WO2009024964A2

WO2009024964A2 - Composition and method for the treatment of otitis externa

Info

Publication number: WO2009024964A2
Application number: PCT/IL2008/001107
Authority: WO
Inventors: Nitsan Primor; Eran Eilat
Original assignee: Nitsan Primor; Eran Eilat
Priority date: 2007-08-22
Filing date: 2008-08-12
Publication date: 2009-02-26
Also published as: WO2009024964A3

Abstract

The present invention relates to compositions and method for preventing and/or treating otitis externa, including the condition known as 'swimmer's ear'. Particularly, the compositions of the invention are highly effective in removing water from the outer ear canal and in treating the symptoms of otitis externa, particularly when applied as a spray.

Description

COMPOSITION AND METHOD FOR THE TREATMENT OF OTITIS

EXTERNA

FHCLD OF THE INVENTION The present invention relates to compositions and methods for preventing and/or treating otitis externa. Particularly, the compositions of the invention are highly effective in removing water from the outer ear canal and in protecting the ear from infection.

BACKGROUND OF THE INVENTION

Exposure to excess moisture can cause several types of skin problems. The outer ear canal, also known as the external auditory canal, is lined with epithelium, and is susceptible to the same types of diseases that affect skin in other parts of the mammalian body including, for example, eczema and psoriasis. The external ear canal is a closed pouch with an inner lining of stratified squamous epithelium, but the thickness of the epithelial barrier is not uniform. Toward the outer third of the ear, the lining is thick and supported by a base of cartilage. This is the location for hair follicles and the glands that secrete a waxy exudate known as cerumen having a protective function against damage to the outer ear canal. In the inner two thirds of the canal, the epithelium is much thinner and rests on periostial bone.

Otitis externa (also known as "swimmer's ear") is an inflammatory process of the external auditory canal. The unique structure of the external auditory canal contributes to the development of otitis externa, in that it provides a warm, dark and potentially moist environment conducive to bacterial and fungal growth. Further, the canal is easily traumatized and the exit of debris, secretions and foreign bodies is impeded by a curve at the junction of the cartilage and bone. The presence of hair, especially the thicker hair common in older men, can be a further impediment. The external auditory canal has some special defenses, most notably cerumen which creates an acidic coat containing lysozymes and other substances that probably inhibit bacterial and fungal growth. The lipid-rich cerumen is also hydrophobic and prevents water from penetrating to the skin and causing maceration. Too little cerumen can predispose the ear canal to infection, but excessive or overly viscous cerumen can lead to obstruction, retention of water and debris, and infection. Additionally, the canal is defended by epithelial migration that occurs from the tympanic membrane outward, carrying any debris with it.

When these defenses fail or when the epithelium of the external auditory canal is damaged, it results in otitis externa. There are many precipitants of this infection, but the most common is excessive moisture that elevates the pH and removes the cerumen. Once the protective cerumen is removed, keratin debris absorbs the water, which creates a nourishing medium for bacterial growth.

When water enters the ear canal (external acoustic meatus) during bathing, showering or swimming, it usually drains spontaneously as a result of routine movements of the head. Residual water evaporates quickly since body temperature keeps the ear canal warm. However, in a high percentage of the population some activities may result in trapping of water within the ear canal. When a certain amount of moisture is trapped for a sufficient period of time, it promotes maceration and destruction of the thinner epithelium of the inner otic canal. Chlorine, which accelerates keratin degradation, increases the risk of swimmer's ear due to swimming in a pool as opposed to swimming in lakes, ponds, or the ocean.

Bacterial growth most commonly causes otitis externa infection, although fungal overgrowth is a principle cause in about 10% of the cases, and viral infection may also occur. Similar to skin, the external auditory canal has a normal bacterial flora and remains free of infection unless its defenses are disrupted. When disruption occurs, a new pathogenic flora develops that is dominated by the pathogenic bacteria Pseudomonas aeruginosa and Staphylococcus aureus. The most common fungal pathogens arc Aspergillus (80 to 90 percent of cases), followed by Candida. Classically, fungal infection is the result of prolonged treatment of bacterial otitis externa that alters the flora of the ear canal. Mixed bacterial and fungal infections are thus common. However, fungus is occasionally the primary pathogen in otitis externa, especially in the presence of excessive moisture or heat. Non-microbial antigenic material is causative of another form of otitis externa, specifically allergic otitis externa, and non-infectious dermatological processes can also cause the disease. The presence of water in the ear canal not only provides the moisture required for bacterial and fungal growth, but it also causes alkalization of the normally acidic epithelial lining of the external auditory canal, such alkalization being an additional growth-promoting factor.

Swimmer's ear is characterized by diffuse inflammation of the external auditory canal wall skin and may involve the auricle. The two most characteristic presenting symptoms of otitis externa are otalgia (ear pain and discomfort) and otorrhea (discharge in or coming from the external auditory canal).

Discomfort caused by otitis externa ranges from a slight itch to severe pain that is exacerbated by motion of the ear, including chewing. In severe cases temporary deafness or impaired hearing may occur as swelling and discharge physically closes off the ear canal and prevents conduction of ambient sound to the ear drum.

The signs and symptoms of otitis externa with a bacterial etiology tend to be more intense than in other forms of the disease. Otalgia may be severe enough to require systemic analgesics such as codeine and nonsteroidal anti-inflammatory drugs. Significant swelling of the canal is common. Fever may be present and the post-auricler and upper cervical lymph nodes may be enlarged. Occasionally, otitis externa may even simulate acute mastoiditis. Otitis externa may develop into a persistent low-grade infection and inflammation. In these cases, the external auditory canal lacks cerumen and is lined by dry, hypertrophic skin with variable swelling and stenosis.

Otitis externa is typically a localized process that can be easily controlled with topical agents, yet systemic medications are sometimes required. . If otitis externa is not optimally treated, especially in immunocompromised patients, the potentially life- threatening infection can spread to the surrounding tissues. Commercial ear drop products aiming at drying of water-clogged ears consist of isopropyl alcohol 95% in an anhydrous glycerin 5% base, and are approved by the US Food and Drug Administration for "over the counter" (OTC) use (http://www.fda.gov/ohrms/dockets/98fr/081 OOOa.txt).

U.S. Patent Nos. 4,073,937 and 4,278,664 disclose a preventive treatment for otitis externa and for eliminating the discomfort of water remaining in the external canal, which comprises applying to the skin surface of the external auditory canal a pharmaceutically safe, liquid, nonionic, substantially water insoluble, aqueous surface tension reducing agent.

Compositions for treating otitis externa after the condition has occurred, typically include agents with antimicrobial and anti-inflammatory activity. Topical otic suspensions may contain broad spectrum anti-bacterial agents such as neomycin sulfate, colistin sulfate, polymyxin B, or combinations thereof. Anti-mycotic agents, such as nystatin and clotrimazole have been employed to destroy underlying fungal disease. In addition, the acyclovir has been utilized to treat viral based otits externa including herpes zoster.

Anti-inflammatory agents, mainly steroids such as hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate, are often combined with such antimicrobial agents in otic suspensions. In order to enhance delivery of such medications to the epithelial lining of the outer ear canal, wicks, comprised of absorbent material such as, for example, cotton, may be utilized.

U.S. Patent Nos. 6,509, 327 and 6,740,664 disclose topical ophthalmic, otic and nasal compositions containing antibiotics such as moxifioxacin), and one or more antiinflammatory agents. The compositions may reportedly be utilized to treat acute otitis externa infections attributable to one or both of Microbacterium otitidis and Microbacterium alconae.

U.S. Application Publication No. 2004/0126414 relates to methods of treating or preventing ear infections by topically administering a rifamycin compound.

International Application Publication No. WO/2005032528 discloses a method of treating otitis externa, particularly of fungal etiology, by topical application of known antifungal agents.

U.S. Patent No. 7,064,132 discloses a compound, process and method for increasing external auditory canal potency while simultaneously preventing the occurrence of otitis externa, wherein an aerosolized mixture of lipid crystals comprising a mixture of one or more lipids surfactants and one or more spreading agents in powder form, and one or more fluorocarbon propellants is administered directly to the external auditory canal so as to form a barrier against exogenous water. Current methods for management of otitis externa are mainly directed to mechanically removing water after swimming and treating infection and/or inflammation after the condition has occurred. There is a recognized need for convenient, effective, and non-prescription medications for preventing and treating otitis externa. SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition combining several ingredients with different modes of activities effective in preventing and/or treating otitis externa. Particularly, the composition of the present invention is formulated to remove excess water and moisture from the ear canal, to disinfect the ear canal, and to protect and sooth irritated skin of the affected ear. Furthermore, the composition of the present invention is formulated for easy and efficient application, particularly via spray application. The present invention is based in part on the unexpected discovery that combining an agent that causes rapid evaporation of water and moisture from the ear canal with therapeutically effective agents provides a means for preventing and reducing the risk of developing swimmer's ear. The invention also provides effective treatment of otitis externa if it occurs. Without wishing to be bound by any particular theory or mechanism of action the efficacy of the subject compositions may be attributed to the unique combination which provides uniform coating of the ear canal and thus quick and efficient delivery of each of the active components to the affected ear.

According to one aspect, the present invention provides a pharmaceutical composition for preventing or treating otitis externa, comprising (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin- panthenol; and (iii) a pharmaceutically acceptable disinfecting agent, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In one embodiment, the moisture-evaporating agent is selected from the group consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol. In one embodiment, the moisture-evaporating agent is present in the composition in an amount from about 80% to about 95% (w/w). In particular embodiments, the moisture-evaporating agent is isopropyl alcohol, and is present in the composition in an amount from about 80% to about 95% (w/w). In particular embodiments, the disinfecting agent is present in the composition in an amount from about 0.1% to about 1.5% (w/w). In one embodiment, the disinfecting agent is boric acid. According to certain embodiments, the boric acid is present in the composition in an amount from about 0.1% to about 1.5% (w/w), typically 1.0% (w/w).

Allantoin-panthenol has anti-inflammatory, soothing, healing and moisturizing properties. It is highly effective, and thus may be used at low concentrations. According to certain embodiments, the allantoin-panthenol is present in the composition in an amount from about 0.1% to about 5% (w/w). According to a particular embodiment, the allantoin-panthenol is present in the composition in an amount of about 0.5% (w/w).

According to certain embodiments, the composition of the present invention further comprises glycerin. According to particular embodiments, the glycerin is present in the composition in an amount from about 2% to about 15% (w/w), typically about 5% (w/w).

The composition of the present invention may further comprise at least one additional active agent selected from the group consisting of an additional antiinflammatory agent, an anti-bacterial agent, an anti-fungal agent, an anti-viral agent, and combinations thereof. The additional anti-inflammatory agent may be a herbal anti-inflammatory agent, a steroid or a non-steroidal anti-inflammatory drug. Herbal anti-inflammatory agents include for example cat's claw; rosemary; chamomile, ginseng and arnica. Steroids include for example hydrocortisone, hydrocortisone acetate, dexamethasone sodium phosphate, betamethasone valerate, betamethasone propionate and triamcinolone. Non- steroidal anti-inflammatory drugs include for example an oxican, a salicylate, an acetic acid derivative, a fenamate, a propionic acid derivative, a pyrazole, a substituted phenyl compound and a 2-naphthyl containing compound. The additional anti-inflammatory agent may comprise combinations of any of the aforementioned.

Examples of anti-bacterial agents include, but are not limited to neomycin sulfate, colistin sulfate, polymyxin B, mupirocin, chloramphenicol or combinations thereof. Anti-mycotic agents include, for example nystatin and clotrimazole. Anti-viral agents include, for example acyclovir.

According to osome embodiments, the pharmaceutical composition further comprises at least one agent selected from the group consisting of a preservative, a thickener, a dispersing agent, an emulsifier, a colorant and a fragrant oil. According to one embodiment, the fragrant oil is rose oil. The compositions of the present invention can be formulated for topical application to the external ear canal as is known in the art. Formulation can be in the form of a liquid, a solution, a suspension, an ointment, a lotion, a cream, a tincture, a paste, an anhydrous or aqueous gel and a powder. According to certain embodiments, the composition of the present invention is formulated as a solution or suspension that can be administered to the ear as a spray.

In a particular embodiment, the composition of the present invention comprises:

(i) isopropyl alcohol in an amount of about 80% to about 95% (w/w); (ii) allantoin-panthenol in an amount of about 0.1% to about 5%

(w/w); and

(iii) boric acid in an amount of about 0.1 % to about 1.5% (w/w). In another particular embodiment, the composition further comprises: (iv) glycerin in an amount of about 2% to about 15% (w/w). In a further particular embodiment, the composition further comprises:

(v) rose oil at an amount of about 0.01% to about 0.1. (w/w).

In a currently preferred embodiment, the composition of the present invention comprises:

(i) isopropyl alcohol in an amount of about 93.45% (w/w); (ii) allantoin-panthenol in an amount of about 0.5% (w/w);

(iii) boric acid in an amount of about 1% (w/w);

(iv) glycerin in an amount of about 5% (w/w), and .

(v) rose oil in an amount of about 0.05% (w/w).

In another embodiment, the composition consists essentially of: (i) isopropyl alcohol in an amount of about 93.45% (w/w);

(ii) allantoin-panthenol in an amount of about 0.5% (w/w);

(iii) boric acid in an amount of about 1% (w/w); (iv) glycerin in an amount of about 5% (w/w), and (v) rose oil in an amount of about 0.05% (w/w).

In a particular embodiment, a device for the administration of the pharmaceutical composition of the invention in the form of a spray comprises said pharmaceutical composition in a form selected from the group consisting of a liquid, a solution and a suspension, and a spray dispenser for containing the pharmaceutical composition, hi a particular embodiment, the spray dispenser is selected from an aerosol spray dispenser and a pump-type spray dispenser. In a particular embodiment, the aerosol spray dispenser further comprises an aerosol propellant. hi a particular embodiment, the spray dispenser is a metered dose spray dispenser.

According to another aspect, the present invention provides a method for preventing and/or treating otitis externa in a subject in need thereof, the method comprising topically administering to the ear canal of the subject a therapeutically effective amount of the composition according to the present invention, thereby preventing and/or treating otitis externa.

In a particular embodiment, the composition is administered in a form selected from the group consisting of an ointment, a gel, drops, a liquid and a spray, hi a particular embodiment, the composition is administered in the form of a spray. In a particular embodiment, the administrating is carried out using a spray dispenser, hi a particular embodiment, the spray dispenser is selected from an aerosol spray dispenser and a pump-type spray dispenser. In a particular embodiment, the aerosol spray dispenser further comprises an aerosol propellant. In a particular embodiment, the spray dispenser is a metered dose spray dispenser.

In a particular embodiment, the administering is carried out following an activity selected from the group consisting of bathing, immersion in a ritual bath and participation in an aquatic sport. In a particular embodiment, the administering is carried out following participation in an aquatic sport. In a particular embodiment, the aquatic sport is selected from the group consisting of pool swimming, synchronized swimming, underwater swimming, deep sea diving, scuba diving, water polo and combinations thereof. hi a particular embodiment, the administering is carried out one to three times a day for a period of 2 to 21 days, hi a particular embodiment, the administering is carried out twice a day for a period of 7 days. In a particular embodiment, an effective amount comprises about 0.1 to 1 ml. In a particular embodiment, an effective amount comprises about 0.8 ml.

According to another aspect, the present invention provides a use of (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin- panthenol; (iii) a pharmaceutically acceptable disinfecting agent, and at least one pharmaceutically acceptable excipient, diluent or carrier for the preparation of a medicament for preventing and/or treating otitis externa in a subject in need thereof, wherein the medicament is topically administered to the ear canal of the subject. According to another aspect, the present invention provides a topical composition comprising (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin-panthenol; (iii) a pharmaceutically acceptable. disinfecting agent, and at least one pharmaceutically acceptable excipient, diluent or carrier for the prevention and/or treatment of otitis externa. In particular embodiments, the composition further comprises glycerin.

Particular embodiments of the disclosed components are as hereinbefore described.

Other objects, features and advantages of the present invention will become clear from the following description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions and methods for preventing and/or treating otitis externa, also known as "swimmer's ear". The present invention provides a composition formulated for topical administration to the external ear canal, particularly as a spray. The subject compositions and methods combine agents that cause rapid evaporation of moisture from the ear canal with therapeutically effective agents for treating inflammation, skin degradation and infection associated with otitis externa.

Definitions

As used herein, the singular forms "a", "an" and "the" include plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "an antiinflammatory agent" includes combinations of anti-inflammatory agents, and so on. As used herein, the term "moisture evaporating agent" refers to a compound which enhances the evaporation of water at the temperature present in the ear canal, which is close to that of the core body temperature.

As used herein, the terms "anti-inflammatory agent", "soothing agent", and "healing agent" are used interchangeably referring to a pharmaceutical ingredient that reduces, diminishes or eliminates one or more symptoms of inflammation, including but not limited to swelling, pain, redness, itching, heat and tenderness.

As used herein, the term "additional anti-inflammatory agent" refers to an antiinflammatory agent other than allantoin-panthenol. As used herein the term "pharmaceutically acceptable disinfecting agent" refers to a compound capable of inhibiting the growth of any of bacteria, fungi and viruses. The disinfecting agent is also capable of buffering the pH at the ear canal to the range of from about 4.5 to about 6.0, when present at an amount of no more than 1.5% w/w. The disinfecting agent is non-irritating to the skin and has no adverse effects. As used herein, a "subject in need thereof refers to a subject who is at risk of, susceptible to and/or exhibits at least one clinical sign or symptom of otitis externa.

It is to be noted that unless otherwise specified, percentages stated herein are in relation to the final weight of the total composition. It is further to be noted that all numerical values stated herein include a range of standard deviations that is acceptable in the pharmaceutical arts, and appropriate for any particular component.

Otitis Externa

The primary etiologic factors in the occurrence of swimmer's ear are excessive moisture, duration of exposure to the moisture, infection and temperature. When sufficient moisture is trapped in the ear for a sufficient period of time, swimmer's ear is almost a certainty. Sustained exposure to moisture allows maceration and destruction of the thinner epithelium of the inner otic canal. When sports and other activities occur in contaminated water (e.g., pools, ponds, lakes, ritual baths), microorganisms enter the ear. However, this does not invariably lead to swimmer's ear because retention leading to maceration must also occur, as previously mentioned. Once protective keratin cells are lost or damaged, underlying living cells are susceptible to attack by pathogens. Finally, the temperature of the ear canal is close to that of core body temperature, and is conducive to the rapid growth of microorganisms. Minor injury may also be a contributing factor in otitis externa. The onset of swimmer's ear is generally associated with inflammation and pruritus of the otic canal. Attempts to relieve itching through scratching with the fingernails or a rigid object can further abrade tissues and exacerbate infection. The risk of swimmer's ear is increased in individuals having a condition that leads to moisture retention in the ear canal, such as tortuous or abnormally narrow canals, or bony growths that partially occlude the canal lumen. Scales produced in the ear canal due to a dermatosis can retard moisture evaporation and enhance retention. Such skin conditions include seborrheic dermatitis, psoriasis, eczema, contact dermatitis, or neurodermatitis. If a partial cerumen impaction is present, water may become trapped between the impaction and the tympanic membrane. Upon exposure to water, the impaction may absorb moisture and expand, completely occluding the otic canal.

Changes in otic pH may increase the risk of swimmer's ear. The normal pH is 4-5, which helps to inhibit the growth of microorganisms. However, if the pH changes from acidic to basic, for example due to the presence of debris or exposure to soap, the ear loses this natural protection. Misguided otic cleaning efforts can also lead to swimmer's ear, due to disruption of the normal self-cleaning mechanism of the ear.

Symptoms of swimmer's ear may occur shortly after an aquatic activity or several days later, and include a full and wet sensation in the ear, otalgia (ear pain and discomfort), otorrhea (exudates in the ear canal which may vary in consistency), pruritus, swelling, dermatitis on the facial area proximal to the ear opening, partial hearing loss, fever and lymphadenopathy.

Components of the Composition The present invention provides a composition designed to address all the causative factors described above, and thus provide full protection against otitis externa.

The composition of the invention comprises (i) at least one moisture-evaporating agent; (ii) at least one anti-inflammatory, soothing agent, which is allantoin-panthenol; and (iii) at least one pharmaceutically acceptable disinfecting agent. The moisture-evaporating agent is suitably an alcohol such as methyl alcohol, ethyl alcohol or isopropyl alcohol, hi one embodiment, the moisture-evaporating agent is isopropyl alcohol. In one embodiment, the moisture-evaporating agent is present in the composition in an amount from about 80% to about 95% (w/w).

The moisture-evaporating agent should be such that the attraction between the molecules thereof is not as strong as that between water molecules. Accordingly, the moisture-evaporating agent will evaporate faster than water. The moisture-evaporating agent should have a very low specific gravity rate. When the moisture-evaporating agent mixes with water or moisture trapped in the external ear canal, it lowers the specific gravity of the trapped water, increases the distance between the water molecules, and thus eases and speeds its evaporation out of the ear

For example, when the composition of the invention, comprising for example isopropyl alcohol as the moisture-evaporating agent, is sprayed into to the external ear canal, the isopropyl alcohol molecules mix with water molecules within the ear, weaken the attraction between the molecules and enhance the evaporation of both water and isopropyl alcohol.

According to a particular embodiment, the composition comprises isopropyl alcohol in an amount from about 80% to about 95% (w/w). This amount, particularly when the composition is administered as a spray as detailed herein below accomplishes the full evaporation of water and moisture within 3-4 minutes after application.

The moisture-evaporating agent may additionally or alternately be a volatile silicone compound, for example cyclomethicone, or a volatile silicone substitute, for example isohexyl decanoate, octyl isononanoate, isononyl octanoate or diethylene glycol dioctanoate.

The composition comprises allantoin-panthenol as an anti-inflammatory agent, soothing and healing agent. Allantoin-panthenol (CAS 71673-21-7) is a complex derived from allantoin and panthenol in a ratio of 1:1, and is recognized as a chemical compound distinct from both of the parent compounds. Allantoin-panthenol is available commercially, for example, under the trade name Alpantha™ marketed by Akema, and is generally used in cosmetic and cosmeceutical applications, including dry skin, sun, shaving, baby and hair products. It is to be understood that the term "allantoin- panthenol" as used throughout the present invention refers to the complex and not to the addition of each of the components separately. In certain embodiments, the antiinflammatory agent allantoin-panthenol is present in the composition in an amount of about 0.1 to about 5.0% (w/w), for example about 0.5 to about 1.5% (w/w), or about 0.5%.

In particular embodiments, the disinfecting agent is present in the composition in an amount from about 0.1% to about 1.5% (w/w). According to a particular embodiment, the disinfecting agent is boric acid. Boric acid and other borates clean and bleach by converting water molecules to hydrogen peroxide. Boric acid buffers the pH in the ear canal to its physiological range of about 4.5-6.0, thus also providing protection against bacterial and fungal growth. Borates bonds with other particles to keep ingredients dispersed evenly in a mixture, which maximizes the surface area of active particles to enhance its activity. In a particular embodiment, the boric acid is present in the composition in an amount of about 1%.

According to certain embodiments, the composition further comprises glycerin. Glycerin, also known as glycerol, propane-l,2,3-triol, 1,2,3-propanetriol, 1,2,3- trihydroxypropane, glyceritol, and glycyl alcohol is a colorless, odorless, hygroscopic, viscous liquid frequently used in pharmaceutical preparations for improving smoothness, providing lubrication and as a humectant. According to particular embodiments, the glycerin is present in the composition in an amount from about 2% to about 15% (w/w). In a currently preferred embodiment, the glycerin is present in an amount of about 5% (w/w). The composition may further comprise an additional anti-inflammatory agent selected from a herbal anti-inflammatory agent, a steroid and a non-steroidal anti- inflammatory drug, or a combination thereof. Suitable herbal anti-inflammatory agents include, but are not limited to cat's claw; rosemary; chamomile, ginseng, arnica and combinations thereof. Suitable steroidal drugs include, but are not limited to hydrocortisone, hydrocortisone acetate, dexamethasone sodium phosphate, betamethasone valerate,betamethasone propionate and triamcinolone. Suitable nonsteroidal anti-inflammatory drugs include, but are not limited to oxicans, salicylates, acetic acid derivatives, fenamates, propionic acid derivatives, pyrazoles, substituted phenyl compounds, 2-naphthyl containing compounds, and combinations thereof. Oxicams include, but are not limited to piroxicam, isoxicam, tenoxicam and sudoxicam. Salicylates include, but are not limited to aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal. Acetic acid derivatives include, but are not limited to diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac. Fenamates include, but are not limited to mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids. Propionic acid derivatives include, but are not limited to ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic. Pyrazoles include, but are not limited to phenybutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone. Substituted phenyl compounds are disclosed, for example in U.S. Patent No. 4,708,966, and include 4-(4'-pentyn-3'-one)-2,6-di-t-butylρhenol; 4-(5'-hexynoyl)- 2,6-di-t-butylphenol; 4-((S)-(-)-3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol; 4-((R)-(+)- 3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol; and 4-(3',3'-dimethoxypropionyl)-2,6-di-t- butylphenol. Specific 2-naphthyl-containing ester compounds, include, but are not limited to (S)-naproxen-(S)-2 -butyl ester, (S)-naproxen-(R)-2-butyl ester, (S)-naproxol- (R)-2-methyl butyrate, (S)-naproxol-(S)-2-methyl butyrate, diasteromeric mixtures of (S)-naproxen-(S)-2-butyl ester and (S)-naproxen-(R)-2-butyl ester, and diasteromeric mixtures of (S)-naproxol-(R)-2-methyl butyrate and (S)-naproxol-(S)-2 -methyl butyrate.

The composition may further comprise an anti-bacterial agent, including but not limited to bacitracin, clindamycin, erythromycin, gentamicin, mupirocin, neomycin, tetracyclines, polymyxin B₅ benzalkonium chloride, boric acid, hexachlorophene, iodine, iodoquinol, mafenide, mercury ammoniated, metronidazole, nitrofurazone, selenium sulfide, silver sulfadiazine, salts thereof and combinations thereof.

The composition may further comprise an anti-fungal agent, including but not limited to amphotericin B, butefanine, butoconazole, carbol-fuchsin, ciclopirox, clioquinol, clotrimazole, econazole, gentian violet, ketoconazole, miconazole, naftifϊne, nystatin, oxiconazole, sodium thiosulfate, terbinafine, terconazole, tolnaftate, undecylenic acid, salts thereof and combinations thereof.

The composition may further comprise an anti-viral agent, including but not limited to acyclovir, amantadine, cidofovir, famciclovir, foscarnet, ganciclovir, palivizumab, penciclovir, ribavirin, rimantadine, valcyclovir, salts thereof and combinations thereof.

The composition may further comprise a preservative for inhibiting contamination of the composition by microorganisms. Such agents are well known in the art and are readily selected by those of skill in the art. Antimicrobial preservatives include, but are not limited to methylparaben; ethylparaben; propylparaben; butylparaben; isobutylparaben; phenoxyethanol; imidazolidinyl urea; diazolidinyl urea; triethylene glycol; benzyl alcohol; propylene glycol; sodium hydroxymethylglycinate, benzalkonium chloride; sodium dodecyl sulfate; carageenan; cellulose acetate phthalate; undeclenic acid and combinations thereof. As is common practice in the art, a commercially available combination of preservatives may be used, for example, Phenonip™, Nipaguard™ and Germaben™. The composition further comprises at least one pharmaceutically acceptable excipient, diluent or carrier. Excipients include for example, thickeners, dispersing agents, emulsifiers, colorants and fragrant oils. According to one embodiment, the fragrant oil is rose oil.

It is to be understood that any specific ingredient disclosed herein may fulfill more than one disclosed function in the composition of the invention.

According to a particular embodiment, the composition comprises isopropyl alcohol as the moisture-evaporating agent, allantoin-panthenol as the anti inflammatory, healing agent, and boric acid as the disinfecting agent.

In a particular embodiment, the composition of the present invention comprises: (i) isopropyl alcohol in an amount of about 80% to about 95%

(w/w);

(ii) allantoin-panthenol in an amount of about 0.1%-5% (w/w); and (iii) boric acid in an amount of about 0.1% to about 1.5% (w/w). In another particular embodiment, the composition further comprises: (iv) glycerin in an amount of about 2% to about 15% (w/w)

In a further particular embodiment, the composition further comprises: (v) rose oil at an amount of about 0.01 % to about 0.1% (w/w). In another embodiment, the composition consists essentially of: (i) isopropyl alcohol in an amount of about 93.45% (w/w); (ii) allantoin-panthenol in an amount of about 0.5% (w/w); (iii) boric acid in an amount of about 1% (w/w);

(iv) glycerin in an amount of about 5% (w/w), and (v) rose oil in an amount of about 0.05% (w/w). Formulations and Mode of Administration

The composition may be in the form of a liquid formulation such as a solution or suspension, and may contain any pharmaceutically acceptable and suitable excipients, as are known in the art. Alternatively, the composition of the present invention may be formulated as an ointment, lotion, cream, tincture, paste, aqueous or anhydrous gel, or powder using pharmaceutically acceptable and suitable excipients, as are known in the art. According to particular embodiments, the composition is formulated as a liquid, a solution or suspension, which is particularly useful when the composition is to be administered in the form of a spray.

The composition of the present invention can be administered by any route and through any means where delivery of the formulation to the ear canal can be achieved. For example, the formulations are administered by spray, gel, eardrop, or other methods of administration well known to those of skill in the relevant art. Fluid substances or medicaments are commonly administered to the ear using a standard "dropper" device. Although the dropper has become widely accepted as a satisfactory means for administering medicaments to the external ear canal, use of the dropper for this procedure is often difficult and dangerous. It is especially difficult to administer ear medicine to children via the dropper device unless they are able to maintain their head in a relatively still position. Moreover, the dropper device dispenses medicine in droplet form, which flows into the ear canal along the lower wall only. Thus, the upper and sidewalls or surfaces of the ear canal are not exposed to the medicament and the treatment may be incomplete. According to currently preferred embodiments, the fluid compositions of the present invention are administered to the ear canal in the form of a spray. The unique combination of components of the composition in the form of a spray enable gentle, yet uniform dispersion of the composition in the ear canal cavity. The even spreading is highly important and results in rapid action of the active ingredients of the composition, such that water evaporation is achieved within 3-4 minutes.

As used herein, the term "spray" refers to a jet or mass of finely divided liquid particles or droplets.

As used herein, a "spray dispenser" refers to a container for holding the composition of the invention, and includes a mechanism for ejecting the composition in the form of a spray. The mechanism is typically activated by the application of finger pressure onto a nozzle.

In a particular embodiment, a dispensing device for the administration of the pharmaceutical composition of the invention in the form of a spray comprises the pharmaceutical composition in a form selected from the group consisting of a liquid, a solution and a suspension, and a spray dispenser for containing the pharmaceutical composition.

The spray dispenser used may be any type known in the art, which typically includes a nozzle having an outlet aperture through which the formulation is expelled or ejected in the form of a spray upon depression of the nozzle, for example, by application of finger pressure. The activation of the device by depression of the nozzle may also be referred to as "actuation".

The spray dispenser may be selected from a pump-type spray dispenser and an aerosol spray dispenser. A pump-type spray dispenser dispenses the formulation under normal atmospheric pressure; application of finger pressure temporarily pressurizes the formulation to cause a portion of it to leave the dispenser as a spray. The pressure in the mechanism returns to atmospheric soon after the portion of formulation has been dispensed. Pump-type spray dispensers are disclosed, for example in U.S. Patent Nos. 3,159,316; 4,034,900, and 4,050,860. A suitable pump-type spray dispenser for administering medicaments to the ear is disclosed for example, in U.S. Patent No. 5,176,654.

An "aerosol" spray dispenser refers to a spray dispenser that contains the formulation to be dispensed, and a gas under pressure. Such a dispenser typically comprises a metal container (made for example, from aluminum or tinplate) for holding the formulation and gas, so that the dispenser can withstand pressure higher than atmospheric pressure. The formulation is typically a liquid or gel in mono-phasic solution (i.e. homogeneous solution) or in bi-phasic solution (i.e. aqueous solution and oil solution). The container is tightly closed with a valve orifice, and then an aerosol propellant (i.e. a liquefied gas), such as butane, propane, a hydrofluoroalkane mixture or any other propellant as is known in the art, is inserted, thus creating pressure inside the container (e.g. 3 atmospheres). Agitation of the container, even minimally, causes the gas and liquid to mix; depression of the nozzle results in the ejection of the pressurized formulation. Aerosol spray dispensers are disclosed, for example, in U.S. Patent Nos. 5,322,683; 5,397,564; and 6,730,288.

The spray dispenser may be a metered dose spray dispenser. Such a dispenser expels a pre-determined volume of the formulation i.e. a metered dose, with each actuation of the device. Advantageously, a metered dose spray dispenser prevents the waste and messiness of excess dosing, and ensures that a precise amount of the composition is inserted to the ear canal. Metered dose dispensing may be accomplished using either a pump-type spray dispenser or an aerosol spray dispenser.

Metered dose devices are known in the art for different applications, described for example, in US Patent Nos. 6,032,836; 5,697,532; 5,502,076, and 6,702,155, and in US Patent Application No. 2003/0178022.

The amount of the composition ejected per actuation of the dispenser is suitably in the range of about 0.1 to 1.0 ml, for example, about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,

0.9 or 1.0 ml. The specific amount ejected may be adjusted according to the age and approximate ear canal volume of the subject. The determination of the appropriate volume per actuation is within the ability of those of skill of the art.

Methods of Treatment and Use

The present invention provides a method for preventing and/or treating otitis externa ("swimmer's ear") comprising topically administering to the ear canal of a subject in need thereof an effective amount of the composition of the invention. The composition may be administered in the form of an ointment, gel, drops, liquid or spray. According to particular embodiments, the composition is administered in the form of a spray, ensuring gentle and even spreading of the composition within the ear canal. According to this embodiment, the composition is administered using a spray dispenser, such as an aerosol spray dispenser or a pump-type spray dispenser, as hereinbefore described.

Administration of the composition of the invention is conveniently carried out following exposure to water, such as due to bathing, immersion in a ritual bath or participation in an aquatic sport. The method may be particularly useful for individuals who participate in aquatic sports on a regular and frequent basis. Such aquatic sports include pool swimming, synchronized swimming, underwater swimming, deep sea diving, scuba diving and water polo. According to the methods disclosed herein, the administering may be carried out following each exposure to water in susceptible individuals, even if no symptoms are apparent i.e. on a preventative basis. Alternately or in addition, the administering may be carried out following emergence of symptoms. Conveniently, the composition may be administered for example, one to three times a day for a period of 2 to 21 days, or twice a day for a period of 7 days. An effective amount of the composition may be about 0.1 to 1 ml, for example, about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 ml. The determination of the appropriate dosing schedule according to the age and weight of the subject, the severity of the condition, and any other factors deemed important, is within the ability of those of skill of the art. According to another aspect, the present invention provides a use of (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin- panthenol; (iii) a pharmaceutically acceptable disinfecting agent, and at least one pharmaceutically acceptable excipient, diluent or carrier for the preparation of a medicament for preventing and/or treating otitis externa in a subject in need thereof, wherein the medicament is topically administering to the ear canal of the subject.

According to another aspect, the present invention provides a topical composition comprising (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin-panthenol; (iii) a pharmaceutically acceptable disinfecting agent, and at least one pharmaceutically acceptable excipient, diluent or carrier for the prevention or treatment of otitis externa.

In particular embodiments, the composition further comprises glycerin, for example in an amount from about 2% to about 15% (w/w). In a particular embodiment, the glycerin is present in an amount of about 5% (w/w).

According to certain embodiments, the composition is administered after exposure to water, for example due to bathing, immersion in a ritual bath or participation in aquatic sports as hereinbefore described.

The following examples are presented in order to more fully illustrate certain embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

EXAMPLES

Example 1. Preparation of a representative composition.

A liquid composition for preventing and treating otitis externa was prepared by dissolving boric acid and OAlpantha™ in isopropyl alcohol, followed by addition of glycerin to the mixture, according to the proportions shown in Table 1. The mixture was mixed in a low speed mixer while adding rose oil.

After 5 minutes of mixing, the composition was filled to spray canisters. Table 1.

Example 2. Clinical trial.

A clinical trial to assess the efficacy of the composition described in Example 1 was held at the Department Ear Nose and Throat and Head and Neck Surgery, Bikur Cholim Hospital, Jerusalem, Israel, August 2006.

Objectives: The purpose of the trial was to evaluate the results of treatment with the composition of Example 1 (Table 1) in the form of a spray in patients with ear discomfort and irritation due to ear wetting and in patients with hearing aids.

Methods: Prospective study with 27 patients in a primary outpatient clinic: eighteen (18) patients suffered chronically from water in the ear (due to swimming or immersion in a ritual bath "Mikve") and nine (9) patients had hearing aids in one or both ears.

The complaints of pain, stuffiness, irritation, and secretion were recorded before and after treatment.

Patients were treated once or twice a day with the spray for a period of 10 days to three weeks.

Results: Results after treatment were recorded by degree of improvement of symptoms.

25 patients (92.6%) reported significant improvement of symptoms. 2 Patients (7.4%) had residual symptoms of ear stuffiness and irritation. Conclusions: Treatment with the composition of Table 1 in the form of a spray was found to improve patients' complaints of ear irritation and discomfort, and contributed significantly to quality of life in affected patients.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The means, materials, and steps for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention.

Claims

1. A pharmaceutical composition for preventing or treating otitis externa, comprising (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin-panthenol; (iii) a pharmaceutically acceptable disinfecting agent, and at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1, wherein the moisture-evaporating agent is selected from the group consisting of methyl alcohol, ethyl alcohol, and isopropyl alcohol.

3. The pharmaceutical composition according to claim I₅ wherein the moisture-evaporating agent is present in an amount of about 80% to about 95% (w/w).

4. The pharmaceutical composition according to claim 2, wherein the moisture-evaporating agent is isopropyl alcohol.

5. The pharmaceutical composition according to claim 4, wherein the isopropyl alcohol is present in an amount of about 80% to about 95% (w/w).

6, The pharmaceutical composition according to claim 1, wherein the disinfecting agent is boric acid.

7. The pharmaceutical composition according to claim 6, wherein the boric acid is present in an amount of about 0.1% to about i.5% (w/w).

8. The pharmaceutical composition according to claim 7 wherein the boric acid is present in an amount of 1.0% (w/w).

9. The pharmaceutical composition according to claim 1, wherein the disinfecting agent is present in an amount of about 0.1% to about 1.5%

(w/w).

10. The pharmaceutical composition according to claim 1, wherein the allantoin-panthenol is present in an amount of about 0.1% to about 5%..

11. The pharmaceutical composition according to claim 10, wherein the allantoin-panthenol is present in an amount of about 0.5%.

12. The pharmaceutical composition according to claim 1, further comprising glycerin.

13. The composition according to claim 12, wherein the glycerin is present in an amount of about 2% to about 15% (w/w).

14. The pharmaceutical composition according to claim 13, wherein the glycerin is present in an amount of about 5% (w/w).

15. The pharmaceutical composition according to claim 1, further comprising at least one additional active agent selected from the group consisting of an additional anti-inflammatory agent, an anti-bacterial agent, an anti-fungal agent, an anti- viral agent and combinations thereof.

16. The pharmaceutical composition according to claim 15, wherein the additional anti-inflammatory agent is selected from the group consisting of a herbal anti-inflammatory agent, a steroid, a non-steroidal anti- inflammatory drug and combinations thereof.

17. The pharmaceutical composition according to claim 16, wherein the herbal anti-inflammatory agent is selected from the group consisting of cat's claw; rosemary; chamomile, ginseng, arnica and combinations thereof; the steroid is selected from the group consisting of hydrocortisone, hydrocortisone acetate, dexamethasone sodium phosphate, betamethasone valerate, betamethasone propionate, triamcinolone and combinations thereof; and the non-steroidal anti-inflammatory drug is selected from the group consisting of an oxican, a salicylate, an acetic acid derivative, a fenamate, a propionic acid derivative, a pyrazole, a substituted phenyl compound, a 2-naphthyl containing compound and combinations thereof.

18. The pharmaceutical composition according to claim 15, wherein the antibacterial agent is selected from the group consisting of neomycin sulfate, colistin sulfate, polymyxin B, mupirocin, chloramphenicol and combinations thereof; and the anti-fungal agent is selected from the group consisting of nystatin, clotrimazole and a combination thereof.

19. The pharmaceutical composition according to claim 1, comprising

(i) isopropyl alcohol in an amount of about 80% to about 95% (w/w); (ii) allantoin-panthenol in an amount of about 0.1% to about 5% (w/w); and (iii) boric acid in an amount of about 0.1 % to about 1.5% (w/w).

20. The pharmaceutical composition according to claim 19, further comprising glycerin in an amount of about 2% to about 15% (w/w).

21. The pharmaceutical composition according to claim 19, further comprising rose oil in an amount of about 0.01% to about 0.1% (w/w).

22. The pharmaceutical composition according to claim 1, consisting essentially of:

(iii) boric acid in an amount of about 1% (w/w);

(iv) glycerin in an amount of about 5% (w/w), and

(v) rose oil in an amount of about 0.05% (w/w).

23. The pharmaceutical composition according to claim 1, in a form selected from the group consisting of a liquid, a solution, a suspension, an ointment, a lotion, a cream, a tincture, a paste, an anhydrous or aqueous gel and a powder.

24. A device for the administration of the pharmaceutical composition according to any of claims 1-22 in the form of a spray, the device comprising said pharmaceutical composition in a form selected from the group consisting of a liquid, a solution and a suspension, and a spray dispenser for containing the pharmaceutical composition.

25. The device according to claim 24, wherein the spray dispenser is selected from the group consisting of an aerosol spray dispenser, a pump-type spray dispenser, a metered dose spray dispenser and a combination thereof.

26. A method for preventing and/or treating otitis externa in a subject in need thereof, the method comprising topically administering to the ear canal of the subject a therapeutically effective amount of the composition according to any of claims 1-23, thereby preventing and/or treating otitis externa.

27. The method according to claim 26, wherein the composition is administered in a form selected from the group consisting of an ointment, a gel, drops, a liquid and a spray.

28. The method according to claim 27, wherein the composition is administered in the form of a spray.

29. The method according to claim 26, wherein the administrating is carried out using a spray dispenser.

30. The method according to claim 26, wherein the administering is carried out following an activity selected from the group consisting of bathing, immersion in a ritual bath and participation in an aquatic sport.

31. The method according to claim 26, wherein the administering is carried out one to three times a day for a period of 2 to 21 days.

32. The method according to claim 31, wherein the administering is carried out twice a day for a period of 7 days.

33. Use of (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin-panthenol; and (iii) a pharmaceutically acceptable disinfecting agent, and at least one pharmaceutically acceptable excipient, diluent or carrier for the preparation of a medicament for preventing and/or treating otitis externa in a subject in need thereof, wherein the medicament is topically administered to the ear canal of the subject.

34. A topical composition comprising (i) a moisture evaporating agent; (ii) an anti-inflammatory, soothing agent which is allantoin-panthenol; (iii) a pharmaceutically acceptable disinfecting agent, and at least one pharmaceutically acceptable excipient, diluent or carrier for the prevention or treatment of otitis externa.

35. The composition according to claim 34, further comprising glycerin.