Roflumilast, a topical preparation with antifungal properties.

Abstract

To provide methods for treating fungal infection.SOLUTION: The disclosure relates to a method for treating fungal infection, comprising topically administering an antifungally effective amount of roflumilast to a subject in need of treatment for a fungal infection. Preferably, topically administered roflumilast is used to treat fungal infections, fungal growth, and / or allergy to the fungal malassezia. Patients may also suffer from seborrheic dermatitis, dandruff, dupilumab facial redness, tinea versicolor, pityriasis versicolor, tinea cirrhosa, tinea pedis, tinea unguium, tinea manus, tinea cruris, tinea corporis, tinea faciei, tinea capitis or atypical tinea. The topically administered roflumilast is a fast and potent antifungal agent and represents a viable alternative means to current antifungal treatments.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This invention relates to fungal infections, the use of PDE4 inhibitors having antifungal properties for treating inflammation caused by fungal infections, or the treatment of fungal infections and the abnormal proliferation of fungi on hair, skin, or nails. More specifically, this invention relates to a method for treating fungal infections using topically administered roflumilast. [Background technology]

[0002] Fungal infections of the skin, nails, and hair Bacteria, viruses, and fungi are all part of the microbiome of healthy human and animal skin. Malassezia species are a genus of microscopic single-celled fungi (or yeasts) that are among the most common fungi found naturally on the skin surface. The most common and well-known species of Malassezia are Malassezia furfur ("M. furfur"), Malassezia globosa, Malassezia restricta, and Malassezia pachydermatis.

[0003] Malassezia species generally inhabit the superficial layers of the dermis, primarily in sebum-rich areas such as the trunk, face, scalp, ears, forehead, nasolabial folds, glabella, and beard area. They are symbiotic organisms of the skin microbiome and are generally known to strengthen the body's defenses and protect the immune system from dangerous pathogens. Specifically, Malassezia species have been shown to stimulate the immune system and, among other cytokines, produce the cytokine interleukin-17, which is involved in controlling these pathogens and mediates the induction of inflammatory molecules that prevent the abnormal proliferation of fungi in the skin. However, if this immunological process breaks down, for example, if cytokines are not released or immune cells that produce interleukin-17 are lost, Malassezia species proliferate and parasitize the skin. This fungus effectively becomes an allergen to the skin, causing an imbalance in the skin's bacterial flora and ultimately triggering an overreaction of the immune system to inflammation. Malassezia species may also acquire pathogenicity and grow uncontrollably during their life cycle when they transform from yeast to hyphae (branched filamentous fungal structures) through unknown molecular changes.

[0004] While the causal relationship between fungal commensalism and disease manifestation remains incomplete, pathogenic Malassezia species are associated with a variety of skin conditions, including seborrheic dermatitis, dandruff, pityrosporum folliculitis, atopic dermatitis, tinea versicolor, and pityriasis versicolor, generally presenting clinically as skin lesions in the form of hypopigmented or hyperpigmented spots, patches, or scaly papules or plaques, often accompanied by various erythematous lesions. In the case of seborrheic dermatitis, in addition to abnormal immune responses or fungal activity, Malassezia species may be involved in the pathogenesis of the disease as a result of excessive sebum production, which is thought to cause abnormal proliferation of lipophilic yeasts. Other potential pathological mechanisms and potential disease factors that may trigger a reaction to Malassezia species include impaired skin barrier function, hormonal fluctuations (particularly those affecting sebum production), neurological factors, and exogenous factors such as lack of sunlight or feeding disorders.

[0005] Pathogenic Malassezia species are also associated with dupilumab facial redness (DFR) and inflammation. Dupilumab inhibits IL-4 and IL-13 by blocking the IL-4 receptor α and is the first-line biological treatment for moderate to severe atopic dermatitis. One known side effect of dupilumab treatment is the development of eczematous facial rash several months after the start of dupilumab treatment. DFR is known to affect approximately 5-10% of patients treated with dupilumab and to worsen with continued dupilumab administration. Patients are often reluctant to discontinue dupilumab treatment because their atopic dermatitis has improved significantly. In the literature (de Beer et al., JAAD CASE REPORTS Vol5(10) pages888-891(2019)), Malassezia hypersensitivity was suggested as a possible cause of DFR, because M. farfar can easily penetrate the impaired skin barrier function (as a result of atopic dermatitis), causing local damage and activating keratinocytes, thereby exacerbating inflammation (see also Strong, Colby, Oral and Topical Antifungals Beneficial for Dupilumab Facial Redness in Atopic Dermatitis, Dermatology Advisor, Published online Oct. 27, 2021; dermatologyadvisor.com / home / topics / dermatitis / oral-and-topical-antifungals-beneficial-for-dupilumab-facial-redness-in-ad / ). Dupilumab-induced facial redness is being treated with corticosteroids and topical calcineurin inhibitors.Recent articles in dermatology have shown that oral and topical antifungal agents are effective in patients with atopic dermatitis (AD) who develop dupilumab-induced facial redness (DFR) and inflammation after dupilumab treatment (Ordonez-Rubiano MF, Casas M, Balaguera-Orjuela V et al., "Dupilumab facial redness: Clinical characteristics and proposed treatment in a cohort," Dermatol Ther. Published online September 21, 2021. doi:10.1111 / dth.15140). These results suggest a stronger association between pathogenic Malassezia species and DFR.

[0006] While some fungi, such as Malassezia species, cause infections limited to the outermost layer of skin and hair (superficial mycoses), other fungi cause cutaneous mycoses by penetrating the keratinized layer of skin, hair, and nails, leading to pathological changes in the host. For example, fungi known as dermatophytes can parasitize the keratinized layer and cause dermatophytosis.

[0007] Dermatophytes are divided into three genera: Trichophyton, Microsporum, and Epidermophyton. The genus Trichophyton includes species such as T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum, T. schoenleinii, T. tonsurans, T. concentricum, and T. equinum. The genus Microsporum includes species such as Microsporum canis, Microsporum gypseum, Microsporum audouinii, Microsporum cookei, Microsporum equinum, Microsporum ferrugineum, Microsporum gallinae, and Microsporum nanum. The genus Epidermophyton includes species such as E. floccosum. The most common dermatophytes are Trichophyton rubra, Trichophyton tonsurans, and Trichophyton mentagrophytes. Dermatophytes feed on keratin and typically infect the stratum corneum of the epidermis, nails, and hair follicles, causing superficial lesions. The name for dermatophytosis (fungal skin disease) varies depending on the location. The disease name is given with the related common name in parentheses. These include tinea pedis (athlete's foot), tinea or onychomycosis, tinea manus, tinea cruris, tinea corporis, tinea faciei, tinea capitis, and tinea incognito.

[0008] A specific example of a fungal infection caused by the above-mentioned fungi and yeasts is onychomycosis (mainly caused by dermatophytes, including the genera Trichophyton, Epidermophyton, and Microsporum). Onychomycosis is a chronic and persistent fungal, yeast, and / or mold infection of the nail bed and nail plate, causing thickening and discoloration of the nail, sometimes accompanied by pain and impairment. Fungal infections affecting the nails and scalp are very difficult to treat because the fungal infection is located beneath the roots of the hair follicles and the nail itself. Onychomycosis is also particularly difficult to treat due to the length of time it takes for the nail to grow and the impermeability of the nail plate. A similar situation occurs in tinea capitis, where the scalp and hair shafts are infected. Therefore, in onychomycosis and tinea capitis, eradication of symptoms is very slow, sometimes taking several months or even more than a year.

[0009] Conventional treatments for fungal infections Fungal infections are currently managed using topical antifungal agents, keratolytic agents (exfoliating agents that can reduce flaking and scaling), and / or oral medications. However, these treatments often fail or have safety concerns that limit their use. For example, orally administered drugs are generally more effective than topically administered drugs because they act systemically rather than locally, but the side effects of orally administered drugs can be far more severe. Known side effects are very serious and include, to name just a few, liver and / or cardiac toxicity, headache, dizziness, extreme fatigue, lack of energy, flu-like symptoms, difficulty breathing or swallowing, seizures, heartburn, depression, stomach upset, and adverse drug interactions. Similarly, while topical corticosteroids are effective anti-inflammatory agents, long-term use of moderate to high-potency corticosteroids is known to cause burning, stinging, swelling, redness, discoloration, and skin hypersensitivity, and may cause or worsen other skin disorders such as acne, rosacea, perioral dermatitis, telangiectasia (small broken blood vessels), and pulsation (stretch marks).

[0010] Common topical antifungal treatments include drugs containing cyclopirox, drugs containing miconazole (Daktarin®, Micatin®, and Monistat®), drugs containing clotrimazole (Canesten®, Hydrozole®), and drugs containing butenafine (Lotrimin Ultra). These include drugs containing Ultra (registered trademark), Mentax (registered trademark), terbinafine (Lamisil (registered trademark)), amorolfine (Curanail (registered trademark), Loceryl (registered trademark), Locetar (registered trademark), and Odenil (registered trademark)), naphthifine (Naftin (registered trademark)), tolnaftate (Tinactin (registered trademark)), efinaconazole (Jublia (registered trademark)), and ketoconazole (Nizoral (registered trademark)). Other drugs that can be used to eliminate fungal infections include ethylparaben, flucytosine, salicylic acid, selenium sulfide, and undecylenic acid.

[0011] Cyclopirox olamine (Batrafen (registered trademark), Loprox (registered trademark), Penlac (registered trademark), and Cyclopirox (also known as Stieprox®) is a synthetic antifungal agent for topical dermatology with a high affinity for trivalent metal cations. Cyclopirox is typically supplied as a solution for application to the scalp, nails, and the skin immediately surrounding and beneath the nails. However, while cyclopirox can improve the condition of nails, it does not completely cure nail fungi. Furthermore, it may take more than six months for signs of improvement in infected nails to appear. In addition, cyclopirox topical solutions are flammable and may include side effects such as redness, irritation, itching, burning, blistering, swelling, or oozing at the application site, pain in the affected nail or surrounding area, discoloration or deformation of the nail, and ingrown toenails.

[0012] Ketoconazole cream (Nizoral®) is commonly used to treat tinea corporis (a fungal skin infection that causes red, scaly rashes on various parts of the body), tinea cruris, tinea pedis, tinea versicolor (a fungal infection that causes brown or light-colored patches on the chest, back, arms, legs, or neck), and yeast infections of the skin. Prescription ketoconazole shampoo is used to treat tinea versicolor. However, ketoconazole can cause side effects such as changes in hair texture, blistering of the scalp, dry skin, itching, oily or dry hair or scalp, irritation, itching, or stinging at the application site, rash, hives, difficulty breathing or swallowing, and redness, tenderness, swelling, pain, or warmth at the application site.

[0013] Therefore, in the art, there is a need for improved treatment options for patients suffering from fungal infections, including fungal infections of the nails, hair, and skin. Specifically, there is a striking need for a highly effective fungicide that a) rapidly and completely eradicates fungal infections of the nails, hair, and skin, and b) reduces facial redness or inflammation caused by Malassezia hypersensitivity resulting from Malassezia infections, the treatment of Malassezia infections, and / or the treatment of moderate to severe atopic dermatitis. The present invention provides roflumilast for topical administration as a viable and successful alternative to current antifungal treatments.

[0014] Locally administered roflumilast Roflumilast is known to be suitable for the treatment of inflammatory diseases. Compositions containing roflumilast have been used in human and veterinary medicine and have been proposed for the treatment and prevention of diseases including, but not limited to, inflammatory and allergen-induced airway disorders (e.g., bronchitis, asthma, COPD), skin diseases (e.g., proliferative, inflammatory, and allergen-induced skin disorders), and systemic inflammation of the gastrointestinal region (e.g., Crohn's disease and ulcerative colitis).

[0015] Roflumilast and its synthesis are described in U.S. Patent No. 5,712,298 ("'298 Patent"), which is incorporated herein by reference. * Pharmaceutical compounds with phosphodiesterase (PDE) inhibitory properties, such as roflumilast, have long been recognized as useful in the treatment of psoriasis and atopic dermatitis (298 patent, column 11, lines 52-61), as well as other chronic inflammatory and allergen-induced dermatitis. For the treatment of such skin diseases, emulsions, suspensions, gels, or solutions of roflumilast for topical application have been described (298 patent, column 12, lines 37-64).

[0016] * Unless otherwise indicated, references incorporated herein by reference are incorporated in their entirety for all purposes. Topical application of potent pharmacological agents like roflumilast to treat skin diseases has been found to provide patients with superior delivery, lower systemic exposure, and greater ease of use. The molecular structure of a compound ultimately determines the drug's ability to penetrate the epithelium of the tissue to which the product is applied. In the case of topical application to the skin, the selection of ingredients in the formulation is achieved by the compounder. Determine the maximum possible skin penetration. Creams, lotions, gels, ointments, and foams are just a few of the more familiar forms of topical products containing active pharmaceutical ingredients (APIs) for application to the skin. [Overview of the project]

[0017] According to the present invention, it has been discovered that topically administered roflumilast exhibits antifungal properties in addition to its known anti-inflammatory properties as a PDE4 inhibitor. These characteristics make topical roflumilast an optimal treatment for fungal infections, abnormal growth of fungi in hair, skin or nails, and inflammation due to fungal allergies. Topical roflumilast shows a significant and rapid reduction of Malassezia fungi and a high success rate in the treatment of seborrheic dermatitis. The success rate of the global assessment by the trial responsible physician at week 8 was 73.8% for 0.3% roflumilast, compared to 40.9% for the vehicle foam formulation. This rapid and successful treatment outcome indicates that topically administered roflumilast is an effective antifungal agent and presents a viable alternative to current antifungal treatments.

Brief Description of the Drawings

[0018] [Figure 1] The results of an in vitro microdilution susceptibility assay for testing the antifungal activity of roflumilast are shown. As shown in Figure 1 and Table B, roflumilast has been shown to exhibit antifungal activity against Malassezia species.

Modes for Carrying Out the Invention

[0019] Roflumilast is a compound of formula (I):

[0020]

Chemical

[0021] Here, R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyridin-4-yl. The chemical name of this compound is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast).

[0022] Hexylene glycol (pharmaceutical grade USP / NF) is 2-methyl-2,4-pentanediol of formula (II).

[0023] [ka]

[0024] Cetearyl alcohol (CAS 67762 30 0), dicetyl phosphate (CAS 2197 63 9), and ceteth-10 phosphate (CAS 50643-20-4) The emulsifier blend is manufactured by Croda under the trade name CRODAFOS® CES. CRODAFOS® CES PHARMA is manufactured using the same starting materials and processes, but undergoes enhanced quality control and release testing, and follows standard practices for the naming of pharmaceutical excipients, using the nomenclature cetearyl alcohol, cetearyl phosphate, and ceteareth-10 phosphate. This commercially available emulsifier blend is primarily composed of the waxy substance cetearyl alcohol (cetyl alcohol (C)). 16 H 34 O) and stearyl alcohol (C) 18 H 38 This is a self-emulsifying wax combining a mixture of (O) with 10-20% dicetyl phosphate (cetearyl phosphate) and 10-20% ceteth-10 phosphate (ceteareth-10 phosphate). The self-emulsifying wax forms an emulsion when blended with water. When CRODAFOS® CES is added to water, it naturally forms an emulsion with a pH of approximately 3. Sodium hydroxide solution is added to raise the pH to the desired value.

[0025] [ka]

[0026] Topical roflumilast product formulations that can be used to treat fungal infections or fungal overgrowth include, but are not limited to, aerosols, foams, sprays, emulsions (which may also be called creams, lotions, or ointments), gels (two-phase or single-phase), liquids, ointments, pastes, shampoos, suspensions, and systems. These are dosage forms containing the active pharmaceutical ingredient (US Pharmacopeia). <1151> This is a term in the second stage of the general classification method of ). In a preferred embodiment, the topical roflumilast product formulation includes a foam. More preferably, the topical roflumilast product formulation includes an ARQ154 foam.

[0027] Roflumilast can be prepared by methods known in the art (see, for example, the '298 patent and U.S. application number 14 / 075,035). Roflumilast formulations are also disclosed in U.S. Patent No. 9,884,050, U.S. application number 15 / 712,900, U.S. application number 16 / 426,492, U.S. application number 16 / 563,435 and U.S. application number 16 / 778,845, the entirety of which is incorporated herein.

[0028] Preferably, the topical formulation for treating fungal infections includes a composition containing 0.005 to 2.0%, preferably 0.3%, of roflumilast, which may be in one of the following forms.

[0029] Oil-in-water emulsions: This product may be a formulation in which hexylene glycol, a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate, and / or a solvent are added to an emulsion comprising a discrete phase of hydrophobic components, water and optionally one or more polar hydrophilic excipients, and a continuous aqueous phase containing additional solvents, cosolvents, salts, surfactants, emulsifiers, and other components. These emulsions may contain water-soluble or water-swellable polymers that help stabilize the emulsion. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0030] Aerosol foams: These products can be manufactured when an oil-in-water emulsion product concentrate is mixed with a liquid propellant, which is then mixed with the internal oil phase of the emulsion. The emulsifier in the oil-in-water emulsion also functions as a foaming agent. Rapidly breaking foams form a foam when released from a container, but the foam collapses relatively quickly. This type of foam is used to apply product concentrates over large areas without the need to rub or spread the product by hand. Also, because the foam collapses quickly, the active agent is available more rapidly. Using emulsifiers with limited solubility in both the organic and aqueous phases produces a stable foam. The emulsifier or emulsifying wax concentrates at the interface between the propellant / oil phase and the aqueous phase, forming a thin film called a "lamellae." It is the specific composition of these lamellae that determines the structural strength and general properties of the foam. Thick and tightly layered lamellae produce a highly structured foam that can support its own weight. One or more polar hydrophilic excipients, as well as additional solvents, cosolvents, salts, surfactants, emulsifiers, and other components, can be added to the emulsion product concentrate. These emulsions may contain water-soluble or water-swellable polymers that help stabilize the emulsion. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0031] Thickened aqueous gels: These systems include an aqueous phase thickened with a suitable natural, modified natural, or synthetic thickener, as described below. Alternatively, the thickened aqueous gel can be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic systems.

[0032] Thickened aqueous alcohol gels: These systems contain a blend of water and alcohol as a polar phase and are thickened with suitable natural, modified natural, or synthetic polymers as described below. Alternatively, thickened aqueous alcohol gels can be thickened using suitable polyethoxylate alkyl chain surfactants or other nonionic, cationic, or anionic systems. The alcohol may be ethanol, isopropyl alcohol, or other pharmaceutically acceptable alcohols.

[0033] Hydrophilic gels: These are gels in which the continuous phase is a water-soluble or water-dispersible hydrophilic gel with at least one water-soluble or water-dispersible hydrophilic component other than water. This system contains an aqueous component. This formulation may also optionally contain up to 60% by weight of water. In some compositions, higher levels may be appropriate. Suitable hydrophilic components include one or more glycols such as glycerin, propylene glycol, butylene glycol, polyethylene glycol (PEG), random or block copolymers of ethylene oxide, propylene oxide, and / or butylene oxide, polyalkoxylated surfactants having one or more hydrophobic moieties per molecule, silicone copolyols, blends of ceteareth-6 and stearyl alcohol, and combinations thereof.

[0034] Water-in-oil emulsions: The composition may be a formulation in which Roflumilast is incorporated into an emulsion comprising a continuous phase of hydrophobic components and an aqueous phase containing water and optionally one or more polar hydrophilic carriers, as well as salts or other components. These emulsions may contain oil-soluble or oil-swelling polymers, and one or more emulsifiers that help stabilize the emulsion. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0035] Hydrophilic or hydrophobic ointments: The composition contains a hydrophobic base (e.g., petrolatum, thickened or gelled water-insoluble oil, etc.) and optionally a small amount of water-soluble phase. Hydrophilic ointments generally contain one or more surfactants or humectants.

[0036] solvent The compositions according to the present invention may comprise one or more solvents or co-solvents to obtain a desired level of solubility of the active ingredient in a topical product. The solvent may also modify skin permeability or the activity of other excipients contained in the formulation. Solvents include, but are not limited to, acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methylpyrrolidinone, polyethylene glycol, glycerol, propylene glycol, and SD alcohol. When treating patients with inflammatory conditions, the solvent is preferably not ethanol, isopropyl alcohol, or denatured alcohol.

[0037] Moisturizer The composition according to the present invention may contain a humectant to increase the hydration level. The humectant may be a hydrophilic material containing a wetting agent or a hydrophobic material containing a emollient. Suitable humectants include 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl ester wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, and oleate. This includes, but is not limited to, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, white petrolatum, isopropyl palmitate, and stearyl alcohol.

[0038] Surfactants and emulsifiers The compositions according to the present invention optionally emulsify the composition and the surface of the activator or excipient. To help wet the water, one or more surfactants may be included. As used herein, the term “surfactant” means an amphiphilic substance (a molecule having both covalently polar and nonpolar regions) that can reduce the surface tension of water and / or the interfacial tension between water and an immiscible liquid. Surfactants include alkylaryl sodium sulfonates, amelcol-CAB, ammonium lauryl sulfate, apricot kernel oil PEG-6 ester, aracel, benzalkonium chloride, ceteareth-6, ceteareth-12, ceteareth-15, ceteareth-30, cetearyl alcohol / ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide sulfate ether, cocamine oxide, etc. Cobetaine, Cocodiethanolamide, Cocomonoethanolamide, Cococaprylate / Caprate, Disodium Cocoamphodiacetate, Disodium Laureth Sulfosuccinate, Disodium Lauryl Sulfoacetate, Disodium Lauryl Sulfosuccinate, Disodium Oleamide Monoethanolamine Sulfosuccinate, Sodium Doxate, Laureth-2, Laureth-23, Laureth-4, Lauric Diethanolamide, Lecithin, Mefoxy PEG-16, Methyl Gluceth-10, Methyl Gluceth-20, Methyl Glucose Sesquistearate, Oreth-2, Oreth-20, PEG-6-32 Stearate, PEG-100 Stearate, PEG-12 Glyceryl Laurate, PEG-120 Methyl Glucose Dioleate, PEG-15 Cocamine, PEG-150 Distearate, PEG-2 Stearate, PEG-20 Methyl Glucose Sesquistearate, PEG-22 Methyl Ether, PEG-25 Propylene Glycol Stearate, Nila PEG-4 Phosphate, PEG-4 Laurate, PEG-45 / Dodecyl Glycol Copolymer, PEG-5 Oleate, PEG-50 Stearate, PEG-54 Hydrogenated Castor Oil, PEG-6 Isostearate, PEG-60 Hydrogenated Castor Oil, PEG-7 Methyl Ether, PEG-75 Lanolin, PEG-8 Laurate, PEG-8 Stearate, Pegoxol-7 Stearate, Pentaerythritol Cocoate, Poloxamer 124, Poloxamer 181, Poloxamer 182,Poloxamer 188, Poloxamer 237, Poloxamer 407, Polyglyceryl-3 Oleate, Polyoxyethylene Alcohol, Polyoxyethylene Fatty Acid Ester, Polyoxyl 20 Cetostearyl Ether, Polyoxyl 40 Hydrogenated Castor Oil, Polyoxyl 40 Stearate, Polyoxyl 6 and Polyoxyl 32, Polyoxylglyceryl Stearate, Polyoxyl Stearate, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 6 5. The emulsifier includes, but is not limited to, polysorbate 80, PPG-26 oleate, PROMULGEN® 12, propylene glycol diacetate, propylene glycol diccaprate, propylene glycol monostearate, sodium xylene sulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2, steareth-20, steareth-21, steareth-40, tallow glycerides, and emulsifying waxes. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0039] Polymers and thickeners For certain applications, it may be desirable to formulate products thickened with soluble, swelling, or insoluble organic polymer thickeners such as natural and synthetic polymers, or with inorganic thickeners such as acrylate copolymers, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxyvinyl copolymers, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline waxes, and methylcellulose.

[0040] Additional ingredients The composition according to the present invention may contain additional components such as fillers, carriers, and excipients conventionally found in topical cosmetic and pharmaceutical products. In a preferred embodiment, The fillers, carriers, and excipients are suitable for topical administration. Additional components, including but not limited to antifoaming agents, preservatives (e.g., p-hydroxybenzoic acid esters, benzyl alcohol, phenylmercury salts, chlorocresol, methylparaben, propylparaben), antioxidants, metal ion chelating agents, stabilizers, buffers, pH adjusters, skin penetration enhancers, film-forming agents, dyes, pigments, diluents, fillers, fragrances, and other excipients, may be added to the composition to improve stability or aesthetics.

[0041] The compositions according to the present invention may be formulated with additional activators depending on other symptoms being treated. Additional activators include NSAIDs (e.g., aspirin, ibuprofen, ketoprofen, naproxen), apremilast, JAK inhibitors (e.g., tofacitinib, ruxolitinib, oclacit), leukotriene inhibitors (e.g., diluton, zafilkast, montelukast), mast cell stabilizers (e.g., nedocromil, cromolin sodium, ketotifen, pemirolast), anthralines (dislanol), azathioprine, tacrolimus, pimecrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylturacil, 6-thioguanine, sulfasalazine, mycophenolate tomofetil, fumarate esters, corticosteroids (e.g., Examples include, but are not limited to, acromethasone, amcinonides, betamethasone, clobetasol, crocotron, mometasone, triamcinolone, fluocinolone, fluocinonide, flulandrenolide, diflorason, desonide, desoximethasone, dexamethasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, prednicarbate, prednisone), corticotropins, vitamin D analogues (e.g., calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, tapinarof, cortisin, bronchodilators (e.g., betaagonists, anticholinergics, theophylline), and antibiotics (e.g., erythromycin, ciprofloxacin, metronidazole).

[0042] The compositions according to the present invention may be formulated with additional antifungal agents depending on the specific fungal infection being treated. These additional antifungal agents include miconazole (Daktarin, Micatin, and Monistat), cyclopirox olamine (Batrafen, Loprox, Penlac, and Stieprox), clotrimazole (Canesten, Hydrozole), butenafine (Lotrimin, Ultra, Mentax), terbinafine (Lamisil, Terbicil, Zabel), amorolfine (Curanail, Loseyl, Losetal, and Odenyl), and naphthifine. This includes, but is not limited to, drugs containing (naphthin), tolnaftate (tinactin), ketoconazole (nizoral), griseofulvin, imidazoles (bifonazole, clomidazole, econazole, fenticonazole, isoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, thioconazole), triazoles (fluconazole, itraconazole, posaconazole (noxafil), voriconazole (Vfend), benzimidazole (thiabendazole), ethylparaben, flucytosine, salicylic acid, selenium sulfide, and undecylenic acid. Alternatively, additional antifungal agents may be administered as separate compositions.

[0043] The composition according to the present invention can contain common topical anti-inflammatory agents, including diflucortolone valerate, fluocinonide, flulandrenolide, halobetasol propionate, amcinonide, desoxymethasone, diflorason, halcinonide, betamethasone valerate, diflorason diacetate, fluticasone propionate, mometasone furoate, triamcinolone acetonide, crocortolone pivalate, fluocinolone acetonide, fluticasone propionate, hydrocortisone valerate, mometasone furoate, desonide, and hydrocortisone butyrate. This includes, but is not limited to, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, betamethasone dipropionate-enhanced clobetasol propionate, alclomethasone dipropionate, hydrocortisone (base, ≥2%), hydrocortisone (base, <2%), calcineurin inhibitors, and hydrocortisone acetate. Alternatively, anti-inflammatory agents may be administered as separate compositions.

[0044] Dosage and administration The compositions according to the present invention can be administered by any suitable route of administration, including, but not limited to, oral, rectal, parenteral (e.g., intradermal, subcutaneous, intramuscular, intravenous, intramedullary, intraarterial, intrathecal, epidural), ocular, inhalation, spray, skin (topical), intradermal, and mucous membrane (e.g., sublingual, buccal, intranasal). In a preferred embodiment, the composition is administered topically.

[0045] Appropriate pharmaceutical dosage forms include, but are not limited to, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels, foams, transdermal patches, and solutions (e.g., injectable, oral).

[0046] The composition preferably contains roflumilast, a salt of roflumilast, N-oxide of roflumilast, or salts thereof in an amount of 0.005 to 2% w / w, more preferably 0.05 to 1% w / w, and most preferably 0.1 to 0.5% w / w per dose unit.

[0047] The composition preferably contains hexylene glycol in an amount between 0.1% and 20% w / w, more preferably between 0.25% and 8% w / w, and most preferably between 0.5% and 2% w / w.

[0048] The composition preferably contains a phosphate ester surfactant in an amount sufficient to produce a stable emulsion having a uniform sphere size. The concentration of the phosphate ester surfactant can generally be any concentration between 1.0% and 25% w / w. The preferred concentration may vary depending on the dosage form. In a preferred embodiment, if the formulation is a cream or ointment, the concentration of the phosphate ester surfactant is between 2.5% and 20%, a more preferred concentration range is between 5% and 15%, and the most preferred concentration is about 10% w / w. If the formulation is in the form of a foam, the concentration is preferably between 1.0% and 10%, more preferably between 1.0% and 10%, and most preferably 2%. Preferably, the phosphate ester surfactant is provided as a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0049] The composition preferably contains a sufficient amount of solvent to obtain the desired level of solubility of the active ingredient in the formulation. The amount of solvent is preferably 10-30% (w / w). The ratio of solvent to water is preferably 1:10-20:1. Preferably, the solvent is diethylene glycol monoethyl ether (DEGEE).

[0050] Topical formulations containing roflumilast are applied to the skin in an amount sufficient to obtain the desired pharmacological effect (typically, improvement of the signs and / or symptoms of a fungal infection). The amount of formulation applied may vary depending on the amount of roflumilast contained in the formulation, the concentration of roflumilast in the formulation, and the frequency at which the formulation is intended to be applied. Generally, the formulation is applied at a frequency of once a week to several times a day, preferably every other day to three times a day, most preferably once or twice a day.

[0051] The composition can be used in veterinary and human medicine for the treatment and prevention of fungal infections of the skin, nails, and hair. Preferably, the composition is used for fungal infections It is used to treat the abnormal proliferation of fungal species of the genus Malassezia, Trichophyton, Epidermophyton, or Microsporum. The Malassezia species are preferably Malassezia furfur, Malassezia globosa, Malassezia restricta and / or Malassezia pachydermatis. More preferably, the composition is used to treat proliferative and inflammatory fungal infections, such as seborrheic dermatitis, dandruff, dupilumab facial erythema, tinea versicolor, pityriasis versicolor, tinea annularis, and dermatophytosis, including tinea pedis (athlete's foot), dermatophytosis or onychomycosis, tinea manus, tinea cruris, tinea corporis, tinea faciei, tinea capitis, and tinea incognito.

[0052] Topical formulations containing roflumilast can be prepared by processes commonly used in the field of manufacturing topical pharmaceutical formulations. To produce a single-phase formulation such as a liquid, the components of the formulation can be combined and mixed until a homogeneous solution or suspension of the active ingredient is obtained. For example, to produce a multiphase formulation such as an emulsion, the components of the aqueous phase and the oil phase can be combined separately and mixed until a homogeneous solution is obtained, and then the aqueous solution and the oil solution can be combined and mixed by shear mixing or other means to form the formulation. One or more pharmacoactive substances can be dissolved (molecularly dispersed), complexed or associated with excipients or other active substances, or may be in particulate form (amorphous or crystalline). The oil phase can be added to the aqueous phase, or the aqueous phase can be added to the oil phase. These phases can be combined and mixed, for example, at a high temperature of 50-90°C, at room temperature between 20-30°C, or at a temperature between room temperature and high temperature.

[0053] The following examples are provided to enable those skilled in the art to manufacture and use the methods and compositions of the present invention. These examples are not intended to limit the scope that the inventors consider to be their invention. Additional advantages and modifications will be readily apparent to those skilled in the art. This specification encompasses the following embodiments of the invention. [ 1) A method for treating a fungal infection in a subject requiring treatment for a fungal infection, comprising the step of administering a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt thereof to the subject, wherein the fungal infection is caused by a species of Malassezia. [2] The method according to [1], wherein roflumilast is administered locally. [3] The method according to [1], wherein the Malassezia species is selected from the group consisting of M. furfur, M. restricta, and M. globosa. [4] The method according to [3], wherein the Malassezia species is M. furfur. [5] The method according to [1], wherein the fungal infection includes an abnormal proliferation of fungi on the hair, skin, or nails. [6] The above subjects include seborrheic dermatitis, dandruff, dupilumab facial redness, and tinea (tinea Tinea versicolor, pityriasis versicolor, tinea circinata, tinea pedis, tinea unguium, tinea manus, tinea cruris, tinea corporis, tinea fasciosa The method described in [1] for patients suffering from tinea faciei, tinea capitis, or tinea incognito. [7] The method according to [6], wherein the subject is suffering from seborrheic dermatitis. [8] The method according to [1], comprising the composition with a carrier suitable for local administration. [9] The method according to [1], wherein the composition is selected from the group consisting of aerosols, foams, sprays, emulsions, gels, liquids, ointments, pastes, shampoos, suspensions, and systems.

[10] The method according to [9], wherein the composition is a form.

[11] The method according to [1], wherein the composition comprises 0.3% w / w roflumilast.

[12] The method according to [1], wherein the composition comprises loflumilast, white petrolatum, isopropyl palmitate, cetearyl alcohol, dicetyl phosphate, ceteth-10 phosphate, hexylene glycol, diethylene glycol monoethyl ether, methylparaben, propylparaben, and water.

[13] The composition is Loflumilast 0.3% w / w White petrolatum 10.0% w / w Isopropyl palmitate 5.0% w / w Cetearyl alcohol, Dicetyl phosphate and a blend of Ceteth-10 phosphate 10.0% w / w Hexylene glycol 2.0% w / w Diethylene glycol monoethyl ether 25.0% w / w Methylparaben 0.2% w / w Propylparaben 0.05% w / w and Add purified water to make a total of 100 (47.45%) The method described in [1], comprising:

[14] The method according to [1], further comprising the step of administering an additional antifungal and / or anti-inflammatory agent.

[15] The method according to

[14] , wherein the additional antifungal agent is selected from the group consisting of drugs including miconazole, cyclopyroxolamine, clotrimazole, butenafine, terbinafine, amorolfine, naphthifine, tolnaftate, ketoconazole, efinaconazole, griseofulvin, imidazole, triazole, voriconazole, benzimidazole, ethylparaben, flucytosine, salicylic acid, selenium sulfide, and undecylenic acid.

[16] The method according to

[14] , wherein the additional anti-inflammatory agent is a corticosteroid or a calcineurin inhibitor.

[17] A method for reducing facial redness or inflammation caused by Malassezia infection, treatment of Malassezia infection and / or Malassezia hypersensitivity, comprising the step of topically administering an effective amount of roflumilast to a patient in need of such treatment.

[18] The method according to

[17] , wherein the Malassezia hypersensitivity is treated with dupilumab.

[19] The method according to

[17] , wherein the roflumilast is administered in a composition that does not contain ethanol, isopropyl alcohol, or denatured alcohol.

[20] The method according to

[19] , wherein the composition comprises loflumilast, white petrolatum, isopropyl palmitate, cetearyl alcohol, dicetyl phosphate, ceteth-10 phosphate, hexylene glycol, diethylene glycol monoethyl ether, methylparaben, propylparaben, and water.

[21] The method according to

[17] , wherein the Malassezia hypersensitivity is caused by M. furfur, M. restricta, and / or M. globosa.

[22] The method according to

[17] , further comprising the step of administering an anti-inflammatory agent.

[23] A method for treating a fungal infection, fungal overgrowth and / or hypersensitivity to a Malassezia species in a subject in need, comprising the step of topically administering a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt thereof to the subject, wherein the fungal infection or overgrowth is caused by a Malassezia species.

[24] A method for reducing facial redness and inflammation caused by treatment of moderate to severe atopic dermatitis, comprising the step of topically administering a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the facial redness and inflammation are caused by an infection of a species of Malassezia.

[25] The method according to

[24] , wherein an infection of the Malassezia species has been treated with dupilumab or is currently being treated with dupilumab.

[0054] Example 1 Samples of ARQ154 forms containing roflumilast at a concentration of 0.3% w / w and vehicle (0.2% MP, 0.05% PP) were used to prepare the formulations of the present invention. Hereinafter, it is referred to as Formulation 1. Formulation 1 was administered to M. furfur bacteria at 6.5×10 5 CFU / g. As shown in the table below, 24 hours after local administration of Formulation 1, the amount of remaining M. furfur bacteria was 5.3×10 3 CFU / g, and the log reduction was 2.1. This data indicates that the topically administered roflumilast formulation (Formulation 1) was successful in reducing the amount of M. furfur bacteria.

[0055] [Table 1]

[0056] Example 2 A comparative formulation was prepared using a sample of ARQ 154 form containing only vehicle (0.2% MP, 0.05% PP) (without roflumilast). Hereinafter, it is referred to as Comparative Formulation 1. Comparative Formulation 1 was topically administered to M. furfur bacteria at 6.5×10 CFU / g. As shown in the table below, 24 hours after local administration of Comparative Formulation 1, the amount of remaining M. furfur bacteria was 5.6×10 5 CFU / g, and the log reduction was 1.1. This data indicates that the topically administered Comparative Formulation 1 was not as successful as the roflumilast formulation (Formulation 1) in reducing the amount of M. furfur bacteria. 4 CFU / g, and the log reduction was 1.1. This data indicates that the topically administered Comparative Formulation 1 was not as successful as the roflumilast formulation (Formulation 1) in reducing the amount of M. furfur bacteria.

[0057] [Table 2]

[0058] Example 3 A comparative formulation was prepared using a sample of ARQ 154 form containing only the vehicle (without preservatives and roflumilast). This is hereinafter referred to as comparative formulation 2. Comparative formulation 2 was measured in 6.5 × 10⁻⁶ units. 5 The formulation was administered topically to M. farfar bacteria with a CFU / g concentration. As shown in the table below, 24 hours after topical administration of comparative formulation 2, the amount of residual M. farfar bacteria was 3.2 × 10⁶. 4 The CFU / g value was 1.3, and the logarithmic decrease was 1.3. This data indicates that the locally administered comparative formulation 2 was not as successful in reducing the amount of M. farfar as the roflumilast formulation (formulation 1).

[0059] [Table 3]

[0060] Therefore, Examples 1-3 demonstrate that topically administered roflumilast is a rapid and effective antifungal agent, offering a viable alternative to conventional topical antifungal preparations. Example 4 Loflumilast cream was prepared according to the following prescription.

[0061] Formulation A Loflumilast 0.3% w / w White petrolatum 10.0% w / w Isopropyl palmitate 5.0% w / w Crodafos CES 10.0% w / w (A blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate) Diethylene glycol monoethyl ether 25% w / w (Transcutol P) Methylparaben 0.2% w / w Propylparaben 0.05% w / w Add an appropriate amount of purified water to make a total of 100 (49.45%) Formulation B Loflumilast 0.3% w / w White petrolatum 10.0% w / w Isopropyl palmitate 5.0% w / w Crodaphos CES 10.0% w / w (A blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate) Hexylene glycol 2.0% w / w Diethylene glycol monoethyl ether 25.0% w / w (Transcutol P) Methylparaben 0.2% w / w Propylparaben 0.05% w / w Add an appropriate amount of purified water to make a total of 100 (47.45%) Example 5 In vitro susceptibility of Malassezia species to roflumilast The in vitro susceptibility of Malassezia species to roflumilast was determined using three Candida species as internal control isolates in all tests. These three isolates were C. albicans (American Type Culture Collection (ATCC) 90028), C. crusay (ATCC 6258), and C. parapsilosis (ATCC 22019). In addition to testing for roflumilast, all susceptibility assays were performed using ketoconazole and hydrocortisone as positive and negative control compounds, respectively. All assays were placed in a humidified incubator set to 32°C for a total of 7 days. Each assay was evaluated after 12 hours of incubation and every 24 hours thereafter for a total of 7 days. The assays were evaluated for visual growth of each pathogen in the untreated control and for determining the minimum inhibitory concentration (MIC) value. 3 log of fungal load from baseline on day 0 10The concentration that provides a reduction in CFU / mL was defined as the minimum fungicidal concentration (MFC) and was determined by quantifying the fungal load found in microplates on day 7.

[0062] The Rojas method (Rojas FD et al., "Antifungal drug susceptibility of Malassezia furfur, Malassezia sympodialis, and Malassezia globose to azoles and amphotericin B was evaluated using the broth microdilution method," 2014. Medical Mycology. 52:641-646) was used. The liquid broth medium used here was RPMI1640 supplemented with 1.8% glucose, 1% peptone, 0.5% oxbeil, 0.5% malt extract, 1% glycerol, 0.5% Tween 40, and 0.05% Tween 80. A round-bottom 96-well microplate was used. Inoculum was prepared with sterile saline and replenished with RPMI in 0.5 × 10⁶ wells. 5 ~2.5×10 5 The solution was diluted to the final target concentration of CFU / mL. Data for ketoconazole-positive controls and hydrocortisone-negative controls are shown in Table A. To confirm that the modified liquid broth medium did not significantly alter the ketoconazole sensitivity of the internal control isolate, the expected values ​​published by the Clinical Laboratory Standards Institute (CLSI) can be compared to the values ​​in Table A. The expected CLSI values ​​for the internal control isolate C. crusey (ATCC6258) were 0.12–1 (24 hours) and 0.25–1 (48 hours). As seen in Table A, ketoconazole was slightly less effective against the C. crusey (ATCC6258) isolate than expected based on CLSI guidelines. For the internal control isolate C. parapsilosis (ATCC22019), the expected CLSI values ​​for ketoconazole of 0.03–0.25 (24 hours) and 0.06–0.5 (48 hours) were consistent with the 2-day value (Table A) of 0.5. Hydrocortisone, used as a negative control, did not exhibit antifungal activity.

[0063] In vitro microdilution sensitivity assay Table A: Results of in vitro microdilution sensitivity assays using LOHAS methodology to test ketoconazole-positive controls and hydrocortisone-negative controls.

[0064] [Table 4]

[0065] As shown in Table B, roflumilast exhibits antifungal activity against Malassezia species compared to hydrocortisone-negative controls. The MIC value of roflumilast ranged from 32 to 128 mg / L on day 2. Roflumilast did not show antifungal activity against the Candida species tested using the LOHAS method.

[0066] Table B: Results of in vitro microdilution sensitivity assays using the LOHAS methodology for testing roflumilast.

[0067] [Table 5]

[0068] Example 6 Determining the level of Malassezia Seborrheic dermatitis is a common chronic inflammatory skin condition characterized by erythematous, scaly plaques, often with a yellowish, oily, moist, and / or greasy appearance, affecting areas rich in sebaceous glands. Commonly involved areas include the scalp (including the area behind the ears), eyebrows, ears, nasolabial folds, eyelids, trunk, and interstitial areas.

[0069] Topical roflumilast was administered once daily for two weeks in the form of a 0.3% foam formulation to 10 subjects with seborrheic dermatitis. Samples were taken from two sampling sites per participant using four skin swabs. At two time points, two skin swabs were taken from the treated area and two from the untreated area. The first time point was day 1 of treatment to establish baseline, and the second time point was 15 days later. Samples were taken by swabbing a 2cm × 2cm or 3cm × 3cm surface area of ​​skin for 2–4 minutes (using a ZymoR1109 DNA / RNA collection tube w / swab), and for each sampling site, two swabs (held together) were collected, rotating each time. For untreated areas, samples were taken from the shoulder / posterior deltoid region. For treated areas, if seborrheic dermatitis (SD) was present, samples were taken from the winged crease area of ​​the face. If SD was not present in this region, samples were taken from the body region most representative of the SD disease process. Samples were stored on-site at -80°C and shipped with dry ice until shipment to Microbac Laboratories. Samples were stored at Microbac Laboratories at -80°C until processing.

[0070] Primers / probes suitable for qPCR of Malassezia furfur, Malassezia globosa, Malassezia restricta, and other Malassezia species were identified in a peer-reviewed article, "Real-time PCR Identification of Six Malassezia Species," published in Current Microbiology, Vol. 74, pp. 671-677, in 2017. Controls were established via cells of Malassezia furfur, Malassezia globosa, and Malassezia restricta obtained from the American Type Culture Collection (ATCC) and synthetic DNA obtained from Integrated DNA Technologies (IDT).

[0071] Preliminary tests and verifications were carried out in the following manner: a. Creation of response curves using targets of known concentrations. b. This response curve was also used to determine the limit of detection (LOD) and limit of quantification (LOQ) of the assay.

[0072] qPCR analysis was performed using microorganisms according to in-house standard operating procedures. DNA extraction was performed using Qiagen's DNEasy kit (with modifications), and then qPCR was performed on the DNA extracted from each subject's swab as a single analysis for each target. In the initial analysis, both gene copy (gc) count and cycle threshold (Ct) were analyzed. Results showed a near-identical difference between untreated baseline and 15-day samples, while there was an order of magnitude decrease between treated baseline and treated 15-day samples. Statistical significance was found for treated sites. When using qPCR probes appropriate for Malassezia furfur, Malassezia globosa, Malassezia restricta, and Malassezia species as a whole, 7 out of 10 subjects experienced a significant decrease in Malassezia gene count (Malassezia furfur, Malassezia globosa, and / or Malassezia restricta) in the treated area over time. Nine of the subjects showed no change in the number of Malassezia genes in the untreated area, but one of the participating subjects showed a decrease.

Claims

1. Use of roflumilast or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating a fungal infection, fungal overgrowth, or fungal hypersensitivity in a subject requiring treatment, wherein the subject suffers from seborrheic dermatitis, the fungal infection, fungal overgrowth, or fungal hypersensitivity is caused by a Malassezia species, and the pharmaceutical composition is administered topically to the subject.

2. The use according to claim 1, wherein the fungal infection, fungal overgrowth, or fungal hypersensitivity is caused by a fungus selected from the group consisting of Malassezia furfur, Malassezia restricta, and Malassezia globosa.

3. The use according to claim 2, wherein the fungal infection, fungal overgrowth, or fungal hypersensitivity is caused by Malassezia furfur.

4. The use according to any one of claims 1 to 3, wherein the subject is a human.

5. The use according to any one of claims 1 to 3, wherein the composition comprises 0.3% w / w roflumilast.

6. Use of roflumilast or a pharmaceutically acceptable salt thereof in the preparation of a foam composition for use in a method for treating a fungal infection or fungal overgrowth in a person suffering from seborrheic dermatitis, the method comprising topically administering to the person a foam composition containing an antifungal effective amount of roflumilast or a pharmaceutically acceptable salt thereof, wherein the fungal infection or fungal overgrowth is caused by Malassezia furfur, and the antifungal effective amount of roflumilast is 0.3% w / w.

7. Use of roflumilast or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for reducing the number of at least one Malassezia species in a patient suffering from seborrheic dermatitis, wherein the pharmaceutical composition is administered topically.

8. The use according to any one of claims 1, 6, and 7, wherein the composition is a foam.

9. The use according to claim 8, wherein the composition further comprises a phosphate ester surfactant.

10. The use according to claim 9, wherein the phosphate ester surfactant comprises a blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

11. The use according to claim 9, comprising a phosphate ester surfactant in an amount of 1% to 25% w / w.

12. The use according to claim 9, comprising a phosphate ester surfactant in an amount of 2% w / w.

13. The use according to claim 1 or 7, wherein the composition further comprises diethylene glycol monoethyl ether.

14. The use according to claim 13, comprising diethylene glycol monoethyl ether in an amount of 10 to 30% w / w.

15. The use according to claim 13, comprising diethylene glycol monoethyl ether in an amount of 25% w / w.

16. The use according to claim 1 or 7, wherein the composition further comprises hexylene glycol.

17. The use according to claim 16, comprising hexylene glycol in an amount of 0.1% to 20% w / w.

18. The use according to claim 17, comprising hexylene glycol in an amount of 0.5% to 2% w / w.

19. The use according to claim 18, comprising hexylene glycol in an amount of 2% w / w.

20. The use according to claim 7, wherein the Malassezia species is selected from the group consisting of Malassezia furfur, Malassezia restricta, and Malassezia globosa.

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