KR20180061359A - Compositions and methods for treating otitis media - Google Patents

Abstract

The present invention relates to compositions and methods for treating ear infections, including otitis or otitis media, which comprise povidone iodine and dimethylsulfoxide (DMSO) and optionally a gelling agent.

Description

Compositions and methods for treating otitis media

Millions of human patients are suffering from infection or inflammation of the teeth, whether they are external (otitis externa) or middle ear (otitis media). For purposes of the present invention, these conditions may collectively be referred to as "dye transfer ". The mite may be acute or chronic and may represent effusion.

Current treatments for bacterial, fungal / yeast, and viral infections in the dogs may be ineffective in that they treat only some of the infecting pathogens. Many of the current treatments incorporate undesirable ingredients such as steroids or other potentially harmful components.

See, for example, U.S. Patent Application Publication No. 2009/0263345; 2012/0003174; And 2013/0089510 describe the treatment of migraine using PVP-I and steroids. According to these applications, otitis (external ear infection) is an inflammation of the external ear and the ear canal. This is a common cause of migraine in humans and is a common problem in dogs, cats and other mammals. It also occurs in many other species. This disorder involves skin irritation of the teeth. Inflammation can be caused by active fungi, viruses, or bacterial organisms. The glandular skin is often swollen and may have pain and tenderness on contact.

Otitis media (middle ear infection) occurs at the site between the eardrum and the inner ear, including the eustachian tube. Otitis media is very common in childhood, and normal infants almost always have two to three episodes a year with viral upper respiratory infection (URI), mostly with cold. Renoviruses and adenoviruses that cause many cold symptoms cause swelling and congestion in the inner ear, which can permanently damage the middle ear structures. Otitis media is also frequently caused by various bacteria and other viruses.

In addition, ear infections (especially in children) are among the many diseases that have become difficult to treat with traditional antibiotic drugs due to antibiotic resistant bacteria and antibiotic-resistant microorganisms. For example, in most cases of otitis media are several major pathogens, Streptococcus pneumoniae (Streptococcus pneumonia), Haemophilus influenzae (Haemophilus influenza), morak Cellar Kata LAL-less (Moraxella catarrhalis), Staphylococcus aureus ( Staphylococcus aureus , Staphylococcus epidermidis , or Pseudomonas aeruginosa .

Thus, in view of the known disadvantages of antibiotic resistance, potentially harmful side effects of steroids, which may arise from the use of compositions comprising conventional antibiotics or steroids, those diseases which do not require the use of conventional antibiotics or steroids There is an urgent need to develop new approaches for prevention and management.

Recent discoveries by Capriotti et al. Disclose compositions comprising iodophors such as povidone-iodine (PVP-I) as an active ingredient and dimethylsulfoxide (DMSO) used as a penetration enhancer for active ingredients There is one. These compositions have been suggested to be useful for treating fungal infections of the skin and nails. See, for example, U.S. Publication No. US2014 / 0205559 (Caprio '559), the disclosure of which is incorporated herein by reference in its entirety. PVP-I is a well-known disinfectant with broad spectrum activity against viruses, fungi and bacterial species, as well as Demodex, and has no known bacterial, fungal or viral resistance. PVP-I has also been shown to inhibit the formation of biofilms and to remove already formed biofilms.

Various organic solvents, including dimethyl sulfoxide (DMSO), are known to promote transdermal absorption of certain medicinal products. However, it has long been accepted in the pharmaceutical arts that DMSO enhances the penetration of small molecules or low molecular weight (LMW) compounds or drugs, but does not effectively enhance the penetration of high molecular weight (HMW) compounds, such as polymers, above about 10,000 Daltons come.

U.S. Patent Publication No. 2009/0263345; 2012/0003174; And 2013/0089510 do not disclose steroid-free compositions and the advantages of compositions comprising PVP-I and DMSO as described and claimed herein in treating mucous membranes are not recognized or considered.

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 infestations of the ileum.

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% dimethylsulfoxide (DMSO). The topical gel compositions of the present invention comprise from about 0.1% to about 10% povidone-iodine (PVP-I), from about 30% to about 99% dimethylsulfoxide (DMSO) and from about 1% to about 10% . Unexpectedly, the topical gel composition of the present invention is substantially free of gelling agent, and can be used to treat dyes as compared to liquid compositions comprising from about 0.1% to about 10% povidone-iodine and from about 30% to about 99% DMSO Which may be more efficacious in the treatment of cancer. Unexpectedly, the topical gel compositions of the present invention are very stable at room temperature in the presence of aqueous or anhydrous components.

Preferred compositions comprise from about 0.25% to about 0.35% PVP-I. Another preferred composition comprises from 0.25% to about 0.5% PVP-I and another composition comprises from 1% to about 5% PVP-I. A more preferred composition may comprise about 1% PVP-I or about 2% PVP-I. PVP-I using a povidone grade of K30 is preferred for use in the compositions of the present invention.

Preferred compositions comprise from about 30% to about 70% DMSO. A more preferred composition may comprise from about 40% to about 49% DMSO, and even more preferably about 44% DMSO.

Preferred compositions comprise from about 0.5% to about 5% gelling agent. More preferred compositions may comprise about 1-2% gelling agent. Particularly useful compositions prepared for testing are 2% PVP-I; 44% DMSO; 2% hydroxyethylcellulose; And a 52% aqueous solvent. Preferred aqueous solvents are water or isotonic buffers.

The compositions of the present invention may comprise a gelling agent, such as gum, agar, carrageenan, petrolatum or cellulose polymers, as is well known in the relevant art. One preferred cellulose polymer as a gelling agent is hydroxyethyl cellulose. An alternative cellulosic polymer gelling agent is hydroxymethylcellulose.

The compositions of the present invention preferably comprise povidone-iodine or PVP-I having an average molecular weight of more than 10,000. More preferably, the compositions of the present invention comprise PVP-I having an average molecular weight of from about 20,000 to about 1,000,000. One preferred embodiment comprises PVP-I having an average molecular weight of from about 30,000 to about 60,000, or greater. Each PVP-I component is referred to herein as "high molecular weight PVP-I" or "HMW PVP-I".

Another embodiment of the composition according to the present invention is a composition comprising 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% gelling agent; Herein, each component in the composition is a stable topical gel formulation for the ear that is acceptable for the ear, and the gel composition for the ear contains substantially no gelling agent in treating the tooth, and in particular the infectious condition of the outer or middle ear And exhibit greater efficacy compared to liquid compositions comprising from about 0.1% to about 10% povidone-iodine and from about 30% to about 99% DMSO.

A preferred gel composition for the ear comprises from about 0.25% to about 2.55% PVP-I. More preferred gel compositions for the ear comprise from about 1% to about 3% PVP-I, and most preferred gel compositions for the ear comprise about 1% PVP-I.

The compositions of the present invention preferably comprise povidone-iodine or PVP-I having an average molecular weight of more than 10,000. More preferably, the compositions of the present invention comprise PVP-I having an average molecular weight of from about 20,000 to about 1,000,000. One preferred embodiment comprises a high molecular weight (HMW) PVP-I.

Preferred gel compositions for the ear comprise from about 30% to about 70% DMSO. More preferred gel compositions for the ear may comprise from about 40% to about 49% DMSO, and even more preferably about 44% DMSO.

A preferred gel composition for the ear comprises from about 2% to about 5% gelling agent. A more preferred gel composition for the ear may comprise about 4% gelling agent. Particularly useful compositions prepared for use in treating infections of the eye or eyelid include 1% PVP-I; 44% DMSO; 2% hydroxyethylcellulose; And a 53% aqueous solvent. A preferred aqueous solvent is water.

The gel composition for the ear of the present invention may comprise a gelling agent selected from gums, agar, carrageenan, petrolatum or cellulose polymers and the like, as is well known in the relevant art. One preferred cellulose polymer useful as a gelling agent is hydroxyethyl cellulose (HEC). An alternative cellulosic polymer gelling agent is hydroxymethylcellulose. In one embodiment, treatment of a mucus comprising an iodophore, such as povidone-iodine (commonly abbreviated as "PVP-I") and dimethylsulfoxide (commonly abbreviated as "DMSO" A steroid-free composition is disclosed herein, wherein the composition is capable of infiltrating epithelial glands or penetrating the eardrum to treat an outer or middle ear infection.

In one embodiment, the compositions disclosed herein for treating diarrhea are substantially anhydrous. In one embodiment, the composition is anhydrous.

In one embodiment, the compositions disclosed herein for the treatment of diarrhea comprise from about 0.01% to about 10% (w / w) of PVP-I. In one embodiment, the PVP-I is from about 0.05% to about 10%, from about 0.1% to about 5%, from about 0.2% to about 2.5%, and from about 0.5% to about 1% (w / It exists in the selected range. In one embodiment, the PVP-I comprises 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 5% (w / w). In one embodiment, PVP-I is present at about 1% (w / w).

In one embodiment, the composition disclosed herein for the treatment of diarrhea further comprises at least one naturally occurring substance. In one embodiment, the compositions disclosed herein for the treatment of diarrhea include, but are not limited to, Punica Granatum extract, Camellia Sinensis leaf extract, ascorbic acid, Calendula Officinalis extract, And at least one substance selected from the group consisting of Glycyrrhiza Glabra extract, Allantoin and Cucumis Sativus fruit extract.

In one embodiment, the compositions disclosed herein for the treatment of diarrhea include, but are not limited to, tolnaphthate, terbinafine, undecylenic acid, clioquinol, myconezol, myconezolinate, clorinazole, thioconazole, nystatin, The composition further comprises at least one antifungal agent selected from the group consisting of quinazoline, quinazoline, quinazoline, quinazoline, quinazoline, quinazoline, quinazoline, quinazoline, In one embodiment, the antifungal agent is present in an amount from about 1% to about 25% (w / w).

In one embodiment, a composition for treating a mucus comprising iodophor, such as PVP-I and dimethylsulfoxide (DMSO) is disclosed herein, wherein the composition penetrates through the epithelial glands or eardrum, Or middle ear infection, and further wherein the composition does not comprise a steroid or is "steroid-free ".

In one embodiment, the compositions of the present invention are formulated for topical administration, as a liquid point, either in liquid form or as a gel.

In one embodiment, the compositions of the present invention comprise a gelling agent in an amount to form a final composition that is a gel. In one embodiment, the composition of the present invention is formulated as a topical gel.

Each embodiment of the composition described herein does not contain a steroid, i. E. It is a steroid-free composition.

In embodiments comprising the described embodiments and specifically gelling agents, the composition forms a non-foamable topical composition for administration to the teeth. The non-foaming topical composition may be free of a foaming agent, or alternatively, where the formulation includes other ingredients or excipients that may or may not cause foaming, the composition may be a non-foamable topical composition, Other anti-foaming agents may be included to impart foam properties. Commonly used agents are insoluble oil, polydimethylsiloxane and other silicones, certain alcohols, stearates and glycols. Additives are used to prevent the formation of bubbles or added to destroy already formed bubbles.

In one embodiment, the infections being treated are fungal infections. In one embodiment, the infection is a dermatomyositis infection.

In one embodiment, the infected infection is a bacterial ear infection. In one embodiment, the infection is selected from Streptococcus, Staphylococcus, Haemophilus influenzae, and Pseudomonas infection.

In one embodiment, the infection being treated is a viral infection. In one embodiment, the infection is an adenovirus infection.

In one embodiment, the infection being treated is an amoeba infection.

In one embodiment, a method is provided herein for treating a diarrhea, comprising administering a composition as disclosed herein to an infected idiot, and repeating the contacting step as needed until the diarrhea is treated. 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 a particularly surprising embodiment, it has been found that even a single dose of high viscosity gel formulations (viscosities above about 100,000 cps) can completely eradicate pediatric middle ear infections.

In one embodiment, a method is provided herein for treating a diarrhea, comprising administering the composition of claim 1 to an infected subject and repeating the administration step for at least one week. In one embodiment, the administration step is repeated for at least two weeks. In one embodiment, the dosing step is repeated for at least 3 weeks. In one embodiment, the administration step is repeated for at least 4 weeks. In one embodiment, the dosing step is repeated for a maximum of 12 weeks.

The compositions of the present invention may be useful for treating fungal infections of the ear canal, wherein the infection is selected from the group consisting of Trichophyton rubrum , T. mentagrophytes , Epidermophyton floccosum , < RTI ID = 0.0 > T. < / RTI > T. violaceum , Microsporum gypseum , T. tonsurans , T. T. soudanense , tea. A member selected from the group consisting of Candida species, Neoscytalidium species, Scopulariopsis species and Aspergillus species, and a member selected from the group consisting of T. verrucosum , and a member selected from the group consisting of Candida species, Neoscytalidium species, Scopulariopsis species and Aspergillus species ≪ / RTI >

The present invention relates to a topical composition, preferably a topical gel composition, comprising an iodophore, a penetration enhancer and, in the case of a gel composition, a gelling agent, wherein the composition is in general formulated as a dyed or, in particular, Virus, demodex, fungal / yeast, bacterial or amoeba infections. Accordingly, the present invention further comprises a method of treating viral, demodex, fungal / yeast, bacterial or amoebic infections of the tract using a topical composition, preferably a topical gel composition, as disclosed herein. The composition may further comprise optional pharmaceutically acceptable excipients or solvents or co-solvents.

The compositions of the present invention preferably comprise active pharmaceutical ingredients (APIs) recognized by the US Food and Drug Administration (FDA) as suitable and acceptable for use in pharmaceutical preparations. Preferred compositions of the present invention further comprise an inert ingredient or excipient that is recognized and acceptable for use in pharmaceutical preparations for topical administration. FDA-approved APIs or acceptable inert ingredients or excipients are referred to herein as "pharmaceutically acceptable ". Thus, a topical composition, formulation or formulation of the invention comprising a pharmaceutically acceptable API, inert ingredient or excipient is referred to herein as a "pharmaceutically acceptable" topical composition.

Similarly, compositions for the ear of the present invention comprising an FDA-approved active or inactive ingredient that is acceptable for use in a formulation for the ear are herein referred to as "pharmaceutically acceptable" or " &Quot; A composition for " a pharmaceutically acceptable ear, "comprising an API, excipient or solvent, or an" ear acceptable "composition.

More particularly, the present invention relates, in a preferred embodiment, to a process for the preparation of a pharmaceutical composition comprising iodoform, dimethylsulfoxide (DMSO) and a gelling agent having a molecular weight of more than 10,000 daltons, and optionally further pharmaceutical or ear- Solvate < / RTI >

Compositions and methods are useful for treating any combination of one or at least two of the above diseases, conditions, or pathogens.

In one embodiment of the composition, the composition comprises at least one therapeutic agent and at least one solvent and / or penetrator. In one aspect, iodophor is a remedy. In one embodiment, the composition comprises at least one disinfecting compound. In one aspect, the disinfecting compound is a therapeutic agent. In one embodiment, the composition comprises an iodophores disinfectant. As used herein, "iodoform" refers to a material comprising iodine and at least one additional agent (e.g., solubilizer) that releases free ion in the presence of a solution. Examples of iodophors include, but are not limited to, povidone iodine (PVP-I), iodine tincture, rugol solution and iodine salts (e.g., potassium iodide, sodium iodide).

In one embodiment, the composition comprises at least one iodophor. The composition encompasses any iodophor, as well as iodophor, which is now to be developed or discovered. In one embodiment, the iodophor is PVP-I. In another embodiment, the composition comprises iodine. In one embodiment, the composition comprises iodine and at least one iodophor.

In one embodiment, PVP-I functions as a therapeutic in the composition. In one aspect, the PVP-I therapeutic agent functions as a disinfectant. In another embodiment, 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 embodiment, PVP-I functions in at least one capability in the composition. In another embodiment, PVP-I functions in at least two capabilities in the composition.

In another embodiment, the composition further comprises at least one non-iodoform, non-iodine therapeutic agent. In one embodiment, at least one non-iodoform, non-iodine therapeutic agent is a disinfectant. In another embodiment, at least one non-iodoform, non-iodine therapeutic agent is not a disinfectant.

In one embodiment, at least one non-iodoform, non-iodine therapeutic agent is an antifungal agent. Suitable antifungal agents include, for example, allylamines and azoles. In one embodiment, the antifungal agent is selected from the group consisting of tolnaphthate, terbinafine, undecylenic acid, clioquinol, myconezol, myconezolinate, clorinazole, thioconazole, nystatin, terconazole, , Cyclopiroxolamine, econazole nitrate, triacetin, flucytosine, halopropazine, and ketoconazole.

In one embodiment, the composition comprises one or more natural remedies. Natural remedies include, but are not limited to, Pucca Granatum (pomegranate) extract, Camellia sinensis leaf (green tea) extract, ascorbic acid (vitamin C), calendula ophthanilis extract, glycyrrhiza gabra (licorice extract) But are not limited to, Cucumis sativus (cucumber) fruit extract. In one embodiment, the composition is selected from the group consisting of DMSO, PVP-I, Ponikagranatum (pomegranate) extract, Camellia sinensis leaf (green tea) extract, ascorbic acid (vitamin C), calendula ophthanilis extract, Glabra (licorice) extract, allantoin and cucumis sativus (cucumber) fruit extract.

In one embodiment, the composition comprises at least one solvent and / or penetrant. In one embodiment, a single component may function as both a solvent and a penetrant in the composition. In one embodiment, the composition comprises DMSO. In one aspect, DMSO functions as a penetrator for the active component. In one aspect, DMSO functions as a solvent. In another aspect, DMSO functions as both a solvent and a penetrant. In one embodiment, DMSO is the sole penetrator in the composition. In one embodiment, DMSO is the sole solvent in the composition. In one embodiment, DMSO is the sole penetrant and solvent in the composition.

In one embodiment, the composition comprises PVP-I and DMSO. In another embodiment, the composition comprises PVP-I and DMSO. In another embodiment, the composition consists essentially of PVP-I and DMSO.

Those of ordinary skill in the relevant art will appreciate, on the basis of the disclosure herein, how to identify penetrants useful in compositions and methods encompassed herein. In one embodiment, the penetrants are useful for allowing the composition to penetrate the nail. As a non-limiting example, methylsulfonylmethane can be used as a penetrating agent in compositions such as those covered herein.

In one embodiment, the composition comprises at least one co-solvent. In one embodiment, the composition comprises DMSO as the major solvent and further comprises at least one co-solvent. In one embodiment, water is co-solvent. In one embodiment, the composition comprises DMSO as the major solvent and water as co-solvent. In one embodiment, the composition consists of DMSO as the major solvent and water as the co-solvent. In another embodiment, the composition consists essentially of DMSO as the major solvent and water as the co-solvent. In one embodiment, the composition comprises at least one co-solvent such as, but not limited to, water or ethanol. In one embodiment, the co-solvent is at least one polar aprotic solvent. In one embodiment, the co-solvent is ethyl acetate. In one embodiment, the co-solvent is at least one of ethyl acetate, acetone, acetonitrile, tetrahydrofuran, methylene chloride, and dimethylformamide. Those of ordinary skill in the pertinent art will appreciate the advantages and limitations of the use of co-solvents based on the properties and physical effects of such co-solvents, in view of the disclosure provided herein.

In one embodiment, the composition comprises at least one excipient such as, but not limited to, sodium chloride, sodium dihydrogenphosphate monohydrate, disodium hydrogenphosphate and water. It will be appreciated that the compositions encompassed herein optionally include one or more other excipients as is known to those of ordinary skill in the relevant art. Those of ordinary skill in the relevant art will recognize how to identify such excipients useful in the compositions and methods of the invention, for example, when such excipients enhance the therapeutic efficacy, stability, or efficacy of the compositions or methods.

Dose, Form and Formulation

In one embodiment, the composition comprises a therapeutically effective amount of at least one therapeutic agent. As used herein, the term "therapeutically effective amount " is used to describe the amount of a compound used to produce or bring about the intended therapeutic effect, unless otherwise indicated. In one embodiment, the intended treatment outcome is associated with the treatment of the nail fungus. In one embodiment, the therapeutically effective amount is an amount sufficient to treat the mucus, treatment of the mucus may include preventing or delaying the progress of the infection, preventing the spread of the infection, at least partially eradicating the infection, And completely eradicating it. In one aspect, the therapeutically effective amount can be determined on a single dose basis or can be determined on a multi-dose basis of the composition. It will be appreciated that determination of a therapeutically effective amount may require trial and error and may require adjustment of dose and / or dosage regimen. Such treatment optimization and adjustment is encompassed by the methods encompassed herein.

The term "pharmaceutically acceptable" as used herein in connection with a compound or composition refers to the ability of a compound or composition to increase or enhance the solubility or utilization of a compound in a subject to promote or enhance the bioavailability of the compound or composition. Quot; In one aspect, the disclosure herein also encompasses pharmaceutically acceptable hydrates, solvates, stereoisomers, or amorphous solids of the compounds and compositions embodied herein.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterials, Antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavors, dyes, (See, for example, Remington ' s Pharmaceutical Sciences, 1990, which is incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient or method of use, its use in pharmaceutical compositions is contemplated.

The percentages set forth herein are, unless otherwise indicated, (w / w) with respect to the specified components in the overall composition. For example, a composition comprising 1% PVP-1 and 99% DMSO has 1 wt% PVP-I for the total composition.

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

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

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

In one embodiment, the composition comprises about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5% , 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% 15.0% PVP-I. In one embodiment, the composition may comprise from 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% I, PVP-I, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 5%, 7.5%, 10.0%, 12.5%, or 15%. In another embodiment, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% I. In yet another embodiment, the composition comprises less than about 0.1%, less than about 0.5%, less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5% , Up to about 8%, up to about 9%, or up to about 10% PVP-I. In another embodiment, the composition comprises at least about 0.01%, at least about 0.05%, at least about 0.075%, 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 0.7 percent, at least about 0.8 percent, at least about 0.9 percent, at least about 1 percent, at least about 2 percent, at least about 3 percent, at least about 4 percent, at least about 5 percent, at least about 6 percent, , At least about 8%, at least about 9%, or at least about 10% PVP-I. In yet another embodiment, the composition may comprise from 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% or 10.0% PVP-I.

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

In one embodiment, anhydrous DMSO is used in the composition. In one embodiment, substantially anhydrous DMSO is used in the composition. It will be understood by one of ordinary skill in the art that DMSO can be made and / or obtained in different grades, and one of the variables between the different grades of DMSO formulation is the water content. By way of example, DMSO can be completely anhydrous (also referred to herein also simply as "anhydrous"), substantially anhydrous, or can contain measurable water. It will be appreciated that the amount of water measurable in a DMSO formulation can vary depending on the limitations of the equipment and techniques used to perform such measurements. In one embodiment, the DMSO, which is not completely anhydrous, can be substantially anhydrous and can contain water at levels below the detection sensitivity level. In one embodiment, the DMSO, which is not fully anhydrous, may contain water wherein the water content 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% About 0.07%, about 0.09%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6% , At least about 0.5%, 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% %, Or more. In one embodiment, the DMSO, which is not completely anhydrous, may contain water wherein the water content is less than 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 0.8%, 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%, less than about 5%, less than about 7.5% , Or more. It will be understood that DMSO may contain one or more other impurities besides water.

In one embodiment, the composition comprises an iodophore, a penetrant, and further comprises water. In one embodiment, the composition comprises anhydrous iodophor and / or anhydrous penetrants and further comprises water. In one embodiment, the composition comprises PVP-I, DMSO, and further comprises water. In one embodiment, the composition comprises an iodoform and a penetrant, and further comprises water wherein the water content 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 0.7%, 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 12.5%, or more. Wherein the water content is less than about 0.01%, less than about 0.02%, less than about 0.03%, less than about 0.04%, less than about 0.05% water, , 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 0.7%, 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%, less than about 5%, less than about 7.5% , Less than about 12.5%, or more. In one embodiment, the composition comprises iodoform and a penetrator and further comprises water wherein the water content is from about 0.01% to about 12.5%, from about 0.02% to about 10.0%, from about 0.03% to about 7.5% , From about 0.04% to about 5%, from about 0.05% to about 2.5%, from about 0.06% to about 2%, from about 0.07% to about 1.5%, from about 0.08% to about 1%, from about 0.09% 0.1% to about 0.8%, or about 0.2% to about 0.7%. In one aspect, water may be derived from the components of the composition. In another aspect, water may be added to the composition in particular.

In one embodiment, the composition comprises at least one of the following United States Pharmacopeia Committee (USP) grade DMSO, active pharmaceutical ingredient (API) grade DMSO, assay grade DMSO and American Chemical Society (ACS) spectrophotometric grade DMSO. In one embodiment, the composition comprises DMSO with < 0.1% water by KF titration and > 99.9% DMSO determined on anhydrous basis.

As indicated above, the percent amount of DMSO in the composition is described as weight to weight (w / w) ratio for one or more other components of the composition, unless otherwise indicated. In one embodiment, the weight percent DMSO is the remaining weight percent after addition of PVP-I. As a non-limiting example, the composition may comprise 1 weight percent (1%) PVP-1 and 99 weight percent (99%) DMSO. In this example, the DMSO component of the composition will be understood to be fully anhydrous, substantially anhydrous, or may contain water to a measurable degree. In one embodiment, the weight percent DMSO is the remaining weight percent after addition of PVP-I and any other component (e.g., co-solvent, water, additional active ingredient, etc.). In one embodiment, the weight percent DMSO is the residual weight percent after addition of the iodophore and, if present, other components. In one embodiment, the weight percent penetrant in the composition is the remaining weight percent after addition of the iodophore and, if present, other components.

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

In one embodiment, the composition comprises DMSO, but does not include any additional solvents (e. G., Co-solvent) or penetrants. In another embodiment, the composition comprises DMSO in the range of about 0.01% to 99.99%, and further comprises at least one co-solvent in the range of 0.01% to about 99.99%. In one embodiment, the composition comprises DMSO and further comprises at least one co-solvent in the range of about 0.1% to about 50%.

In another embodiment, the composition comprises DMSO and further comprises at least one co-solvent in the range of about 5% to about 50%. In another embodiment, the composition comprises DMSO and further comprises at least one co-solvent in the range of about 10% to about 99%. In another embodiment, the composition comprises DMSO and further comprises at least one co-solvent in the range of about 20% to about 95%. In one embodiment, the composition comprises DMSO, and comprises at least one of the following ranges: from about 50% to about 60%, from about 60% to about 80%, from about 70% to about 90%, and from about 80% Co-solvent. &Lt; / RTI &gt; In one aspect, water is a co-solvent. In one embodiment, the composition comprises DMSO, water and at least one additional co-solvent.

In one embodiment, the composition comprises DMSO in the range of about 0.01% to 99.99%, and further comprises at least one penetrator in the range of 0.01% to about 99.99%. In one embodiment, the composition comprises DMSO, and further comprises at least one penetrants in the range of about 0.1% to about 50%. In another embodiment, the composition comprises DMSO and further comprises at least one penetrants in the range of about 5% to about 50%. In another embodiment, the composition comprises DMSO and further comprises at least one penetrants in the range of about 10% to about 99%. In one embodiment, the composition comprises DMSO, at least one co-solvent and at least one penetrator. In one embodiment, the co-solvent is also a penetrating agent.

In one embodiment, the composition comprises from about 0.01% to about 10% of a gelling agent. In another embodiment, the composition comprises a gelling agent in the range of 0.05% to 7.5%. In another embodiment, the composition comprises a gelling agent in the range of 0.1% to 5.0%. In another embodiment, the composition comprises a gelling agent in the range of 0.25% to 4.5%. In another embodiment, the composition comprises a gelling agent in the range of 0.5% to 4.0%. In another embodiment, the composition comprises a gelling agent in the range of 1.0% to 3.0%. In another embodiment, the composition comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3% , 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0% 4.5%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4% 4.8%, 4.9%, 5.0%, or, if desired, a gelling agent in excess. Preferred embodiments of the composition comprise less than 10% of the gelling agent.

In one embodiment, the composition is selected from the group consisting of tolnaphthate, terbinafine, undecylenic acid, clioquinol, myconazole, myconezolinate, clorinazole, thioconazole, nystatin, terconazole, , At least one antifungal agent selected from the group consisting of cyclopiroxolamine, econazole nitrate, triacetin, flucytosine, haloprofen and ketoconazole. In one embodiment, the at least one antifungal agent comprises about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5% , 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 25%, about 30%, about 40%, or about 50%. In one embodiment, the composition may comprise 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.25% At least one antifungal agent selected from the group consisting of at least one antifungal agent, at least one antifungal agent, at least one antifungal agent selected from the group consisting of: . In yet another embodiment, the composition comprises less than about 0.1%, less than about 0.5%, less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5% , Less than about 10%, less than about 20%, less than about 25%, less than about 30%, less than about 40%, or less than about 50% of at least one antifungal agent . In another embodiment, the composition comprises at least about 0.1%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5% , At least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or at least about 50% of at least one antifungal agent do. In another embodiment, the composition comprises at least one of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% At least one antifungal agent selected from the group consisting of 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 20%, 25%, 30%, 40% or 50%.

In one embodiment, as a non-limiting example, at least one of the at least one species known in the art, including 1% tolnaphthate, 10-25% undecylenic acid, 3% clioquinol and / A stable formulation of the topical antifungal component may be prepared in a DMSO solvent system, wherein PVP-I is also incorporated as a long-term preservative. These solutions exhibit remarkable long-term stability when both the PVP-I component and the antifungal component can be maintained at or above 90% of the initial concentration. Surprisingly, it has been found that no appreciable reaction occurs between the antifungal agent and PVP-I. These formulations also exhibit remarkable in vitro and in vivo efficacy as antifungal agents.

In one embodiment, where possible, the composition may comprise a pharmaceutically acceptable salt of the compound in the composition. In one embodiment, the composition comprises an acid addition salt of a compound of the present invention. In one embodiment, the composition comprises a base addition salt of a compound of the present invention. As used herein, the term pharmaceutically acceptable salts or complexes refers to those salts or complexes which retain the desired biological activity of the parent compound and which, even if exhibited, exhibit minimal undesirable toxicological effects (e. G., Solvates, Shape.

In compositions for topical administration, the mixture is preferably formulated as an aqueous solution at a pH of from 2.0 to 6.5. Preferably, the pH is adjusted to 2.5 to 4.5. This pH range can be achieved by including an acid / base suitable for the composition.

In one aspect, the composition may include one or more of an excipient, an antimicrobial agent, a preservative, a co-solvent, a surfactant, a thickener, and / or a bioadhesive as detailed elsewhere herein.

In one aspect, the pharmaceutical formulation is a partially-alcoholic formulation. As will be appreciated by those skilled in the art, inclusion of a percentage of alcohol in the formulation will assist in the availability of the component, including PVP-I. The alcohol component will also act as a dewatering component for the surface to which the formulation is applied. Alcohols useful in the present invention include, in particular, methanol, ethanol and isopropanol.

slush

In one embodiment, the composition is selected from the group consisting of propylene glycol, glycerin, polyethylene glycol, dextran, blended polyvinyl alcohols, polyvinyl alcohol, polyethylene glycol, hard mineral oil, hydroxypropyl methylcellulose, hypromellose, Polyvinylpyrrolidone, white petrolatum, soybean lecithin and sodium carboxymethylcellulose, as well as other agents known to those of ordinary skill in the relevant art, or any combination thereof, including, but not limited to, And may include one or more lubricants, including lubricants. Typically, such lubricants are used at levels of from 0.1% to 2% by weight. In one embodiment, the lubricant comprises 1.0% propylene glycol, 0.3% glycerin, 2.7% blended polyvinyl alcohols, 1% polyvinyl alcohol, 1% polyethylene glycol, hard mineral oil, 0.3% hydroxypropyl methylcellulose, 1.0% Soy lecithin, 0.25% or 0.5% sodium carboxymethyl cellulose. In another embodiment, the total weight of the PVP-I, artificial-tear based lubricant is from 0.1% to 4.5%.

Additional antimicrobials and antibiotics

Suitable antibiotic / antimicrobial agents include fluoroquinolones (ciprofloxacin, levofloxacin, oproxacin, moxifloxacin, gatifloxacin, etc.); Aminoglycosides (tobramycin, gentamicin, neomycin, etc.); (Polymegicin B / trimetoprim, polystorphin polyimicin B / bacitracin neosporin polymyxin B / neomycin / gravimycin) and other antibiotics (azithromycin, isletaxine, erythromycin , Bacitracin, and the like).

Local anesthetic

Suitable topical anesthetics for the compositions and methods of the present invention include, but are not limited to, lidocaine, tetracaine or derivatives or combinations thereof.

Anti-allergic component

The antiallergenic component may be selected from the group consisting of epinastine, emeadastin difumarate, azelastine hydrochloride, olopatadine hydrochloride, olopatadine, ketotifen fumarate, femirorast potassium, nedocromil, Cromolyn and cromolyn salts, as well as zinc acetate.

Preservative

Preservatives include, but are not limited to, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethylalcohol, EDTA, sorbic acid, Onomar M, other agents known to those of ordinary skill in the relevant art, . Typically, such preservatives are used at levels of from 0.001% to 1.0% by weight of the final composition.

Co-solvent

The compositions of the present invention may contain one or more optional co-solvents. The solubility of the components of the compositions of the present invention can be enhanced in the composition by a surfactant or other suitable co-solvent. These cosolvents / surfactants include polysorbates 20,60 and 80, polyoxyethylene / polyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and P-103), cyclodextrins, tyloxapol , Other agents known to those of ordinary skill in the relevant art, or combinations thereof. Typically, such co-solvents are used at a level of from 0.01% to 2% by weight of the final composition.

Soothing agent

In addition, the composition may comprise an effective amount of a chemical agent that provides a cooling sensation when the PVP-I solution is applied to the ear to alleviate the mild ear irritation, improve comfort, and provide a refreshing effect and improved sensation. Such agents include cooling agents such as menthol derivatives, menthol derivatives including menthol glycerin acetyl and menthyl ester, carboxamides, mentan glycerol ketals, alkyl substituted ureas, sulfonamides, terpene analogs, furanones and phosphine oxides; Or a variety of chemical and chemical classes, including, but not limited to, camphor and borneol.

Thickener

The compositions of the present invention may contain optional thickening agents, i. E. Agents capable of increasing viscosity. Increased viscosity in excess of the viscosity of a simple aqueous solution can be achieved by increasing the ear absorption of the active compound and / or by reducing the variability in the distribution of the formulation and / or by reducing the physical separation of the components of the suspension or emulsion of the formulation and / Or it may be desirable to otherwise improve the formulation for the ear. Such viscosity enhancing agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, others known to those of ordinary skill in the pertinent art Agents, or combinations thereof. Such agents are typically used at levels of from 0.01% to 2% by weight of the final composition.

Bio-adhesive

The bioadhesive may be used in the composition to increase the residence time of the drug gradient on the biological substrate. Examples of the bioadhesive include polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum, hydroxypropyl methylcellulose (HPMC), sodium alginate, pectin, gelatin, carbomer, polyvinyl alcohol, gellan gum, But are not limited to, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, and the like.

Evaluation of Formulation and Validity

In one embodiment, the methods and compositions of the present invention can reduce the progression of infectious otitis media so that no further progress is detected. Any method may be used to determine whether the severity or progression rate of the symptoms of otitis externa has been reduced. For example, a person with otitis may be questioned about pain or discomfort before or after treatment to determine if symptoms of otitis externa (e.g., ear pain or ear itching) have been reduced. In some cases, the mammal may have symptoms of otitis externa before and after treatment with a composition according to the present invention to determine whether the severity of symptoms has been reduced (e. G., Ear secretions, ear sensitivity to pressure, Sensitivity or reduced hearing) of the patient. In some cases, the ENT can assess the severity of otitis externa before and after treatment to determine if the severity of symptoms has been reduced (e. G., By performing a physical examination and comparing it to a grade 1 To 4). To determine whether progression of otitis externa has been reduced, a physical examination may be performed to determine the amount of erythema and / or edema in and around the tooth at different times. The rate of progress can be assessed by comparing the amount of erythema and edema observed at different times. After treatment as described herein, the rate of progress over another time interval can again be determined to determine if the rate of progress has decreased.

Thus, an effective amount of a composition of the invention, including PVP-I and DMSO, will be understood to be any amount that reduces the severity or progression of symptoms of otitis externa without causing significant toxicity to the mammal. For example, an effective amount of PVP-I may be about 0.1% to about 10% (e.g., about 2%) povidone-iodine in the liquid formulation for the ear. In one embodiment, an effective amount of a composition comprising PVP-I and DMSO is from about 2% to about 2% povidone-iodine applied to the ear, and from about 2% It can be about 8 drops.

If the mammal does not appear to be responsive to the particular amount of the composition of the present invention, for example, the amount of at least one of PVP-I and DMSO may be increased. After receiving this higher concentration, the mammal can be monitored for both responsiveness to treatment and toxic symptoms, and adjustments can be made accordingly. An effective amount can be kept constant depending on the response of the mammal to treatment or can be adjusted as a sliding scale or variable capacity. Various factors can affect the actual effective amount used for a particular application. For example, the frequency of administration, the duration of treatment, the use of multiple therapeutic agents, the route of administration, the immunogenicity of the mammal, and the severity of otitis externa may require an increase or decrease in the actual effective amount administered. The frequency of administration may be any frequency that reduces the severity or rate of progression of symptoms of otitis externa without causing significant toxicity to the mammal. For example, the frequency of administration may be from about once a day to about four times a day (e.g., about twice a day). The frequency of administration can be kept constant for the duration of the treatment or can be variable.

In yet another aspect, the treatment process with the composition of the present invention may comprise a cancellation period. For example, the composition may be administered over a period of 1 or 2 weeks followed by a 1 or 2 week withdrawal period, and such therapy may be repeated a number of times. As with effective amounts, various factors can affect the actual dosage frequency used for a particular application. For example, an effective amount, a duration of treatment, the use of multiple therapeutic agents, the route of administration, the immunological fitness of the mammal, and the severity of otitis externa may require an increase or decrease in the frequency of administration. An effective duration for administering the compositions provided herein may be any duration that reduces the severity or rate of progression of symptoms of otitis externa without causing significant toxicity to the mammal. Thus, an effective duration may vary from days to weeks, months, or years. In general, the effective duration for treatment of otitis externa may range from a few days to several weeks. In some cases, the effective duration may be as long as the individual mammal is alive. Many factors can affect the actual effective duration that is used for a particular treatment. For example, the effective duration may vary depending upon the frequency of administration, the effective amount, the use of multiple therapeutic agents, the route of administration, the immunological suitability of the mammal, and the severity of the otitis externa.

The diagnostic and therapeutic considerations may be applied in a similar manner to the treatment of otitis and otitis media.

Manufacturing and use

It is known to those skilled in the art that PVP-I aqueous solutions are difficult to stabilize over a long period of time at low PVP-I concentrations. As a non-limiting example, at a PVP-I concentration of less than about 0.7% (w / w, aqueous), the PVP-I aqueous solution rapidly degrades to form a complex mixture of iodinated and iodine- . Surprisingly, as described herein, it has been found that in a non-protic DMSO solvent system encompassed by the disclosure set forth herein, a PVP-I solution as low as 0.1% is readily prepared and can be maintained as a stable composition for a long period of time . Also as described herein, the hydrated DMSO solution prepared from aqueous PVP-I exhibits increased stability noted for the PVP-I component.

In one embodiment, the composition comprises dry, solid or powdered PVP-I dissolved or suspended in a composition comprising DMSO or consisting of DMSO. In another embodiment, DMSO is added to an aqueous formulation comprising PVP-I or consisting of PVP-I. Based on the teachings of the present disclosure, one of ordinary skill in the art will understand how to make a composition to achieve the desired amount of iodine, iodophor and DMSO, among other possible components of the compositions encompassed herein will be.

As a non-limiting example, therapeutically effective pharmaceutical compositions are prepared by dissolving or suspending solid PVP-I in DMSO. In one aspect, the composition is anhydrous. In one aspect, the composition is substantially anhydrous. In another embodiment, DMSO may be added to an aqueous solution of PVP-I to produce a therapeutically effective pharmaceutical composition. In one embodiment, DMSO is used in the range of 50% -99% with water as co-solvent. In one embodiment, the formulations comprise one or more excipients. As a non-limiting example, excipients include, but are not limited to, sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous dibasic sodium phosphate and water, as well as others known to those of ordinary skill in the relevant art.

In one embodiment, the composition is prepared by adding 10% PVP-I (w / v, aqueous) to a sufficient amount of pure DMSO, thereby producing a solution of 1% PVP-I (w / w) do. In another embodiment, the composition is prepared by dissolving solid PVP-I in a sufficient amount of pure DMSO to form a solution containing 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, 1.25%, 1.5% %, 2.0% or 2.5% PVP-I (w / w), as well as about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1.0%, about 1.25% About 2.0% or about 2.5% PVP-I (w / w) composition. In another embodiment, the composition is prepared by dissolving solid PVP-I in a sufficient amount of pure DMSO to obtain any composition presented, described and / or encompassed herein. A similar composition comprising aqueous PVP-I (with and without excipients conventionally used and / or well known in the art) and DMSO may be prepared from a stock solution of 10% PVP-I and pure DMSO. However, it will be understood by those of ordinary skill in the art that any starting composition of PVP-I, either solid or liquid, can be used, provided that appropriate dilution and adjustment are made that result in the desired final PVP-I concentration. Likewise, any suitable starting composition of iodophors or elemental iodine may be used provided that appropriate dilution and adjustment are made to result in the desired final iodophore or elemental iodine concentration, respectively.

In one embodiment, it is particularly useful that, in the case of dye transfer, a stable anhydrous composition containing 0.01% -10% PVP-I can be prepared in pure USP grade DMSO solvent.

Based on the disclosures set forth herein, given the skill in the relevant art, specific dosages for the compounds and compositions encompassed herein can be determined empirically through clinical and / or pharmacokinetic experiments, May be adjusted according to predetermined efficacy and / or toxicity criteria. In addition, the specific dose and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the characteristics of the patient, the combination of drugs, the judgment of the treating physician and the nature and severity of the particular disease or condition being treated Will be influenced.

In one embodiment, the compositions presented, described and / or encompassed herein are useful in the treatment of, but not limited to, infections of the nail, nasal mucus, warts, infectious contiguous species, non- genital herpes, scarring, It is useful for the treatment of one or more of the dry nail dystrophy and the foot ringworm. In one embodiment, the composition comprises PVP-I and DMSO. In one embodiment, the composition consists essentially of PVP-I and DMSO. In one embodiment, the composition comprises PVP-I and DMSO.

In one embodiment, the therapeutic compositions are prepared by optimizing one or more compounds for use in dosage forms that are typically used for the compounds. In one embodiment, compounds that are not typically administered in topical dosage forms are developed for use in topical dosage forms. The chemical and biological assays required for such development are known to those of ordinary skill in the relevant art. The disclosure herein provides guidance to those of ordinary skill in the art about methods of making such compounds and compositions comprising such compounds.

In one embodiment, a method of treating a subject having a mucus comprises administering a composition as provided, described, and / or encompassed herein, wherein the treatment of the mucus includes preventing or delaying progression of the infection, Preventing the spread of the infection, at least partially eradicating the infection, and completely eradicating the infection.

In one embodiment, the therapeutic composition is administered on a schedule of once a day. In one embodiment, the therapeutic composition is administered twice daily. In one embodiment, the therapeutic composition is administered three times a day, four times a day, five times a day, or more. In one embodiment, the therapeutic composition is administered less frequently than once a day. In one embodiment, the therapeutic compositions are 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 embodiment, the therapeutic composition is administered less frequently than once a week. In one embodiment, the therapeutic composition is administered once a month. In one embodiment, the therapeutic composition is administered twice a month.

In one embodiment, the therapeutic dose regimen is continued 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 embodiment, the therapeutic dosage regimen is administered 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 It continues. In one embodiment, the therapeutic dose regimen is continued 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.

The present invention is further described by the following examples. In one aspect, the following examples demonstrate effective and / or successful treatment using compositions and methods encompassed by this disclosure of identified conditions. It is to be appreciated that variations based on the features of the present invention are within the skill of the ordinary artisan and the scope of the present invention should not be limited by the embodiments. In order to properly determine the scope of the present invention, stakeholders should consider the claims of the present application and any equivalents thereof. In addition, all citations herein are incorporated by reference and unless otherwise specifically stated, all percentages are by weight.

Example 1

Acute otolaryngitis in children treated with 2% povidone-iodine gel

The patient had acute otitis externa. The condition is often very painful due to the extreme irritation that occurs when the child moves or moves his head. A thick gel was formed with a composition as described herein using 2.0% PVP-I in 44% USP grade DMSO with water and 2% hydroxyethylcellulose (HEC). Patients were treated by applying the gel to the ear canal twice daily, topically. The infection was resolved within 4 days and the patient had no pain.

Example 2

Acute otolaryngitis in children treated with high viscosity 2% povidone-iodine gel

The patient had acute otitis externa. The condition is often very painful due to the extreme irritation that occurs when the child moves or moves his head. A viscous gel having a viscosity of greater than 300,000 cps was formed with a composition as disclosed herein using 2.0% PVP-I in 44% USP grade DMSO with water and 4% hydroxyethylcellulose (HEC). The patient was treated by topically applying the gel once a day to the external auditory canal. Within 2 days the infection was resolved and the patient was not painful.

It will be appreciated by those skilled in the art that changes may be made in the exemplary embodiments described and illustrated without departing from the broad inventive concept thereof. Accordingly, the disclosure is not intended to be limited to the exemplary embodiments shown and described, but is intended to cover modifications within the spirit and scope of the invention as defined by the claims. For example, the specific features of the exemplary embodiments may or may not be part of the claimed invention, and the features of the disclosed embodiments may be combined. Unless specifically stated herein, a singular term is not to be construed as an integral part, and should be construed to mean "at least one. &Quot;

Although at least some of the description of the present invention has been simplified for focusing on related elements for a clear understanding of the present invention, it will be appreciated that eliminating other elements to be appreciated by one of ordinary skill in the art for clarity also constitutes a part of the present invention It should be understood that it can be done. However, these elements are well known in the related art, and because they are not intended to be a better understanding of the present invention, a description of such elements is not provided herein.

In addition, the particular order of steps should not be construed as a limitation on the claims, insofar as the methods are not dependent upon the particular order of steps set forth herein.

It should be understood that the claims relating to the method of the present invention should not be limited to the performance of its steps in the order described, and those skilled in the art will readily recognize that the steps may vary and still remain within the spirit and scope of the present invention. can do.

Claims (14)

A composition for the ear comprising 0.1% -10% w / w povidone-iodine and 30% -99% w / w DMSO and at least one ear-tolerant excipient. 2. The composition of claim 1 comprising a gelling agent. The composition of claim 2 wherein the gelling agent is selected from hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methylcellulose. 7. The composition of claim 1 comprising PEG. 2. The composition of claim 1 comprising petrolatum. The composition of claim 1, wherein the composition is steroid-free. A method for preventing or treating ear infections or infestations comprising:
- applying or administering the composition of claim 1
&Lt; / RTI &gt; 7. The method of claim 6, wherein the ear infection or intrusion 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 infestation is a bacterial infection. 7. The method of claim 6, wherein the ear infection or intrusion is a fungal infection. 7. The method of claim 6, wherein the ear infection or intrusion is an amoeba infection or an intrusion. 8. The method of claim 7 wherein the composition of claim 1 is steroid-free.