as polymers, that are greater than about 10,000 daltons. It has been accepted for a long time in the pharmaceutical field that it does not promote penetration.

  [0007] US Patent Publication Nos. 2009/0263345; 2012/0003174; and 2013/0089510 do not describe compositions that do not include steroids, but PVP-I as described and claimed herein. And the benefits of the composition comprising DMSO for the treatment of otitis are not recognized or considered.

  [0008] The compositions of the present invention may be useful in methods for treating viral infections, fungal or yeast infections, bacterial infections, or amoeba infections or amoeba invasions in the ear canal.

  [0009] The topical compositions of the present invention comprise from about 0.1% to about 10% povidone iodine (PVP-I) and from about 30% to about 99% dimethyl sulfoxide (DMSO). The topical gel composition of the present invention comprises about 0.1% to about 10% povidone iodine (PVP-I), about 30% to about 99% dimethyl sulfoxide (DMSO), and about 1% to about 10% gelling agent. Including. The topical gel composition of the present invention is compared to a liquid composition (substantially free of gelling agent, including about 0.1% to about 10% povidone iodine and about 30% to about 99% DMSO). Can show unexpectedly high efficacy in the treatment of otitis. The topical gel compositions of the present invention have unexpectedly high stability at room temperature in the presence of aqueous or anhydrous components.

  [0010] A preferred composition comprises about 0.25% to about 0.35% PVP-I, and another preferred composition comprises 0.25% to about 0.5% PVP-I. The product contains 1% to about 5% PVP-I. More preferred compositions may comprise from about 1% PVP-I to about 2% PVP-I. PVP-I using K30 grade povidone is preferred for use in the present composition.

  [0011] Preferred compositions comprise about 30% to about 70% DMSO. More preferred compositions may include about 40% to about 49% DMSO, and more preferably about 44% DMSO.

  [0012] Preferred compositions comprise from about 0.5% to about 5% gelling agent. More preferred compositions may contain about 1-2% gelling agent. A particularly useful composition that has been prepared for testing comprises 2% PVP-I; 44% DMSO; 2% hydroxyethyl cellulose; and 52% aqueous solvent. A preferred aqueous solvent is water or isotonic buffer.

  [0013] The composition of the present invention may contain a gelling agent as known to those skilled in the art. The gelling agent may be selected from gum, agar, carrageenan, petrolatum, cellulose polymer and the like. One preferred cellulose polymer as the gelling agent is hydroxyethyl cellulose. Another cellulose polymer gelling agent is hydroxymethylcellulose.

  [0014] The composition of the present invention preferably comprises povidone iodine having an average molecular weight greater than 10,000, ie, PVP-I. More preferably, the composition of the present invention comprises PVP-I having an average molecular weight of about 20,000 to about 1,000,000. One preferred embodiment includes PVP-I having an average molecular weight of about 30,000 to about 60,000, or higher. Each of the PVP-I components is referred to herein as “high molecular weight PVP-I”, or “HMW PVP-I”.

  [0015] In another embodiment of the composition of the present invention, the composition comprises from about 0.1% to about 10% povidone iodine (PVP-I); from about 30% to about 99% dimethyl sulfoxide (DMSO); and from about 1% to about 10%. A stable topical otic gel formulation comprising a% gelling agent, wherein each component in the composition is acceptable to the ear and the otic gel composition is substantially free of gelling agent and is about 0 Compared to liquid compositions containing from 1% to about 10% povidone iodine and from about 30% to about 99% DMSO, it is highly effective in treating infections of the ear canal, particularly the outer or middle ear.

  [0016] Preferred otic gel compositions comprise from about 0.25% to about 2.55% PVP-I. More preferred otic gel compositions comprise about 1% to about 3% PVP-I, and most preferred otic gel compositions comprise about 1% PVP-I.

  [0017] The composition of the present invention preferably comprises povidone iodine having an average molecular weight of greater than 10,000, ie, PVP-I. More preferably, the composition of the present invention comprises PVP-I having an average molecular weight of about 20,000 to about 1,000,000. One preferred embodiment comprises high molecular weight (HMW) PVP-I.

  [0018] Preferred otic gel compositions comprise about 30% to about 70% DMSO. More preferred otic gel compositions may comprise about 40% to about 49% DMSO, and even more preferably about 44% DMSO.

  [0019] Preferred otic gel compositions comprise about 2% to about 5% gelling agent. A more preferred otic gel composition may comprise about 4% gelling agent. A particularly useful gel composition that has been prepared for use in treating eye or eyelid infections comprises 1% PVP-I; 44% DMSO; 2% hydroxyethylcellulose; and 53% aqueous solvent. A preferred aqueous solvent is water.

  [0020] The ear gel composition of the present invention may contain a gelling agent as known to those skilled in the art. The gelling agent may be selected from gum, agar, carrageenan, petrolatum, cellulose polymer and the like. One preferred cellulose polymer useful as a gelling agent is hydroxyethyl cellulose (HEC). Another cellulose polymer gelling agent is hydroxymethylcellulose. In one aspect, a composition for treating otitis that does not contain a steroid is disclosed herein. The composition includes an iodophor, such as povidone iodine (commonly abbreviated as “PVP-I”), and dimethyl sulfoxide (commonly abbreviated as “DMSO”), wherein the composition is an outer ear infection or a middle ear infection. Can penetrate the ear canal covered with epithelium, or can penetrate the tympanic membrane.

[0021] In one aspect, the compositions disclosed herein for the treatment of otitis are substantially anhydrous. In one aspect, the composition is anhydrous.
[0022] In one aspect, a composition disclosed herein for the treatment of otitis comprises about 0.01% to about 10% (w / w) PVP-I. In one aspect, the PVP-I is about 0.05% to about 10%, about 0.1% to about 5%, about 0.2% to about 2.5%, and about 0.5% to about 1%. It exists in the range selected from the group consisting of (w / w). In one aspect, PVP-I is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1.0%, about 1.25%. , About 1.5%, about 2.0%, about 2.5% and about 5% (w / w). In one aspect, PVP-I is present at about 1% (w / w).

[0023] In one aspect, the compositions disclosed herein for the treatment of otitis further comprise at least one naturopathic substance. In one aspect, the compositions disclosed herein for the treatment of otitis include a pomegranate (Punica Granatum) extract, a tea (Camellia Sinensis) leaf extract, ascorbic acid, a calendula officinalis extract, a Spanish licorice It further comprises at least one substance selected from the group consisting of (Glycrrhiza Glabra) extract, allantoin and cucumber (Cucumis Sativus) fruit extract.

[0024] In one aspect, the compositions disclosed herein for the treatment of otitis include tolnaftate, terbinafine, undecylenic acid, clioquinol, miconazole, miconazole nitrate, clorrinazole, thioconazole, nystatin, It further comprises at least one antifungal agent selected from the group consisting of terconazoic, butconazole nitrate, ciclopirox olamine, econazole nitrate, triacetin, flucytosine, haloprozin and ketoconazole. In one aspect, the antifungal agent is present in an amount from about 1% to about 25% (w / w).

  [0025] In one aspect, an iodophor such as PVP-I and dimethyl sulfoxide (DMSO) can be penetrated into or through the ear canal covered with epithelium to treat an outer ear infection or middle ear infection, Further disclosed herein are compositions for treating otitis that are free of steroids, ie, “steroid-free”.

In one aspect, the composition is formulated for topical administration, such as a liquid ear drop formulation or a gel. In a preferred embodiment, the composition is non-foaming, i.e. does not include a blowing agent.
[0026] In one aspect, the composition of the present invention comprises an amount of gelling agent to form a final composition that is a gel. In one aspect, the composition is formulated as a topical gel.

[0027] Each embodiment of the compositions described herein is free of steroids, ie a steroid-free composition.
In one aspect, the infection to be treated is a fungal infection. In one aspect, the infection is a dermatophyte infection.

  [0028] In one aspect, the infection to be treated is a bacterial ear infection. In one aspect, the infection is selected from streptococcal infection, staphylococcal infection, Haemophilus influenzae infection, and Pseudomonas aeruginosa infection.

  [0029] In one aspect, the infection to be treated is a viral infection. In one aspect, the infection is an adenovirus infection.

  [0030] In one aspect, the infection to be treated is an amoeba infection.

[0031] In one aspect, the ear comprising the steps of administering a composition disclosed herein to an infected ear canal and contacting as necessary until the otitis is treated A method for treating flame is disclosed herein. In one embodiment, the contacting step is performed at least once a day. In one embodiment, the contacting step is performed at least twice a day. In one particularly surprising aspect, it has been found that even a single administration of a gel formulation of high viscosity (viscosity greater than 100,000 cps) can completely eradicate an infection in a child's middle ear.

  [0032] In one aspect, there is provided herein a method of treating otitis comprising the steps of administering a composition disclosed in claim 1 to an infected ear canal and repeating the administering step for at least one week. It is disclosed. In one aspect, the administering step is repeated for at least 2 weeks. In one aspect, the administering step is repeated for at least 3 weeks. In one aspect, the administering step is repeated for at least 4 weeks. In one aspect, the administering step is repeated for at least 12 weeks.

[0033] The present composition comprises Trichophyton rubrum, T. mentagrophytes, Epidermophyton floccosum, T. violaceum, and plasteroid microspores. Selected from the group consisting of (Microsporum gypseum), Trichophyton tonssurans, T. soudanense, T. verrucosum, and Candida species
spp.), Neoscytalidium spp., Scopulariopsis spp. and Aspergillus spp. members of the outer ear canal caused by a member of the genus Aspergillus spp. May be useful in the treatment of

[0034] The present invention relates to a topical composition, preferably a topical gel composition comprising an iodophor, a penetration enhancer and, in the case of a gel composition, a gelling agent. The composition is particularly effective in the treatment of common otitis or particularly viral infections, acne mite infections, fungal / yeast infections, bacterial infections or amoeba infections that cause otitis externa or otitis media . Accordingly, the present invention further relates to a viral infection of the ear canal, acarid mite infection, a fungal / yeast infection, a bacterial infection, or an amoeba infection using the topical composition disclosed herein, preferably a topical gel composition. Methods of treatment of the disease. The composition may further comprise any pharmaceutically acceptable excipient or solvent or cosolvent.

[0035] The composition of the present invention is an active pharmaceutical ingredient (API) that is recognized as appropriate and acceptable for use in pharmaceutical formulations by the United States Food and Drug Administration (FDA). ) Is desirable. Preferred compositions of the present invention further comprise inert ingredients or excipients that have been found suitable and acceptable for use in pharmaceutical formulations for topical administration. An FDA-approved API or an FDA-approved inactive ingredient or excipient is referred to herein as “pharmaceutically acceptable”. Accordingly, a topical composition, formulation, or formulation of the invention comprising a pharmaceutically acceptable API, an inert ingredient or excipient is referred to herein as a “pharmaceutically acceptable” topical composition. expressed.

  [0036] Similarly, an otic composition of the present invention comprising an FDA-approved active or inactive ingredient that is acceptable for use in an otic formulation is referred to herein as "pharmaceutically acceptable otic". Or “pharmaceutically acceptable otic composition” or “comprising an pharmaceutically acceptable” or “early acceptable” API, excipient, or solvent for otic applications. It is referred to as an “ear acceptable” composition.

  [0037] Notably, the present invention is an iodophor having a molecular weight greater than 10,000 Daltons, dimethyl sulfoxide (DMSO), and a gelling agent, and any additional pharmaceutically acceptable or otic acceptable. Or a stable topical composition comprising a solvent or co-solvent.

  [0038] The compositions and methods are useful for treating one or any combination of at least two of the above diseases, conditions or pathogens.

  [0039] In one aspect, the composition comprises at least one therapeutic agent and at least one solvent and / or penetrant. In one aspect, iodophor is a therapeutic agent. In one aspect, the composition comprises at least one disinfecting compound. In one aspect, the antiseptic compound is a therapeutic agent. In one aspect, the composition comprises an iodophor disinfectant. As used herein, “iodophore” refers to a substance that includes iodine and at least one additional agent (eg, a solubilizer) that releases free iodine when in solution. Examples of iodophors include, but are not limited to, povidone iodine (PVP-I), iodine tincture, Lugol's solution and iodine salts (eg, potassium iodide, sodium iodide).

  [0040] In one aspect, the composition comprises at least one iodophor. The composition includes any iodophor that has not yet been developed or discovered. In one aspect, the iodophor is PVP-I. In another aspect, the composition comprises iodine. In one aspect, the composition comprises iodine and at least one iodophor.

  [0041] In one aspect, PVP-I functions as a therapeutic agent in the composition. In one aspect, the PVP-I therapeutic functions as a disinfectant. In another aspect, PVP-I functions as a preservative in the composition. In one aspect, the PVP-I preservative functions as a disinfectant. In another aspect, the PVP-I preservative functions as a stabilizer. In one aspect, PVP-I functions at least once in the composition. In another aspect, PVP-I functions at least twice in the composition.

  [0042] In another embodiment, the composition further comprises at least one non-iodophore or non-iodine therapeutic agent. In one aspect, the at least one non-iodophore or non-iodine therapeutic agent is a disinfectant. In another aspect, the at least one non-iodophore or non-iodine therapeutic agent is not a disinfectant.

  [0043] In one aspect, the at least one non-iodophore or non-iodine therapeutic agent is an antifungal agent. Suitable antifungal agents include, for example, allylamines and azoles. In one aspect, the antifungal agent includes tolnaftate, terbinafine, undecylenic acid, clioquinol, miconazole, miconazole nitrate, chlorinazole, thioconazole, nystatin, telconazoic, butconazole nitrate, cyclopyroxolamine, econazole nitrate, triacetin, flucytosine, haloprozin And ketoconazole, but are not limited thereto.

  [0044] In one aspect, the composition comprises one or more naturopathic substances. Naturopathic substances include, but are not limited to, pomegranate extract, tea leaf (green tea) extract, ascorbic acid (vitamin C), calendula extract, Spanish licorice (licorice) extract, allantoin and cucumber fruit extract. In one aspect, the composition comprises DMSO, PVP-I, pomegranate extract, tea leaf (green tea) extract, ascorbic acid (vitamin C), calendula extract, Spanish licorice (licorice) extract, allantoin and cucumber fruit extract.

[0045] In one aspect, the composition comprises at least one solvent and / or penetrant. In one aspect, a single component may function as both a solvent and a penetrant in the composition. In one aspect, the composition comprises DMSO. In one aspect, DMSO functions as a penetrant for the active ingredient. In one aspect, DMSO functions as a solvent. In yet another aspect, DMSO functions as both a solvent and a penetrant. In one aspect, DMSO is the only penetrant in the composition. In one aspect, DMSO is the only solvent in the composition. In one aspect, DMSO is the only penetrant and solvent in the composition.

  [0046] In one aspect, the composition comprises PVP-I and DMSO. In another aspect, the composition consists of PVP-I and DMSO. In yet another aspect, the composition consists essentially of PVP-I and DMSO.

  [0047] Based on the disclosure herein, one of ordinary skill in the art knows how to identify penetrants useful in the compositions and methods encompassed herein. In one aspect, the penetrant is a penetrant useful to allow the composition to penetrate the nail. By way of non-limiting example, methylsulfonylmethane may be used as a penetrant in the compositions encompassed herein.

  [0048] In one aspect, the composition comprises at least one co-solvent. In one aspect, the composition comprises DMSO as the primary solvent and further comprises at least one co-solvent. In one aspect, water is a cosolvent. In one aspect, the composition comprises DMSO as the primary solvent and water as the co-solvent. In one aspect, the composition consists of DMSO as the primary solvent and water as the co-solvent. In another aspect, the composition consists essentially of DMSO as the primary solvent and water as the co-solvent. In one aspect, the composition includes at least one co-solvent such as, but not limited to, water or ethanol. In one aspect, the co-solvent is one or more polar aprotic solvents. In one aspect, the co-solvent is ethyl acetate. In one aspect, the co-solvent is at least one of ethyl acetate, acetone, acetonitrile, tetrahydrofuran, methylene chloride, and dimethylformamide. Those skilled in the art will appreciate the advantages and limitations of using co-solvents based on the properties and physical effects of such co-solvent candidates in light of the disclosure provided herein.

  [0049] In one aspect, the composition comprises at least one excipient such as, but not limited to, sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, and water. Including. It should be noted that the compositions encompassed herein may optionally include one or more other excipients known to those skilled in the art. Those skilled in the art will recognize that such excipients are useful in the present compositions and methods, for example, when such excipients promote the therapeutic effect, stability or efficacy of the composition or method. I know how to check.

Dosage, form and formulation
[0050] In one aspect, the composition comprises a therapeutically effective amount of at least one therapeutic agent. The term “therapeutically effective amount” is used herein to describe, in context, the amount of a compound that is used to cause or achieve a desired therapeutic result, unless otherwise indicated. . In one aspect, the targeted therapeutic result relates to the treatment of onychomycosis. In one aspect, the therapeutically effective amount is an amount sufficient to treat otitis, and the treatment of otitis includes preventing or slowing the progression of the infection, preventing the spread of the infection, at least one of the infections. At least one of eradication of the part and eradication of the entire infection. In one aspect, the therapeutically effective amount may be determined based on a single dose of the composition or may be determined based on multiple doses. Of course, determination of a therapeutically effective amount may require trial and error and may require adjustment of dosage and / or dosage regimen. Such treatment optimization and adjustment is encompassed by the methods encompassed herein.

[0051] As used herein with respect to a compound or composition, the term "pharmaceutically acceptable" refers to the subject in the subject to promote or enhance the bioavailability of the compound or composition. Refers to the form of the compound or composition that can increase or promote the solubility or availability of the compound. In one aspect, the disclosure herein includes pharmaceutically acceptable hydrates, solvates, stereoisomers, or amorphous solids of the compounds and compositions embodied herein. Include.

[0052] As used herein, "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives known to those skilled in the art (eg, , Antibacterial agent, antifungal agent), isotonic agent, absorption delaying agent, salt, preservative, drug, drug stabilizer, gel agent, binder, excipient, disintegrant, lubricant, sweetener, wearing Perfumes, dyes, such similar materials and combinations thereof (see, eg, Remington's Pharmaceutical Sciences, 1990, the contents of which are incorporated herein by reference).
Except insofar as any conventional carrier is not compatible with the active ingredient or method of use, their use in the pharmaceutical composition is envisioned.

  [0053] Unless otherwise stated, the ratios described herein for the specified ingredients relative to the total composition are (w / w). For example, a composition comprising 1% PVP-I and 99% DMSO has 1% by weight PVP-I relative to the total composition.

  [0054] In one embodiment, the composition comprises an iodophor in the range of about 0.01% to about 15%. In another aspect, the composition comprises iodophor in the range of 0.05% to 12.5%. In another aspect, the composition comprises iodophor in the range of 0.05% to 10.0%. In another aspect, the composition comprises iodophor in the range of 0.1% to 10.0%. In another aspect, the composition comprises an iodophor in the range of 0.1% to 5.0%. In another aspect, the composition comprises an iodophor in the range of 0.25% to 9.0%. In another aspect, the composition comprises iodophor in the range of 0.2% to 2.5%. In another aspect, the composition comprises iodophor in the range of 0.5% to 7.5%. In another aspect, the composition comprises iodophor in the range of 0.5% to 1.0%. In another aspect, the composition comprises 0.75% to 5.0%, and in yet another aspect, an iodophor in the range of 1.0% to 4.0%. In one aspect, the composition comprises about 0.1% to about 2.5%, about 0.2% to about 2.0%, about 0.3% to about 1.0%, and about 0.4% to Contains iodophor in the range of about 0.75%.

  [0055] In one aspect, the composition comprises elemental iodine in the range of about 0.01% to about 15%. In another aspect, the composition comprises elemental iodine in the range of 0.05% to 12.5%. In another aspect, the composition comprises elemental iodine in the range of 0.05% to 10.0%. In another aspect, the composition comprises elemental iodine in the range of 0.1% to 10.0%. In another aspect, the composition comprises elemental iodine in the range of 0.1% to 5.0%. In another aspect, the composition comprises elemental iodine in the range of 0.25% to 9.0%. In another aspect, the composition comprises elemental iodine in the range of 0.2% to 2.5%. In another aspect, the composition comprises elemental iodine in the range of 0.5% to 7.5%. In another aspect, the composition comprises elemental iodine in the range of 0.5% to 1.0%. In another aspect, the composition comprises 0.75% to 5.0%, and in yet another aspect, elemental iodine in the range of 1.0% to 4.0%. In one aspect, the composition comprises about 0.1% to about 2.5%, about 0.2% to about 2.0%, about 0.3% to about 1.0%, and about 0.4% to Contains elemental iodine in the range of about 0.75%.

[0056] In one embodiment, the composition comprises PVP-I in the range of about 0.01% to about 15%. In another aspect, the composition comprises PVP-I in the range of 0.05% to 12.5%. In another aspect, the composition comprises PVP-I in the range of 0.05% to 10.0%. In another aspect, the composition comprises PVP-I in the range of 0.1% to 10.0%. In another aspect, the composition comprises PVP-I in the range of 0.1% to 5.0%. In another aspect, the composition comprises PVP-I in the range of 0.25% to 9.0%. In another aspect, the composition comprises PVP-I in the range of 0.2% to 2.5%. In another aspect, the composition comprises PVP-I in the range of 0.5% to 7.5%. In another aspect, the composition comprises PVP-I in the range of 0.5% to 1.0%. In another aspect, the composition comprises 0.75% to 5.0%, and in yet another aspect, PVP-I in the range of 1.0% to 4.0%. In one aspect, the composition comprises about 0.1% to about 2.5%, about 0.2% to about 2.0%, about 0.3% to about 1.0%, and about 0.4% to Contains PVP-I in the range of about 0.75%.

  [0057] In one aspect, the composition comprises about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.0. 3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.25% About 1.50%, about 1.75%, about 2.0%, about 2.5%, about 5%, about 7.5%, about 10%, about 12.5 or about 15.0% PVP-I is included. In one aspect, the composition comprises 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%,. 5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2. 25%, 2.5%, 5%, 7.5%, 10.0%, 12.5% or 15% PVP-I. In another aspect, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% PVP. Includes -I. In another aspect, the composition comprises about 0.1% or less, about 0.5% or less, about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6 % Or less, about 7% or less, about 8% or less, about 9% or less, or about 10% or less of PVP-I. In another aspect, the composition comprises about 0.01% or more, about 0.05% or more, about 0.075% or more, about 0.1% or more, about 0.2% or more, about 0.3% or more. About 0.4% or more, about 0.5% or more, about 0.6% or more, about 0.7% or more, about 0.8% or more, about 0.9% or more, about 1% or more, about 2 % Or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, or about 10% or more PVP-I. In another aspect, the composition comprises 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6 0.0%, 7.0%, 8.0%, 9.0% or 10.0% PVP-I.

  [0058] In one aspect, the composition comprises DMSO and PVP-I. In one aspect, the composition consists essentially of DMSO and PVP-I. In one aspect, the composition consists of DMSO and PVP-I. In one aspect, the composition is anhydrous. In one aspect, the composition is substantially anhydrous. In one aspect, the composition comprises a measurable amount of water.

[0059] In one aspect, anhydrous DMSO is used in the composition. In one aspect, substantially anhydrous DMSO is used in the composition. Those skilled in the art know that different grades of DMSO can be produced and / or obtained, and one of the variables between different grades of DMSO formulations is moisture. For example, DMSO may be completely anhydrous (also simply referred to herein as “anhydrous”), substantially anhydrous, or may contain water to a measurable extent. Of course, the amount of water that can be measured in a DMSO formulation may vary depending on the instrumentation and techniques used to make such measurements. In one aspect, DMSO that is not completely anhydrous may contain water at a level that is substantially anhydrous or less than detectable. In one aspect, DMSO that is not completely anhydrous may comprise water, wherein the moisture is at least about 0.01%, at least about 0.02%, at least about 0.03%, at least about 0.0. 04%, at least about 0.05%, at least about 0.06%, at least about 0.07%, at least about 0.08%, at least about 0.09%, at least about 0.1%, at least about 0.2 %, At least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9% At least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 5%, at least about 7.5%, at least about 10%, at least about 12. 5% Is it more. In one aspect, DMSO that is not completely anhydrous may contain water, wherein the moisture is about 0.01%
Less than about 0.02%, less than about 0.03%, less than about 0.04%, less than about 0.05%, less than about 0.06%, less than about 0.07%, less than about 0.08% Less than about 0.09%, less than about 0.1%, less than about 0.2%, less than about 0.3%, less than about 0.4%, less than about 0.5%, less than about 0.6%, Less than about 0.7%, less than about 0.8%, less than about 0.9%, less than about 1.0%, less than about 1.5%, less than about 2.0%, less than about 2.5%, about Less than 5%, less than about 7.5%, less than about 10%, less than about 12.5% or more. Of course, DMSO may contain one or more other impurities in addition to water.

  [0060] In one aspect, the composition comprises an iodophor and a penetrant and further comprises water. In one aspect, the composition comprises anhydrous iodophor and / or anhydrous penetrant and further comprises water. In one aspect, the composition comprises PVP-I and DMSO and further comprises water. In one aspect, the composition comprises an iodophor and a penetrant and further comprises water, wherein the moisture is at least about 0.01%, at least about 0.02%, at least about 0.03%, at least about 0.04%, at least about 0.05%, at least about 0.06%, at least about 0.07%, at least about 0.08%, at least about 0.09%, at least about 0.1%, at least about 0 .2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0. 9%, at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 5%, at least about 7.5%, at least about 10%, at least about 1 It is .5% or more. In one aspect, the composition comprises an iodophor and a penetrant and further comprises water, wherein the moisture is less than about 0.01%, less than about 0.02%, less than about 0.03%, about 0%. 0.04%, less than about 0.05%, less than about 0.06%, less than about 0.07%, less than about 0.08%, less than about 0.09%, less than about 0.1%, about 0.0. <2%, <0.3%, <0.4%, <0.5%, <0.6%, <0.7%, <0.8%, <0.9 %, Less than about 1.0%, less than about 1.5%, less than about 2.0%, less than about 2.5%, less than about 5%, less than about 7.5%, less than about 10%, about 12% Less than 5% or more. In one aspect, the composition comprises an iodophor and a penetrant and further comprises water, wherein the moisture is from about 0.01% to about 12.5%, from about 0.02% to about 10.0%. About 0.03% to about 7.5%, about 0.04% to about 5%, about 0.05% to about 2.5%, about 0.06% to about 2%, about 0.07% About 1.5%, about 0.08% to about 1%, about 0.09% to about 0.9%, about 0.1% to about 0.8%, or about 0.2% to about 0.0. 7%. In one aspect, the water may be derived from a component of the composition. In another aspect, water may be specifically added to the composition.

[0061] In one aspect, the composition is a United States Pharmacopoeia (USP).
) Association grade DMSO, API (Active Pharmaceutical Ingredient) grade DMSO, analytical grade DMSO and American Chemical Society (ACS) spectroscopic grade DMSO. In one aspect, the composition comprises greater than 99.9% DMSO as determined anhydrous by KF titration with less than 0.1% water.

[0062] As noted above, the% amount of DMSO in the composition is stated as a weight / weight (w / w) ratio relative to one or more other components of the composition, unless otherwise specified. In one aspect, the weight percent of DMSO is the remaining weight percent after addition of PVP-I. By way of non-limiting example, the composition may comprise 1 wt% (1%) PVP-I and 99 wt% (99%) DMSO. Of course, in the above example, the DMSO component of the composition may be completely anhydrous, substantially anhydrous, or may contain water to a measurable extent. In one aspect, the weight percentage of DMSO is the remaining weight percentage after addition of PVP-I and any other ingredients (eg, co-solvent, water, additional active ingredients, etc.). In one aspect, the weight percent of DMSO is the remaining weight percent after addition of the iodophor and other ingredients (if present). In one aspect, the weight percent penetrant in the composition is the remaining weight percent after addition of the iodophor and other ingredients (if present).

  [0063] In one aspect, the composition comprises DMSO in the range of 50% to 99.99%. In one aspect, the composition comprises DMSO in the range of 1% to 99.99%. In another aspect, the composition comprises DMSO in the range of 5% to 99.9%. In another aspect, the composition comprises DMSO in the range of 10% to 99.9%. In another aspect, the composition comprises DMSO in the range of 20% to 99.9%. In another aspect, the composition comprises DMSO in the range of 30% to 99.9%. In another aspect, the composition comprises DMSO in the range of 40% to 99.9%. In another aspect, the composition comprises DMSO in the range of 50% to 99.9%. In another aspect, the composition comprises DMSO in the range of 60% to 99.9%. In another aspect, the composition comprises DMSO in the range of 70% to 99.9%. In another aspect, the composition comprises 80% to 99.9%, and in yet another aspect, DMSO in the range of 90% to 99.9%. In one aspect, the composition is at least about 80% by weight, at least about 85%, at least about 87.5%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 99.9% DMSO.

  [0064] In one aspect, the composition comprises DMSO but no additional solvent (eg, co-solvent) or penetrant. In another aspect, the composition comprises DMSO in the range of about 0.01% to 99.99%, and further comprises at least one cosolvent in the range of 0.01% to about 99.99%. In one aspect, the composition comprises DMSO and further comprises at least one co-solvent ranging from about 0.1% to about 50%.

  [0065] In another aspect, the composition comprises DMSO and further comprises at least one co-solvent ranging from about 5% to about 50%. In another aspect, the composition comprises DMSO and further comprises at least one co-solvent ranging from about 10% to about 99%. In another aspect, the composition comprises DMSO and further comprises at least one co-solvent ranging from about 20% to about 95%. In one aspect, the composition comprises DMSO and at least one of a range of about 50% to about 60%, about 60% to about 80%, about 70% to about 90%, and about 80% to about 95%. Further includes a co-solvent. In one aspect, water is a cosolvent. In one aspect, the composition comprises DMSO, water and at least one additional co-solvent.

  [0066] In one aspect, the composition comprises DMSO in the range of about 0.01% to 99.99%, and further comprises at least one penetrant in the range of 0.01% to about 99.99%. Including. In one aspect, the composition comprises DMSO and further comprises at least one penetrant in the range of about 0.1% to about 50%. In another aspect, the composition comprises DMSO and further comprises at least one penetrant in the range of about 5% to about 50%. In another aspect, the composition comprises DMSO and further comprises at least one penetrant in the range of about 10% to about 99%. In one aspect, the composition comprises DMSO, at least one co-solvent, and at least one penetrant. In one aspect, the co-solvent is also a penetrant.

[0067] In one aspect, the composition comprises tolnaftate, terbinafine, undecylenic acid, clioquinol, miconazole, miconazole nitrate, chlorinazole, thioconazole, nystatin, telconazoic, butconazole nitrate, cyclopyroxolamine, econazole nitrate, triacetin, flucytosine, haloprocin At least one antifungal agent selected from the group consisting of gin and ketoconazole. In one aspect, the at least one antifungal agent is about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.25%, about 1.50%, about 1. 75%, about 2.0%, about 2.5%, about 5%, about 7.5%
, About 10%, about 12.5, about 15.0%, about 20%, about 25%, about 30%, about 40% or about 50%. In one aspect, the composition comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%,. 7%, 0.8%, 0.9%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 5% 7.5%, 10.0%, 12.5%, 15%, 20%, 25%, 30%, 40% or 50% of at least one antifungal agent. In another aspect, the composition comprises about 0.1% or less, about 0.5% or less, about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6 % Or less, about 7% or less, about 8% or less, about 9% or less, about 10% or less, about 20% or less, about 25% or less, about 30% or less, about 40% or less, or about 50% or less Contains some antifungal agents. In another aspect, the composition comprises about 0.1% or more, about 0.5% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6 % Or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, or about 50% or more Contains some antifungal agents. In another aspect, the composition comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8 0.0%, 9.0%, 10.0%, 20%, 25%, 30%, 40% or 50% of at least one antifungal agent.

  [0068] In one aspect, known in the art as a non-limiting example, such as 1% tolnaftate, 10-25% undecylenic acid, 3% clioquinol and / or 2% miconazole nitrate. A stable formulation consisting of at least one topical antifungal component can be prepared in a DMSO solvent system that also incorporates PVP-I as a long-term preservative. These solutions exhibit significant long-term stability, where both the PVP-I component and the antifungal component can maintain about 90% or more of the original concentration. Surprisingly, it has been found that there is no appreciable reaction between the antifungal agent and PVP-I. These formulations also show significant in vitro and in vivo efficacy as antifungal agents.

  [0069] In one aspect, if possible, the composition may include a pharmaceutically acceptable salt of the compound in the composition. In one aspect, the composition comprises an acid addition salt of the compound. In one aspect, the composition comprises a base addition salt of the compound. As used herein, the term “pharmaceutically acceptable salt or complex” refers to a salt or compound that retains the desired biological activity of the parent compound and that, if present, exhibits minimal undesirable toxic effects. Refers to a complex (eg, solvate, polymorph).

  [0070] In a composition for topical administration, the mixture is preferably formulated as an aqueous solution having a pH of 2.0 to 6.5. Preferably the pH is adjusted from 2.5 to 4.5. This pH range may be achieved by including an appropriate acid / base in the composition.

  [0071] In one aspect, the composition is one of the excipients, antibacterial agents, preservatives, co-solvents, surfactants, viscosity agents, and / or bioadhesives listed in detail elsewhere herein. One or more of these may be included.

  [0072] In one aspect, the pharmaceutical formulation is a partially-alcoholic formulation. As is well known to those skilled in the art, the addition of a certain proportion of alcohol to the formulation increases the solubility of ingredients including PVP-I. The alcohol component also functions as a dehydrating component for the surface to which the formulation is applied. Alcohols useful in the present invention include methanol, ethanol, and 2-propanol, among others.

lubricant
[0073] In one embodiment, the composition may include one or more lubricants. As a lubricant, propylene glycol, glycerin, polyethylene glycol, dextran, polyvinyl alcohol blend, polyvinyl alcohol, polyethylene glycol, light oil, hydroxypropylmethylcellulose, hypromellose, carbopol, carbomer 940 (polyacrylic acid), polyvinyl pyrrolidone, white petrolatum, Soy lecithin, and sodium carboxymethylcellulose, and other agents known to those skilled in the art, or any combination thereof, include but are not limited to. Typically, such lubricants are used at a level of 0.1% to 2% by weight. In one aspect, the lubricants are 1.0% propylene glycol, 0.3% glycerin, 2.7% polyvinyl alcohol blend, 1% polyvinyl alcohol, 1% polyethylene glycol, light oil, 0.3% hydroxypropyl methylcellulose. 1.0% soy lecithin, 0.25%, or 0.5% sodium carboxymethylcellulose. In another aspect, the total weight of the PVP-I, artificial tear-based lubricant is between 0.1% and 4.5%.

Additional antibacterials and antibiotics
[0074] Fluoroquinones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, gatifloxacin, etc.); aminoglycosides (tobramycin, gentamicin, neomycin, etc.); polymyxin B
Combination (Polymyxin B / Trimethoprim, Polisporin Polymyxin B /
Including, but not limited to, bacitracin neosporine polymyxin B / neomycin / gramicidin), and other antibiotics (azithromycin, ilotaisin, erythromycin, bacitracin, etc.).

Local anesthetic
[0075] Local anesthetics suitable for the compositions and methods of the present invention include, but are not limited to, lidocaine, tetracaine or derivatives thereof or combinations thereof.

Antiallergic ingredients
[0076] Antiallergic components include epinastine, emedastine difumarate, azelastine hydrochloride, olopatadine hydrochloride, olopatadine, ketotifen fumarate, pemirolast potassium, nedocromil, rhodoxamide, cromolyn and cromolyn salts, and zinc acetate However, it is not limited to these.

Preservative
[0077] Preservatives include benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, EDTA, sorbic acid, onamer M, other agents known to those skilled in the art, or combinations thereof. Can be mentioned. Typically, such preservatives are used at a level of 0.001% to 1.0% by weight of the final composition.

Co-solvent
[0078] The composition of the present invention may contain any one or more co-solvents. The solubility of the components of the composition of the present invention may be facilitated by a surfactant or other suitable co-solvent in the composition. Such cosolvents / surfactants include polysorbates 20, 60, and 80, polyoxyethylene / polyoxypropylene surfactants (eg, Pluronic F-68, F-84, and P-103), cyclodextrins, Tyloxapol, other agents known to those skilled in the art, or combinations thereof. Typically, such cosolvents are used at a level of 0.01% to 2.0% by weight of the final composition.

Relaxation agent
[0079] In addition, the composition provides a refreshing sensation when applying a PVP-I solution to the ear to relieve mild ear irritation, increase comfort, provide a clean feeling, and improve sensation. An effective amount of a chemical agent may be included. Such drugs include various chemicals and chemical classifications, including menthol, methone glycerin acetyl, and menthol derivatives including menthyl esters, carboxamides, menthane glycerol ketals, alkyl-substituted ureas. , Sulfonamides, terpene analogs, furanones, and phosphine oxides; or camphor, and borneol.

Viscous agent
[0080] The compositions of the present invention may include any viscous agent, ie, an agent that increases viscosity. Making the viscosity higher than that of a simple aqueous solution increases the absorption of the active ingredient into the ear, reduces variability in the distribution of the formulation, and reduces the physical separation of the components of the formulation suspension or emulsion. And / or other otic formulations are desirable. Examples of such viscosity enhancers include polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, other agents known to those skilled in the art, or combinations thereof. It is done. Typically, such agents are used at a level of 0.01% to 2.0% by weight of the final composition.

Bioadhesive
[0081] A bioadhesive agent can be used in the composition to increase the retention time of the gradient of the drug across the biomatrix. Bioadhesive agents include polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum, hydroxypropyl methylcellulose (HPMC), sodium alginate, pectin, gelatin, carbomer, polyvinyl alcohol, gellan gum, tragacanth, acacia, and sodium carboxymethylcellulose However, it is not limited to these.

Formulation and effect assessment
[0082] In one aspect, the methods and compositions of the present invention can reduce progression so that no further progression of infectious otitis externa is detected. Any method can be used to determine whether the severity or rate of progression of otitis externa is decreasing. For example, a person suffering from otitis externa may be asked about pain or discomfort before and after treatment to determine if symptoms of otitis externa (e.g. ear pain or pruritus of the ear) have been reduced. Good. In some cases, in mammals, symptoms of otitis externa (eg, otorrhea, ear sensitivity to pressure, sensitivity when touching the earlobe, or hearing loss) to determine if severity is reduced
May be observed or examined before and after treatment with the composition according to the invention. In some cases, the otolaryngologist determines the severity of otitis externa before and after treatment (e.g., a physical diagnosis is performed and features well known to those skilled in the art) to determine whether the severity is reduced. May be evaluated (by evaluating 1 to 4 points). To determine whether otitis externa is progressing, physical examinations may be performed at different time points to measure the amount of erythema and / or edema in and around the ear canal. The rate of progression may be assessed by comparing the amount of erythema and edema observed at different time points. To determine whether the rate of progression is decreasing after treatment as described in the present invention, the rate of progression may be determined again at different time intervals.

[0083] Thus, an effective amount of a composition comprising an effective amount of PVP-I and DMSO is any amount that reduces the severity or progression of otitis externa without causing significant toxicity to the mammal. It is understood that there is. For example, an effective amount of PVP-I may be from 0.1% to about 10% (eg, about 2%) povidone iodine in the ear preparation. In one aspect, an effective amount of a composition comprising PVP-I and DMSO is about 2 to about 8 drops of an ear drop formulation applied to an ear comprising about 1% to 2% povidone iodine and about 30% or more DMSO. There may be.

  [0084] When the mammal does not respond to a certain amount of the composition of the invention, the amount of one or more of PVP-I and DMSO may be increased, for example. After being administered this higher concentration, the mammal may be monitored for both response to treatment and toxic symptoms and adjusted accordingly. The effective amount may be kept constant, or the amount may be adjusted by sliding or changing the dose depending on the response of the mammal to treatment. Various factors can affect the actual effective dose when used in a particular case. For example, the actual effective dose administered may need to be increased or decreased depending on the frequency of administration, duration of treatment, use of multiple therapeutic agents, route of administration, mammalian immune responsiveness, and severity of otitis externa. There is a possibility. The frequency of administration may be any frequency that reduces the severity or rate of progression of otitis externa without causing significant toxicity to the mammal. For example, the frequency of administration may be about once a day to about 4 times a day (eg, twice a day). The frequency of administration may remain constant or may vary during the duration of treatment.

  [0085] In other embodiments, a treatment regimen with the composition of the invention may include a rest period. For example, the composition may be administered for a week or two weeks followed by a one or two week rest period. Moreover, such a treatment plan may be repeated a plurality of times. As with the effective dose, various factors can affect the actual frequency of administration when used in a particular case. For example, the frequency of administration may need to be increased or decreased depending on the effective dose, duration of treatment, use of multiple therapeutic agents, route of administration, mammalian immune responsiveness, and severity of otitis externa . The effective administration period of the compositions described herein can be any duration that reduces the severity or rate of progression of otitis externa without causing significant toxicity to the mammal. Thus, the effective administration period may vary from days to weeks, months, years. In general, the effective administration period for the treatment of otitis externa may range from days to weeks. In some cases, the effective administration period may be during the life of an individual mammal. Multiple factors can affect the actual effective duration when used in a particular case. For example, the effective period of administration can vary depending on the frequency of administration, the effective amount, the use of multiple therapeutic agents, the route of administration, the immune response of the mammal, and the severity of otitis externa.

  [0086] The above diagnostic and therapeutic considerations are equally applicable to otitis media and otitis externa.

Preparation and use
[0087] Those skilled in the art have found that aqueous PVP-I solutions are difficult to stabilize at low PVP-I concentrations over long periods of time. As a non-limiting example, at a PVP-I concentration of less than about 0.7% (w / w, aqueous solution), the PVP-I aqueous solution rapidly disintegrates, and the iodinated and iodine-free components A complex mixture results. As described herein, surprisingly, in aprotic DMSO solvent systems encompassed by the disclosure described herein, PVP- concentrations as low as 0.1% It has been found that the solution I can be easily prepared and maintained as a stable composition over time. Also, as described herein, hydrated DMSO solutions prepared from PVP-I aqueous solutions show a significant increase in stability relative to the PVP-I component.

  [0088] In one aspect, the composition comprises dry solid or powdered PVP-I that is dissolved or suspended in a composition comprising or consisting of DMSO. In another embodiment, DMSO is added to an aqueous formulation comprising or consisting of PVP-I. Based on the disclosure herein, one of ordinary skill in the art will be able to achieve a composition that achieves the desired amount of iodine, iodophor and DMSO, among other components that may be included in the compositions encompassed herein. The preparation method is known.

  [0089] As a non-limiting example, a therapeutically effective pharmaceutical composition is prepared using solid PVP-I dissolved or suspended in DMSO. In one aspect, the composition is anhydrous. In one aspect, the composition is substantially anhydrous. In another aspect, DMSO can be added to an aqueous PVP-I solution to prepare a therapeutically effective pharmaceutical composition. In one embodiment, DMSO is used as a cosolvent with water in the range of 50% to 99%. In one aspect, the formulation comprises one or more excipients. By way of non-limiting example, excipients include sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate and water and other excipients known to those skilled in the art. For example, but not limited to.

  [0090] In one aspect, 10% PVP-I (w / v, aqueous solution) is added to pure DMSO (appropriate amount) to obtain a 1% PVP-I (w / w) solution containing DMSO. To prepare the composition. In another embodiment, solid PVP-I is dissolved in pure DMSO (suitable amount) and DMSO is used as a solvent, containing 0.1%, 0.2%, 0.3%, 0.4%,. 5%, 1.0%, 1.25%, 1.5%, 2.0% or 2.5% PVP-I (w / w) and about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1.0%, about 1.25%, about 1.5%, about 2.0% or about 2.5% PVP-I A composition is prepared by obtaining any of the (w / w) compositions. In yet another aspect, the composition is prepared by dissolving solid PVP-I in pure DMSO (suitable amount) to obtain any composition described, described and / or included herein. . From stock 10% PVP-I aqueous solution and pure DMSO, including PVP-I aqueous solution (with or without commonly used and / or known excipients in the art) and DMSO Similar compositions can be prepared. However, one skilled in the art knows that any starting composition (solid or liquid) of PVP-I can be used, with appropriate dilution and adjustment to obtain the desired final PVP-I concentration. Similarly, any starting composition of iodophor or elemental iodine can be used, with appropriate dilution and preparation to obtain the desired final iodophor or elemental iodine concentration, respectively.

  [0091] In one aspect, in the case of otitis, it is particularly useful that a stable anhydrous composition containing 0.01% to 10% PVP-I can be prepared with pure USP grade DMSO solvent. .

  [0092] It will be appreciated that, based on the disclosures provided herein, considering the skills in the art, and based on experience through clinical and / or pharmacokinetic experiments, Specific dosages for the compounds and compositions encompassed by can be determined, and such dosages can be adjusted according to pre-specified effects and / or toxicity criteria. It will also be appreciated that the specific dosage and treatment regimen for any particular patient will depend on the activity of the specific compound used, the characteristics of the patient, the combination of drugs, the judgment of the treating physician, and It depends on a variety of factors including the nature and severity of the particular disease or condition being treated.

  [0093] In one aspect, the compositions described, described and / or encompassed herein include, but are not limited to, onychomycosis, peritonitis, warts, infectious molluscum, non-genital Useful for treating one or more of herpes simplex, scarring, Gram-negative intercostal infections, psoriatic onychodystrophy and tinea pedis. In one aspect, the composition comprises PVP-I and DMSO. In one aspect, the composition consists essentially of PVP-I and DMSO. In one aspect, the composition consists of PVP-I and DMSO.

[0094] In one aspect, a therapeutic composition is prepared by optimizing one or more compounds used in a dosage form different from that typically used for the compounds. In one aspect, compounds that are typically not administered in topical dosage forms are developed for use in topical dosage forms. The chemical and biological assays necessary for such development are known to those skilled in the art. The disclosure herein provides those skilled in the art with guidance on how to prepare such compounds and compositions containing such compounds.

  [0095] In one aspect, a method of treating a subject suffering from otitis includes administration of a composition described, described and / or included herein for treating otitis, Treatment includes at least one of preventing or slowing the progression of the infection, preventing the spread of the infection, eradicating at least a portion of the infection and eradicating the entire infection.

  [0096] In one aspect, the therapeutic composition is administered on a once daily schedule. In one aspect, the therapeutic composition is administered twice daily. In one aspect, the therapeutic composition is administered three times daily, four times daily, five times daily, or more. In one aspect, the therapeutic composition is administered less frequently than once a day. In one aspect, the therapeutic composition is administered once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days. In one aspect, the therapeutic composition is administered less frequently than once a week. In one aspect, the therapeutic composition is administered once a month. In one aspect, the therapeutic composition is administered twice a month.

  [0097] In one aspect, the treatment regimen continues for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days or at least 7 days. In one aspect, the treatment regimen continues for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks or at least 16 weeks. In one aspect, the treatment regimen continues for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months or at least 12 months.

  [0098] The invention is further described by the following examples. In one aspect, the following examples demonstrate effective and / or successful treatment of identified ailments using the compositions and methods encompassed by the present disclosure. It should be noted that variations based on the features of the present invention are within the skill of those skilled in the art, and the scope of the present invention should not be limited by the examples. In order to properly determine the scope of the invention, interested parties should consider the claims herein and any equivalents thereof. Also, all citations herein are incorporated herein by reference, and all percentages are by weight unless otherwise specified.

Example 1
Acute otitis externa in children treated with 2% povidone iodine gel
[0099] The patient suffered from acute otitis externa. The disease is often accompanied by severe irritation and pain that occurs when the child moves or when the head moves. The composition disclosed herein was prepared using 2.0% PVP-I in 44% USP grade DMSO containing water and 2% hydroxyethyl cellulose (HEC) to form a thick gel. . The gel was applied topically to the ear canal twice daily to treat the patient. Within 4 days, the infection resolved and the patient became painless.

Example 2
Acute otitis externa in children treated with high viscosity 2% povidone iodine gel
[0100] The patient had acute otitis externa. The disease is often accompanied by severe irritation and pain that occurs when the child moves or when the head moves. The composition disclosed herein was prepared using 2.0% PVP-I solution in 44% USP grade DMSO containing water and 4% hydroxyethyl cellulose (HEC) to give a viscosity of 300,000 cps. A gel with a viscosity greater than that was formed. The gel was applied topically to the ear canal once daily to treat the patient. Within 2 days, the infection resolved and the patient became painless.

  [0101] Those skilled in the art will recognize that variations may be made to the exemplary embodiments shown and described above without departing from the broad inventive concept. Accordingly, the disclosure herein is not intended to be limited to the exemplary embodiments shown and described, but is intended to include modifications within the spirit and scope of the invention as defined by the claims. I understand. For example, specific features of the exemplary aspects may or may not be part of the claimed invention, and may be combined with features of the disclosed aspects. Unless specifically stated herein, the terms “a”, “an” and “the” are not limited to one element, but instead “ Should be interpreted in the sense of “at least one”.

  [0102] It should be noted that at least a portion of the description of the present invention has been simplified to focus on relevant elements for a clear understanding of the present invention, and other elements have been excluded for clarity. However, it will be appreciated by those skilled in the art that they can also form part of the present invention. However, since such elements are well known in the art and they do not necessarily facilitate a better understanding of the present invention, a description of such elements is provided herein. Not.

  [0103] Furthermore, the specific order of the steps should not be construed as limiting the scope of the claims to the extent that the method does not depend on the specific order of the steps described herein.

  [0104] The claims relating to the method of the present invention should not be limited to performing those steps in the order described, and those skilled in the art can modify the steps, but the spirit of the present invention And it is easily understood that it is included in the range.

[0104] The claims relating to the method of the present invention should not be limited to performing those steps in the order described, and those skilled in the art can modify the steps, but the spirit of the present invention And it is easily understood that it is included in the range.
The following is a description of the claims at the time of filing.
[Claim 1]
0.1% to 10% (w / w) povidone iodine and 30% to 99% (w / w) DMS
An otic composition comprising O and at least one ear-acceptable excipient.
[Claim 2]
The composition of claim 1, wherein the composition comprises a gelling agent.
[Claim 3]
The composition according to claim 2, wherein the gelling agent is selected from hydroxyethylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose.
[Claim 4]
The composition of claim 1, wherein the composition comprises PEG.
[Claim 5]
The composition of claim 1, wherein the composition comprises petrolatum.
[Claim 6]
The composition of claim 1, wherein the composition does not comprise a steroid.
[Claim 7]
A method of preventing or treating an ear infection or invasion comprising applying or administering a composition according to claim 1;
Including methods.
[Claim 8]
7. The method of claim 6, wherein the ear infection or invasion is otitis externa.
[Claim 9]
7. The method of claim 6, wherein the ear infection is otitis media.
[Claim 10]
7. The method of claim 6, wherein the ear infection is a viral infection.
[Claim 11]
7. The method of claim 6, wherein the ear infection or invasion is a bacterial infection.
[Claim 12]
7. The method of claim 6, wherein the ear infection or invasion is a fungal infection.
[Claim 13]
7. The method of claim 6, wherein the ear infection or invasion is an amoeba infection or invasion.
[Claim 14]
8. The method of claim 7, wherein the composition of claim 1 is free of steroids.

Claims (14)

An otic composition comprising 0.1% to 10% (w / w) povidone iodine and 30% to 99% (w / w) DMSO and at least one ear-acceptable excipient. The composition of claim 1, wherein the composition comprises a gelling agent. The composition according to claim 2, wherein the gelling agent is selected from hydroxyethylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose. The composition of claim 1, wherein the composition comprises PEG. The composition of claim 1, wherein the composition comprises petrolatum. The composition of claim 1, wherein the composition does not comprise a steroid. A method of preventing or treating an ear infection or invasion comprising applying or administering a composition according to claim 1;
Including methods. 7. The method of claim 6, wherein the ear infection or invasion is otitis externa. 7. The method of claim 6, wherein the ear infection is otitis media. 7. The method of claim 6, wherein the ear infection is a viral infection. 7. The method of claim 6, wherein the ear infection or invasion is a bacterial infection. 7. The method of claim 6, wherein the ear infection or invasion is a fungal infection. 7. The method of claim 6, wherein the ear infection or invasion is an amoeba infection or invasion. 8. The method of claim 7, wherein the composition of claim 1 is free of steroids.