TECHNOLOGICAL FIELD

The present invention provides a system comprising econazole and mometasone and a pharmaceutically acceptable salt thereof for topical treatment of dermatological infections and regiments for using such.

BACKGROUND OF THE INVENTION

Econazole is an imidazole antifungal agent (l-[2-{(4-chlorophenyl)methoxy}-2- (2,4-dichlorophenyl)ethyl]-lH-imidazole), sold as a 1% active mono nitrate cream, in a water-miscible base for topical use only. Econazole nitrate was shown to be as effective antifungal drug. It is dermatologically administered on the affected areas once daily in patients with tinea pedis, tinea cruris, tinea corporis, and tinea versicolor, and twice daily (morning and evening) in patients with cutaneous candidiasis. Early relief of symptoms was shown by the majority of patients and clinical improvement was seen for most patients fairly soon after treatment is begun. However, patient with candidal infections and tinea cruris and corporis should are treated for two weeks and tinea pedis for one month in order to reduce the possibility of recurrence. Patients with tinea versicolor usually exhibit clinical and mycological clearing after two weeks of treatment. Topical or intravaginal econazole nitrate show side effects being including local irritation in about 1% to 4% of patients in most studies.

Mometasone furoate is a glucocorticosteroid used topically to reduce inflammation of the skin or in the airways. It is a prodrug of the free form mometasone (( 11 β, 16α)-9,21 -dichloro- 11 -hydroxy- 16-methyl-3 ,20-dioxopregna- 1 ,4-dien- 17-yl) . Mometasone furoate is used in the treatment of inflammatory skin disorders (such as eczema and psoriasis), allergic rhinitis (such as hay fever), asthma for patients unresponsive to less potent corticosteroids, and penile phimosis. In terms of steroid strength, it is a medium strength steroid (for example it is more potent than hydrocortisone, and less potent than dexamethasone). Mometazone furoate was shown to reduce inflammation by causing several effects: reversing the activation of inflammatory proteins, activating the secretion of anti-inflammatory proteins, stabilizing cell membranes and decreasing the influx of inflammatory cells. Many methods are known for the topical treatment of fungal infections, including the use of antibiotics (e.g. nystatin and amphotericin B), imidazole antifungal agents such as miconazole, clotrimazole, econazole and sulconazole, and non-imidazole fungal agents such as the allylamine derivatives terbinafine and naftifine, and the benzylamine butenafine. Among the known treatments the combination of imidazole antifungal agents with a corticosteroid has been disclosed for the topical treatment of fungal diseases. The purpose of the steroid is to alleviate the symptoms of erythema and the related itching that are normally associated with fungal infections. Additionally, steroids may also induce fungal spores to be more sensitive to treatment by an antifungal agent. However, since it is highly undesirable to use steroids for topical treatment for an extended period of time, this has become a major disadvantage of such combinations. Steroids can penetrate the skin and cause undesirable side effects, including skin atrophy, suppression of the hypothalamic -pituitary-adrenal axis, Cushing's syndrome, glucosuria, hyperglycemia, etc. Furthermore, the addition of a steroid decreases the effectiveness of some antifungal compounds, because of the potential of steroids to function as a deactivating agent.

The use of corticosteroids in the treatment of topical indications has been connected with several sever harmful effects including hypothalamic pituitary adrenal axis (HPA) suppression, Cushing's syndrome, diabetes mellitus, osteoporosis, topical steroid addiction, allergic contact dermatitis, steroid allergy, steroid atrophy, perioral dermatitis, ocular effects (such as high intra-ocular pressure (IOP) and increase risk of glaucoma, cataract, retinopathy, tachyphylaxis, delivery-related adverse effects, and other local adverse effects (such as for example facial hypertrichosis, folliculitis, miliaria, genital ulcers, and granuloma gluteale infantum. Long term use has resulted in Norwegian scabies, Kaposi's sarcoma, and other unusual dermatosis). It is to be noted that the risk for a patient to experience such harmful effects is significantly increased as the exposure to dosages of corticosteroids is increased, such as for example in long term treatment of a topical disease or disorder.

Reported side effects for a commercially available combination, Lotrisone® cream (clotrimazole 1 /betamethasone dipropionate 0.05%), include paraesthesia, maculopapular rash, edema and secondary infection. According to the FDA Professional Drug Information, Lotrisone cream can cause reversible hypothalamic - pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment. Cushing's syndrome and hyperglycemia may also occur due to the systemic effect of corticosteroids while on treatment. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressing, altered skin barrier, liver failure, and young age.

Common side effects reported for others commercially available combinations, Canesten® hydrocortisone (clotrimazole 1 percent /hydrocortisone 1 percent) and Lotriderm® (clotrimazole 1% percent /betamethasone dipropionate 0.05%) are local mild burning, irritation and hypersensitivity reactions. Moreover, such combination products sometimes fail to provide the fast relief of the inflammatory symptoms which is normally desired for the treatment of a fungal infection.

Adverse effects associated with dermal antifungal/corticosteroid combinations have been reviewed by Erbagci (Am. J. Clin. Dermatol. 2004, 5, 375-384), wherein it is stated that there are conflicting results between the studies investigating which therapy regimen, antifungal alone or antifungal plus corticosteroid, is more effective for the management of dermatophyte infections. Several references to other studies are cited, wherein combination products show equal or lower mycologic and clinical cure rates compared with single antifungal agents in the management of dermatophytoses, as well as to adverse effects observed when the combination is used. Therefore, the combination of an antifungal agent with a corticosteroid is not always the most adequate therapy to relief the symptoms or even the combination may be inappropriate due to adverse effects.

It would therefore be advantageous to have a pharmaceutical topical system that retains the advantages of combining an agent useful for treating fungal diseases with a steroid capable of reducing the associated inflammation, with the ability to rapidly eradicate fungal infections and eliminate the symptoms thereof, and as a consequence minimize the risk of undesirable side effects. Such systems in combination with a unique dosage regiment are designed to deliver the antifungal agent and the steroid to the skin, provide the suitable effect with the ability to avoid the steroid side effects noted above.

SUMMARY OF THE INVENTION

Patients suffering from dermatological and topical infections, such as fungal infections are still in need of treatment that can provide both efficient and fast acting healing and also safe treatment that limits the exposure of the patient to the harmful effect of steroids, especially those that occur upon long term use of steroids. It was surprisingly found that the system of the invention is useful in the treatment of dermatological fungal infections, such as for example tinea pedis, when administered to a subject for a treatment period of up to 7 days (either once or twice daily doses - the administration period), however having a therapeutic effect for at least 14 days past last administration of the system (post administration period).

Thus, in one aspect, the present invention relates to a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof.

In another aspect, the present invention provides a method of treating a dermatological fungal infection (including symptoms thereof) in a subject in need thereof comprising administering to a subject in need thereof a system comprising as active agents econazole or a pharmaceutically acceptable salt thereof and mometasone or a pharmaceutically acceptable salt thereof for a period of up to 7 days.

In a further aspect, the present invention relates to a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof, for use in the treatment of dermatological fungal infection (including symptoms thereof), wherein said system is administered to a subject in need thereof for a period of up to 7 days. DETAILED DESCRIPTION OF THE INVENTION

The term "system" as used herein should be understood to relate to an arrangement representing a product or kit made up by at least one component, at least two components, at least three components and so forth, wherein said component represents a pharmaceutical composition comprising one or two active pharmaceutical agents. A system of the invention may further comprise a composition that comprises a dermatological cosmetic agent (i.e. none pharmaceutical active agent), such as for example toning agent, moisturizing agent, hydrating agent and so forth.

In some embodiments, the econazole and mometasone constitute two separate compositions in a system of the invention. In another embodiment, a system of the invention comprises a composition comprising econazole and a composition comprising mometasone.

In another embodiment, the econazole and mometasone constitute a single composition in a system of the invention.

In some embodiments, the composition comprising econazole is a water based composition.

In further embodiments, the composition comprising mometasone is an oil based composition.

In some embodiments, the system of the invention comprises a composition comprising econazole in the range of 0.5 to 2 weight percent of the composition. In some other embodiments, the econazole is at least 0.5 weight percent of the composition. In further embodiments, the econazole is about 1 weight percent of the composition.

In some other embodiments, the system of the invention comprises a composition comprising mometasone in the range of 0.05 to 0.2 weight percent of the composition. In other embodiments, the mometasone is at least 0.05 weight percent of the composition. In other embodiments, the mometasone is 0.1 weight percent of the composition.

In some embodiments, a system comprises 1 % by weight econazole and 0.1 % by weight of mometasone.

In another one of its aspects, the invention provides a unique method of treating a dermatological fungal infection in a subject in need thereof comprising administering to the subject a system of the invention (as described herein above and below) comprising as active agents econazole or a pharmaceutically acceptable salt thereof and mometasone or a pharmaceutically acceptable salt thereof for a period of up to 7 days.

The invention further provides a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof, for use in the treatment of dermatological fungal infection, wherein said system is administered to a subject in need thereof for a period of up to 7 days.

The invention further provides a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof, for use in the treatment of tenia pedis, wherein said system is administered to a subject in need thereof for a period of up to 7 days.

In some embodiments, the system is administered to the subject for 1, 2, 3, 4, 5, 6 or 7 days. In some embodiments, the system is administered to the subject for 7 days. In certain embodiments, the system is administered to the subject once daily. In certain other embodiments, the system is administered to the subject twice daily.

In some embodiments of a method of the invention, each of the active agents of a system of the invention is contained in a separate composition for administration.

In some embodiments of a method or use of the invention, at least one of the compositions of a system of the invention, is a dermatological/topical composition. In other embodiments of a method or use of the invention, the system comprises a single composition comprising said active agents. In some embodiments, the single composition is a dermatological/topical composition.

In some embodiments of a method or use of the invention, the system comprises a composition comprising econazole in a water based composition. In some other embodiments of a method or use of the invention said system comprises a composition comprising mometasone in an oil based composition.

In some embodiments of a method or use of the invention, the system comprises a composition comprising econazole in the range of between 0.5 to 2 weight percent of the composition. In some embodiments, the econazole is at least 0.5 weight percent of the composition. In some further embodiments, the econazole has a weight percent of about 1 % weight of the composition.

In some embodiments of a method or use of the invention, the system comprises a composition comprising mometasone in the range of between 0.05 to 0.2 weight percent of the composition. In some further embodiments, the mometasone is at least 0.05 weight percent of the composition. In some further embodiments, the mometasone has a weight percent of 0.1 % of the composition.

In another embodiment, a method or use of the invention is intended for the treatment of a dermatological fungal infection selected from a skin mycosis including any disorders, symptoms or conditions associated thereof, tinea pedis, tinea corporis, tinea cruris, jock itch, tinea and ringworm.

In some embodiments, the dermatological fungal infection is a mild to moderate infection. In other embodiments, the dermatological fungal infection is a moderate to severe infection.

It should be understood that the terms "moderate topical fungal infection symptoms" or "moderate to severe topical fungal infection symptoms" relate to the intensity of the dermatological symptoms shown on the skin of said subject at the infection site which include at least one of erythema, scaling, maceration, burning and pruritus or any combinations thereof. Such intensity of infectious symptoms are determined by a medical practitioner, e.g. as defined in the FDA "Draft Guidance on Econozole Nitrate".

In other embodiments, the subject has sensitivity to steroid exposure. It should be understood that the subject was either previously diagnosed as suffering from steroid sensitivity or is being diagnosed as having steroid sensitivity by a medical practitioner based on symptoms and conditions exhibited by the subject. It should be further understood that steroid sensitivity in a subject can be caused by several causes including, but not limited to another disease or disorder the subject is suffering from making him or her more sensitive to exposure of severe agents such as steroid, especially for a long period of exposure time, such disease include for example glaucoma, high-blood pressure, heart disease, diabetes mellitus, obesity, acid reflux/GERD, osteoporosis, cushing syndrome, fibromyalgia and so forth. Subjects that have gone through severe surgery, including bypass surgery, transplant surgery, cancer removing surgery and so forth are also more susceptible to the side effects of steroids. Patient populations having extreme skin sensitivity are also included in the definition of sensitivity to steroid exposure. Such populations include, but are not limited to infants between the age of 0 to 12 months, fibromyalgia patients, patients having skin allergies, patients suffering from skin cancer and so forth.

In some embodiments of a method or use of the invention, after the treatment (administration) period of 7 days the therapeutic efficacy is retained for at least additional 14 days. When referring to "therapeutic efficacy" it should be understood that the combined effect of the antifungal agent and steroid agent is evident even for at least 14 days after the last day of administration of the system of the invention to the subject. The evidence for the therapeutic effectiveness is shown by the reduction in fungal infection signs and dermatological symptoms thereof (mycological signs and symptoms of the infection) at the site of treatment. In some embodiments of a method or use of the invention, after the treatment (administration) period of 7 days the therapeutic efficacy is retained for at least additional 21 days. In some embodiments of a method or use of the invention, after the treatment (administration) period of 7 days the therapeutic efficacy is retained for at least additional 28 days. In some embodiments of a method or use of the invention, after the treatment (administration) period of 7 days the therapeutic efficacy is retained for at least additional 35 days.

In another embodiment of a method or use of the invention, the subject shows improved signs and symptoms of the fungal infection as compared with the single treatment with compositions comprising econazole or momethasone alone. In some embodiments, the improved signs and symptoms are selected from at least one of reduced erythemia, scaling, fissuring, maceration, vesiculation, pruritus and any combinations thereof.

In some embodiments, the subject is a child between the ages of 0 to 5. In some embodiments, the subject is a child between the ages of 0 to 12.

In another embodiment, a method or use of the invention is intended for the treatment of tinea pedis in a subject. In certain embodiments, the system comprising 1% by weight of econazole and 0.1% by weight of mometasone is administered to a subject in need for a period of up to 7 days.

As used herein, when referring to treatment of a disease, a disorder or symptom thereof it should be understood to encompass any qualitative or quantitative slowing of or a reversal of the progress of the disease, a disorder, a condition or any symptom associated thereof. Treating a disease or disorder includes treating a symptom and/or reducing the symptoms of the disease.

As used herein, a "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound for use in the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4 dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, or mandelates.

As used herein, a "pharmaceutically acceptable carrier" refers to a non-API (API refers to Active Pharmaceutical Ingredient) substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency.

Routes of topical administration include nasal, bucal, mucosal, rectal, or vaginal applications. For topical administration, the compositions and system of the invention can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like. A special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by reference.

The system of the invention can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use. In such formulations, diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used. Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included. For example, useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral formulations can be stored in any conventional containers such as vials and ampoules.

The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES

Example 1

A Randomized, Double Blind Study To Compare The Efficacy And Safety of E-06, Combination Cream Econazole 1% + Mometasone 0.1 % Versus Econazole 1 % Cream In Patients With Tinea Pedis

Design:

One-week treatment of E-06 or econazole, followed by 3 weeks treatment of econazole alone (sequential therapy). Visits were conducted as follows: Od (visit 1), after 3d (visit 2), 7d (visit 3), 14d (visit 4), 28d (visit 5), 42d (visit 6).

Main inclusion criteria:

Confirmed clinical diagnosis of interdigital tinea pedis with a sum of at least 6 points of clinical signs and symptoms score of the target lesion, including a minimum score of at least 2 for erythema and 1 for maceration AND a minimum score of 2 for either scaling or pruritus (on a scale of 0-3, where 2 indicates moderate severity). Confirmed mycological diagnosis of interdigital tinea pedis by the observation of segmented fungal hyphae during a microscopic potassium hydroxide (KOH) wet mount examination (potassium hydroxide mount preparation). Identification of an appropriate dermatophyte by culture (confirmed after enrollment).

Clinical signs & Global assessment

Clinical evaluation score included 5 parameters: Erythema, scaling, maceration, burning and pruritus (score between 0-3) Global assessment (global response scale) (% of clearing; 1.100%, 5. <25%) Statistical analysis was performed on the total score, each parameter, the change from baseline of total score & global response rate for all visits.

The change from baseline of the total score was statistically significant different (P value 0.001) for combination (-10.5 points mean reduction) and the Econazole (-7.7 points mean reduction) at visit 4.

In the present example patients with moderate to severe topical fungal infections symptoms (with a total score of at least 11 points) were treated with the combination cream (E-06) or with econazole only (11 patients received combination and 15 received Econazole).

Results:

There were statistical differences between the groups in total score of clinical signs at visits 4-6 (from week 2, Table 1), pointing that the combination is better than econazole.

Table 1

Econazole Combination

n=15 (100%) n=ll (100%)

ClilV 5 i M ^< < > 7 <64'. ί 1

Effective treatment 8 O V , 1 X (7V < )

til cine f S <73M

Example 2

Randomized, double blind, placebo controlled study to compare the efficacy and safety of a fixed-dose combination Econazole Nitrate and Mometasone Furoate Cream, 1 %/0.1 % versus Econazole Nitrate Cream, 1 % ; Mometasone Furoate Cream, 0.1 %; and Vehicle Cream in patients with symptomatic inflammatory interdigital tinea pedis

The primary efficacy endpoints are the eradication of infection (evaluated at Week 1 and Days 21, 28 and 36 from end-of-treatment) and no evidence of clinical disease as indicated by complete resolution of all signs and symptoms (i.e., scores of 0 for erythemia, scaling, fissuring, maceration, vesiculation and pruritus) (evaluated at Week 1 and Days 21, 28 and 36 from start of study).

Efficacy

Complete cure defined as a negative KOH and negative fungal culture and no evidence of clinical disease as indicated by scores of 0 (none, complete absence of any signs or symptoms) for each clinical sign or symptom at Week 1 and Days 21, 28 and 36 from start of study.

Improvement of clinical signs (fissuring/cracking, erythema, maceration, and scaling) and symptoms (pruritus and burning/stinging) at Week 1 as compared to baseline, and comparing the fixed-dose combination vs the Econazole Nitrate Cream, 1% arm.

Improvement is evaluated by: the global response scale: 0 = none (complete absence of any signs or symptoms); 1 = mild (slight); 2 = moderate (definitely present); 3 = severe (marked, intense). Change from baseline of scaling, erythema, maceration, pruritus and burning scores (scaled as 0= absent, l=mild, 2=moderate, 3= severe) for each symptom and total score.

During the baseline visit, a target lesion is identified, and patients undergo a mycological test (positive KOH and fungal culture). Patients return to the clinic following Week 1 and Days 21, 28 and 36, (follow-up visit through 29 days after end of treatment). Mycological test is performed on week 1 and day 36. A follow-up visit is performed five weeks following the completion of the treatment. During this visit safety and efficacy parameters are assessed including mycological test.

Test product, dose, and mode of administration:

• Econazole Nitrate Cream, 1 %

• Mometasone Furoate Cream, 0.1%

• Fixed-Dose Combination Econazole Nitrate and Mometasone Furoate , 1%/0.1%

• Vehicle Cream

Study duration:

A total of 36 days (1 week of treatment with a 29-days follow-up period)