JP2014019697A - Antifungal external composition and application method of antifungal external composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antifungal external composition, the antifungal external composition acting on a fungus 5 present on the surface of a skin area 10, and further a pharmaceutical component being sufficiently delivered to a skin tissue 20 and also a subcutaneous tissue 40 where the fungus 5 is present, effectively acting directly on the fungus 5, and thereby exhibiting significantly excellent antimicrobial performance.SOLUTION: Provided are: an antifungal external composition at least containing a terbinafine-based antifungal agent exhibiting antifungal efficacy of at least one of terbinafine and terbinafine hydrochloride and salicylic acid having skin penetration-facilitating efficacy exhibiting efficacy facilitating skin penetration of an antifungal agent; and an application method of the antifungal external composition.

Description

Detailed Description of the Invention

  The present invention relates to a fungal treatment for treating fungi such as ringworm and athlete's foot, and more particularly to an antifungal composition for treating fungi such as ringworm and athlete's foot and a method for applying the antifungal composition.

As a fungal therapeutic agent for treating fungi such as ringworm and athlete's foot, oral internal preparations used by taking and external preparations used by applying to inflamed areas are known. Examples of external preparations that are applied to the affected area of inflammation include liquid solutions, emulsified cream creams, sparingly water-soluble ointments, aqueous gel gels, and patches that are fixed and held on a planar substrate. Forms such as agents, patches, etc. are commonly used.
As such an external preparation for fungal treatment, an external preparation for fungal treatment having the following various forms, components and application methods has been proposed.

  In Japanese Patent Publication No. 9-504536 (Patent Document 1), an antifungal agent effective against filamentous fungi in a polymer matrix composed of an acrylate copolymer and the penetration of the antifungal agent into the nail are promoted. A nail mycosis treatment plaster is disclosed that is embedded in a nail penetration enhancer and is used by being attached to a nail. Seven types of nail penetration enhancers such as sulfoxides, acid amides, alkyl sulfonates, polyalcohols, salicylic acid keratolytic agent, urea, lactic acid, etc. are disclosed as nail penetration enhancers, and as antifungal agents , Tolcyclate, sulbene, haloprozin, griseofulvin, cyclopilox, propidone iodine, terbinafine, miconazole, econazole, isconazole, thioconazole, ketoconazole, itraconazole, and so on. It is disclosed that the antifungal penetration can be maintained through the nail for a long time, so that it stops for a few days.

  Japanese Patent Application Laid-Open No. 2001-316247 (Patent Document 2) discloses a nail varnish and a spray that achieve high penetrability throughout the nail by combining a keratolytic agent and a wetting agent with an antifungal agent, A total of 20 types of fungi drugs, such as clitrimazole, miconazole nitrate, amphotericin, butefanin, butconazole, futicin carbonate, sodium thiosulfate, terbinafine, and 12 other types, are disclosed, and keratolytic drugs include urea, sulfur, salicylic acid, podophyllum. A total of four types of antifungal agents such as resins are disclosed, achieving high penetrability throughout the nail, and a local sustained release delivery system of antifungal agents to the fingers and toes is disclosed.

  On the other hand, JP-T-2007-523137 (Patent Document 3) discloses a composition comprising salicylic acid or a salt thereof and hydrolyzed milk protein, which is a skin care composition for topical application to the skin, and prevents acne. It is disclosed that it is useful for therapeutic treatments, in particular for improving the therapeutic effect of acne and for creating a normal moisture-skin film on the skin. It is also suggested that the content of salicylic acid in the skin care composition that is effective for the prevention and therapeutic treatment of acne is 0.01% to 10% by weight, most preferably 1% to 3% by weight. Has been. It has also been suggested that excessive use of salicylic acid causes discomfort such as skin peeling, inflammation and redness.

  JP-T-2007-523138 (Patent Document 4) contains salicylic acid or a salt thereof and a gelling agent in the form of an acryloyldimethyltaurine-containing copolymer, and is a gel-form acceptable as a cosmetic in the form of a hydroalcohol gel dispersion. It is disclosed that the skin care composition is useful for cleaning the skin and preventing / treating acne. Here, salicylic acid or a salt thereof is disclosed as an active ingredient that exhibits efficacy in the prevention and treatment of acne. The salicylic acid content in the gel-like skin care composition that is effective for the prevention and treatment of acne is 0.1% by weight to 5% by weight, more preferably 0.5% by weight to 3% by weight. Has also been suggested. In addition to the above composition, triclacene, other 14 types of antibacterial compounds, acyclovir, others, 3 types of antiviral compounds, farnesol, terbinaphene hydrochloride, other 16 types of antifungal compounds, hydrocortisone In addition, a cosmetically acceptable skin care composition containing a total of 19 active ingredients such as anti-inflammatory compounds is disclosed. In general, it has also been suggested that salicylic acid is a local keratolytic agent that works by dissolving the epithelial cell stroma.

  Japanese Patent Publication No. 2005-519126 (Patent Document 5) and Japanese Patent Publication No. 2006-519263 (Patent Document 6) disclose a skin, cosmetic, or pharmaceutical product having a matrix layer of a water-sensitive polymer having bioadhesive properties. Patches for controlled topical or transdermal delivery of active ingredients, where pharmaceutically active ingredients are antioxidants, moisturizers, anti-inflammatory agents, antifungal agents, etc., especially cosmetic, skin One or more of the scientific and pharmaceutically active ingredients is triclosan, popidone iodine, resorcinol, keratolytic agent containing salicylic acid, iodine, mercury, silver, phenol, nitrophenalone, aspirin, isoprofen, antihistamine, calamine, etc. Seventeen active ingredients are disclosed. That is, it has been suggested that salicylic acid acts as a keratolytic agent.

  JP 2002-363070 (Patent Document 7) is a transdermal patch containing an antifungal agent and a dissolution agent for preventing crystal precipitation of the antifungal agent in an adhesive base component, As antifungal agents, bifonazole, terbinafine, naphthifine, salicylic acid, sulfur, and other 45 types of antifungal agents are disclosed, thereby suppressing crystallization of the antifungal agent, good drug release and skin release. Superficial fungi such as athlete's foot, bugs, etc. that have drug transferability, can absorb the drug from the skin, can exert sufficient effects on the treatment of fungal diseases such as ringworm and candidiasis on the skin It is disclosed that it is useful for the treatment of diseases.

  In JP-A-8-20527 (Patent Document 8), at least one of a total of eight types of antifungal agents such as butenafine hydrochloride, bifonazole, eticonazole hydrochloride, ketoconazole, ranoconazole, terbinafine hydrochloride, amorphine hydrochloride, and rilanaphthate is included. In a composition for external use of keratin reservoir type antifungal compounded, one of five types of keratin penetration enhancer such as methyl salicylate, glycol salicylate, crotamiton, mint oil, menthol, etc. is blended, ointment, cream, gel A keratinous storage type antifungal composition for external use having a form of an agent or a gel cream has been proposed. This will promote the penetration of antifungal agents into the epidermal stratum corneum, and further enhance the keratin permeability and storage properties of antifungal agents, such as helping to bind and immobilize components with the epidermal stratum corneum. Has been.

  Japanese National Patent Publication No. 9-504536   JP 2001-316247 A Specification   Special table 2007-523137 specification   JP-T-2007-523138   JP 2005-519126 A Specification   JP-T-2006-519263   Japanese Patent Laid-Open No. 2002-363070   JP-A-8-20527

  In the above prior art, an antifungal external preparation (or antibacterial external preparation) containing a keratolytic agent (or nail penetration enhancer) and an antifungal agent (or antibacterial agent) is disclosed.

  In particular, seven types of nail permeation accelerators, such as sulfoxides, acid amides, alkyl sulfonates, polyalcohols, salicylic acid keratolytic agent, urea, and lactic acid, are disclosed (Patent Document 1). As keratolytic agents for nail sprays, a total of four types such as urea, sulfur, salicylic acid, and podophyllum resin are disclosed (Patent Document 2). The use of salicylic acid as a keratolytic agent in cosmetic, dermatological and pharmaceutically active ingredients is disclosed (Patent Documents 5 and 6).

  In particular, salicylic acid has been disclosed as an effect for preventing and treating acne and acne (Patent Documents 3 and 4).

  In particular, as antifungal agents, Patent Document 1 discloses a total of 13 types of antifungal agents such as terbinafine, Patent Document 2 discloses a total of 20 types of antifungal agents such as terbinafine, and Patent Document 4 discloses terbinafine hydrochloride. 16 types of antifungal agents are disclosed, and Patent Document 7 discloses a total of 45 types of antifungal agents such as terbinafine and salicylic acid.

  In particular, Patent Document 8 discloses a keratin storage type antifungal containing a total of 8 antifungal agents such as terbinafine hydrochloride and 5 keratin penetration enhancers such as methyl salicylate, glycol salicylate, crotamiton, mint oil, and menthol. An external composition is disclosed. The keratin penetration enhancer disclosed here is methyl salicylate and glycol salicylate, and is a substance different from salicylic acid.

  Thus, in the prior art, an antifungal external agent (or antibacterial external agent) containing a keratolytic agent (or nail penetration enhancer) and an antifungal agent (or antibacterial agent) is disclosed, and the keratolytic agent (or Nail permeation enhancers), more than 10 types of keratolytic agents are listed and disclosed, and more than 30 types of antifungal agents (or antibacterial agents) are listed and disclosed. Has been. However, antifungal external preparations containing components of both a specific keratolytic agent (or keratin penetration enhancer) and a specific antifungal agent are not disclosed in any prior art, and further, those The action and effect exhibited by the antifungal external preparation containing both the specific keratolytic agent (or keratin penetration enhancer) and the specific antifungal agent is also not disclosed clearly.

In general, in fungal diseases such as ringworm fungus and athlete's foot on the human skin, the fungus invades and proliferates inside the skin region such as the stratum corneum constituting the skin. Therefore, in order for the antifungal agent to have an excellent medicinal effect against mycosis, in addition to the strong antibacterial performance of the medicinal component, the medicinal component is efficiently delivered into the skin where the fungus is present, and the medicinal component It is important to act directly on the fungus and thereby cure the mycosis.
Generally, in an antifungal composition containing a keratolytic agent and an antifungal agent, the fungal disease healing action effect exerted by the combination of each active ingredient and type of the keratolytic agent and antifungal agent contained is Different.

  The present invention applies these anti-fungal composition containing a medicinal component of both a specific keratin penetration enhancer and a specific anti-fungal agent to mycosis, thereby making these specific keratin penetration enhancer and a specific Synergistic action with antifungal agents acts on the fungi present on the surface of the skin area, and further, the medicinal ingredients are efficiently delivered to the inside of the skin area where the fungi are present, so that the medicinal ingredients are effectively delivered directly to the fungus. It has been found that this makes it possible to cure mycosis while at the same time exhibiting remarkably excellent antibacterial performance.

  The antifungal composition for external use of the present invention is a terbinafine antifungal agent having at least one antifungal effect of terbinafine and terbinafine hydrochloride, and skin having an effect of promoting skin penetration of the terbinafine antifungal agent. And salicylic acid having a penetration promoting effect.

  Desirably, in the antifungal composition for external use, skin composed of a skin tissue comprising an epidermis including a stratum corneum and a dermis located inside the epidermis, and a subcutaneous tissue located inside the skin tissue. When applied to the surface of the region, the salicylic acid has an effect of promoting skin penetration of the terbinafine antifungal agent by altering the state of the skin tissue by altering the state of the skin tissue. The antifungal agent acts on a fungus present on the surface of the skin region, and further penetrates the skin tissue whose state has been altered by the skin state alteration action of the salicylic acid, so that of the skin tissue and the subcutaneous tissue. It permeates into at least one of the skin regions and acts on fungi existing in the skin region.

  Desirably, in the antifungal composition for external use, skin composed of a skin tissue comprising an epidermis including a stratum corneum and a dermis located inside the epidermis, and a subcutaneous tissue located inside the skin tissue. When applied to the surface of the region, in the antifungal composition for external use, the salicylic acid does not alter the state of the skin tissue in the macroscopic observation, does not dissolve the stratum corneum, and in the microscopic observation The terbinafine antifungal agent is contained in a range of concentrations that exhibit a skin state alteration action that alters the state of the skin tissue, and the terbinafine antifungal agent penetrates the skin tissue that has undergone the state alteration and penetrates into the skin region. It is characterized by acting on fungi existing inside the region.

  Preferably, the antifungal composition for external use is characterized in that the salicylic acid is contained in an amount of 0.1 to 0.8% by weight based on the total amount of the composition.

  Preferably, in the antifungal composition for external use, the terbinafine antifungal agent is contained in an amount of 0.5 to 10.0% by weight based on the total amount of the composition.

  Preferably, in the antifungal composition for external use, the salicylic acid is contained in an amount of 0.1 to 0.8% by weight based on the total amount of the composition, and the terbinafine antifungal agent is 0.5% by weight based on the total amount of the composition. It is characterized by containing ˜10.0% by weight.

  Preferably, the antifungal composition for external use further contains water, and at least a part of the terbinafine antifungal agent is dissolved and emulsified in the form of a cream. .

  The method for applying the antifungal composition for external use of the present invention comprises (a) promoting skin penetration of terbinafine antifungal agent having at least one antifungal effect of terbinafine and terbinafine hydrochloride and the terbinafine antifungal agent A step of preparing an antifungal composition for external use containing salicylic acid having an effect of promoting skin permeation, and (b) applying the antifungal composition to the surface of the skin region in which inflammation is caused by the fungus Wherein the skin region is composed of a skin tissue composed of an epidermis including a stratum corneum and a dermis located inside the epidermis, and a subcutaneous tissue located inside the skin tissue, (c) When the antifungal composition for external application is applied to the surface of the skin region, the salicylic acid has a skin state alteration effect to alter the state of the skin tissue. The terbinafine antifungal agent has the effect of promoting skin penetration, and the terbinafine antifungal agent acts on fungi present on the surface of the skin region, and further, by the skin condition alteration effect of the salicylic acid. Permeates the skin tissue whose state has been changed, penetrates into the skin region of at least one of the skin tissue and the subcutaneous tissue, and acts on fungi existing in the skin region, whereby the skin Treating a mycosis caused by a fungus present within at least one of the surface of the region, the skin tissue, and the subcutaneous tissue.

  Preferably, in the method for applying the antifungal composition, (d) the antifungal composition is applied to the surface of the skin region at predetermined time intervals, and the step (c) is repeated. Acting on a fungus present inside the region, thereby treating a mycosis caused by the fungus present in the skin region.

  Desirably, in the method for applying the antifungal composition for external use, the salicylic acid is contained in an amount of 0.1 to 0.8% by weight based on the total amount of the composition, and the terbinafine antifungal agent is added in an amount of 0.00% per total amount of the composition. It is characterized by containing 5 wt% to 10.0 wt%.

  Preferably, in the method for applying the antifungal composition, the antifungal composition is in the form of a cream.

In general, the skin region of the human body is composed of a skin tissue composed of an epidermis including a stratum corneum and a dermis located inside the epidermis, and a subcutaneous tissue located inside the skin tissue. The stratum corneum is composed mainly of the protein on the outermost layer on the outermost side of the skin, and keeps a certain thickness by peeling off as a new dermis is formed from below. The stratum corneum is a state in which the dermis cells have lost their cell nuclei and play various roles. In the present invention, the skin region is defined as being composed of skin tissue and subcutaneous tissue, and the skin tissue is composed of epidermis and dermis including the stratum corneum.
Fungi such as athlete's foot and ringworm live and settle on the surface of the epidermis and in the epidermis such as the stratum corneum. In addition, when the mycosis is seriously injured, the fungus penetrates even into the dermis and subcutaneous tissue inside the epidermis.

  In such a mycosis state, at least one of terbinafine and terbinafine hydrochloride, a terbinafine antifungal agent that exhibits antifungal efficacy, and a skin penetration promoting effect that promotes skin penetration of the antifungal agent An antifungal composition containing salicylic acid having the following formula is applied to the surface of the skin area where the fungus is present and applied to inactivate the fungus present on the skin area surface and inside the skin area, or An extremely excellent antibacterial effect such as killing and treating mycosis caused by fungi is obtained.

Desirably, in such a mycotic condition, at least one of terbinafine and terbinafine hydrochloride, a terbinafine antifungal agent that exhibits antifungal efficacy, and skin that exhibits the effect of promoting skin penetration of the antifungal agent. When an antifungal composition containing salicylic acid having a penetration promoting effect is applied to the surface of the skin region, the salicylic acid exerts a skin state alteration action to alter the state of the skin tissue, thereby terbinafine. It has the effect of promoting skin penetration of antifungal agents, and terbinafine antifungal agents act on fungi present on the surface of the skin area, and further penetrate skin tissue that has been altered by the skin condition alteration of salicylic acid. Penetrates and is present in at least one skin area of skin tissue and subcutaneous tissue. Acting on the fungus.
That is, when the antifungal composition for external use is applied to the surface of a skin region that develops mycosis, the skin tissue is altered to a wet, softened, or swollen state due to the skin condition altering action of salicylic acid. In this skin alteration state, the terbinafine antifungal agent acts on fungi present on the surface of the skin region, and further penetrates into the skin tissue altered by the skin state alteration action of salicylic acid, and the skin tissue and It penetrates at least one skin area of the subcutaneous tissue and acts on fungi present in that skin area. In this way, the terbinafine antifungal agent acts on a fungus existing inside at least one of the surface of the skin area, the skin tissue and the subcutaneous tissue to inactivate or kill the fungus. The effect of treating mycosis caused by fungi is exhibited.

More preferably, in the antifungal composition for external application, the salicylic acid does not alter the state of the skin tissue in the macroscopic observation, does not dissolve the stratum corneum, and alters the state of the skin tissue in the microscopic observation. The antifungal composition for external use is contained in a range of concentrations that exert a skin condition altering action, and is composed of a skin tissue composed of an epidermis including a stratum corneum and a dermis located inside the epidermis, and inside the skin tissue. When applied to the surface of the skin area composed of the subcutaneous tissue located, the skin tissue state does not change in macroscopic observation, the stratum corneum does not dissolve, and the skin tissue in microscopic observation The terbinafine antifungal agent permeates the skin tissue that has undergone the state change, thereby causing the skin region to change. It penetrates into, act on fungi present inside the skin area.
That is, the concentration of salicylic acid is a concentration within a range in which no change in the state of the skin tissue is observed in macroscopic observation, and in addition, no dissolution of the stratum corneum is observed. It is contained at a concentration in a range that exerts a skin condition alteration effect that alters the condition of the tissue. When the antifungal composition containing salicylic acid at such a concentration is applied to the surface of the skin area where mycosis is occurring, the skin tissue is sterilized by macroscopic observation due to the skin state alteration effect of salicylic acid. No alteration of the tissue state is observed, and the tissue is altered to a wet, softened or swollen state in microscopic observation. In this skin alteration state, the terbinafine antifungal agent acts on fungi present on the surface of the skin region, and further penetrates into the skin tissue altered by the skin state alteration action of salicylic acid, and the skin tissue and It penetrates at least one skin area of the subcutaneous tissue and acts on fungi present in that skin area. In this way, the terbinafine antifungal agent acts on a fungus existing inside at least one of the surface of the skin area, the skin tissue and the subcutaneous tissue to inactivate or kill the fungus. The effect of treating mycosis caused by fungi is exhibited.

Further, according to the method for applying an antifungal composition for external application of the antifungal composition of the present invention repeatedly applied to the surface of the skin region every predetermined time, the terbinafine antifungal agent is further improved by the skin condition alteration action of salicylic acid. To fungi that penetrate into skin tissue that has been altered, penetrate further into at least one skin region of skin tissue and subcutaneous tissue, and move or exist deeper into skin tissue or deeper into subcutaneous tissue Acts to exert antifungal efficacy and completely inactivate or kill the fungus. Thus, the mycosis resulting from a fungus is treated by repeatedly applying the antifungal composition for external use to the surface of the skin region every predetermined time.
That is, when the antifungal composition for external application is applied to the surface of the skin region, it acts on the fungus present on the skin tissue surface and inside the skin tissue to deactivate or kill some fungi, however, The fungus may move to the skin or subcutaneous tissue fold without being inactivated or killed, resulting in a state where the fungus has propagated.
In such a state, by repeatedly applying the antifungal composition externally to the surface of the skin region every predetermined time, it is repeated for the fungus that has further migrated and propagated to the back of the skin tissue or subcutaneous tissue, The effect of the above-described salicylic acid on the skin condition alteration and the antifungal effect of the terbinafine antifungal agent is exerted to completely inactivate or kill the fungus.

  In the description of the present invention, the phrases “skin condition alteration” and “alter skin tissue condition” are “the skin tissue change is not recognized with the naked eye”, and “skin tissue is destroyed or dissolved. Without "means" in the microscopic observation, the state of the skin tissue is changed to wet / softened, etc. ". In other words, it means that “the appearance of the skin tissue is altered in the microscopic observation without altering the state of the skin tissue in the macroscopic observation”. Also, the terms “penetration”, “permeation”, “passage” have similar meanings to each other, and the terbinafine antifungal agent is “delivered or reached by some mechanism from the surface of the skin area to the inside of the skin area”. Means "do".

It is a schematic structure diagram for explaining a schematic structure of a human skin region applied to the present invention and fungi existing in the skin region.

FIG. 1 shows a schematic schematic structure of a human skin region applied to the present invention and a schematic structural diagram for explaining fungi existing in the skin region.
In FIG. 1, a skin region 10 includes a skin tissue 20 including a skin 2 including a stratum corneum 2 a and an epidermis functional layer 2 b, and a dermis 3 located inside the skin 2, and a subcutaneous located inside the skin tissue 20. The epidermal functional layer 2b is composed of a granular layer, a spiny layer, and a basal layer. In the skin region 10, pore groups (not shown) reaching the surface of the stratum corneum 2 a from the subcutaneous tissue 40 and capillaries (not shown) are formed from the subcutaneous tissue 40 to the dermis 3.
In general, fungi 5 such as ringworm and athlete's foot are present on the surface of the skin region 10, inside the stratum corneum 2a, or at the boundary between them. When the mycosis is seriously injured, the fungus 5 further exists in the skin tissue 20 such as the epidermis 2 and the dermis 3 including the stratum corneum 2a and the subcutaneous tissue 40.

  The antifungal composition for external use of the present invention is a terbinafine antifungal agent having at least one antifungal effect among terbinafine and terbinafine hydrochloride, and skin having an effect of promoting skin penetration of the terbinafine antifungal agent It contains both components of salicylic acid having a penetration promoting effect.

  Terbinafine hydrochloride is a white or slightly yellow crystal at normal temperature with a melting point of 203-208 ° C. (decomposition), easily soluble in methanol, ethanol, acetic acid, hardly soluble in water, acetic anhydride, and has an antifungal effect against dermatomycosis. This is well known. Terbinafine is a phrase commonly used as an abbreviation for terbinafine hydrochloride. In the present invention, terbinafine means the same substance as terbinafine hydrochloride. Terbinafine and terbinafine hydrochloride are one of about 30 or more types of antifungal agents disclosed in the aforementioned Patent Documents 1, 2, 4, 7 and the like.

  Salicylic acid is a colorless needle-like crystal at a normal temperature with a melting point of 159 ° C., and its solubility in water per 100 ml of water at 20 ° C. is 0.2 g, and it has been used as an analgesic in the past. 1, 2, 4, 5 and 6 are proposed for application as a skin keratolytic agent, and Patent Documents 3 and 4 disclose that they are effective as preventive and therapeutic agents such as acne and acne. It is a substance that has been. Salicylic acid is one of about 10 or more types of keratolytic agents disclosed in the aforementioned Patent Documents 1, 2, 4, 5, 6 and the like.

Thus, in the prior art, salicylic acid has been proposed for use as a keratolytic agent that has the effect of dissolving keratin, whereas in the present invention, salicylic acid is used together with a terbinafine antifungal agent. By using the antibacterial agent, the terbinafine antifungal agent exerts the effect of promoting the skin permeability of the terbinafine antifungal agent, and the terbinafine antifungal agent penetrates into the skin tissue 20 and the subcutaneous tissue 40, so that the skin tissue 20 and the subcutaneous tissue 40 are absorbed. It has been found that it has the effect of inactivating or killing fungi 5 lurking in the interior of the skin by acting on fungi 5 present in the skin.
That is, in particular, the specific combination composition of salicylic acid and a terbinafine antifungal agent inactivates or kills the fungi present on the surface of the skin region 10 and inside the skin region, thereby causing the mycosis caused by the fungus 5 It has been found that remarkably superior antibacterial effects such as treatment can be obtained.

  In particular, “salicylic acid has the effect of promoting skin penetration of a terbinafine antifungal agent by altering the state of the skin tissue 20 by altering the state of the skin condition, and the terbinafine antifungal agent is effective in the skin region 10. In addition to acting on the fungus 5 present on the surface, it further penetrates the skin tissue 20 that has been altered by the skin condition alteration of salicylic acid, and penetrates at least one skin region 10 of the skin tissue 20 and the subcutaneous tissue 40. The fungus 5 present on the surface of the skin region and in the skin region is inactivated or killed, and the mycosis caused by the fungus 5 is treated, etc. It is a thing.

  That is, a skin tissue 20 comprising an epidermis 2 including a stratum corneum layer 2a and an dermis 3 located inside the epidermis 2 in which an antifungal external composition containing at least a terbinafine antifungal agent and salicylic acid, and the skin tissue When applied to the surface of the skin region 10 composed of the subcutaneous tissue 40 located inside the skin 20, salicylic acid exerts a skin state alteration action to alter the state of the skin tissue 20. The terbinafine antifungal agent has the effect of promoting the skin penetration of the fungal agent. The terbinafine antifungal agent acts on the fungus 5 existing on the surface of the skin region 10, and further, the skin tissue 20 whose state has been altered by the skin state alteration action of salicylic acid. Penetrates and penetrates into the skin region 10 of at least one of the skin tissue 20 and the subcutaneous tissue 40, and exists within the skin region. That acts on the fungus 5, inactivated fungi 5, or die. In this way, the mycosis caused by the fungus 5 is treated and a remarkably excellent antibacterial effect is obtained.

  Although "salicylic acid skin condition alteration action" and "salicylic acid promotes skin penetration of terbinafine antifungal agents" have not been clearly clarified academically, as a result of repeating various experiments, By using salicylic acid together with a terbinafine antifungal agent, the effect of promoting the skin permeability of the terbinafine antifungal agent is exerted, and the terbinafine antifungal agent penetrates into the skin tissue 20 and the subcutaneous tissue 40. Thus, it has been found that it acts on the fungus 5 existing in the skin tissue 20 and the subcutaneous tissue 40 to inactivate or kill the fungus 5 lurking inside the skin.

  When an antifungal external composition containing at least a terbinafine antifungal agent and salicylic acid is applied to the surface of the skin region 10, the skin tissue 20 is in a wet or soft state without being destroyed or dissolved. Although it has not been clearly clarified scientifically, the skin penetration of the terbinafine antifungal agent is promoted and the terbinafine antifungal agent is converted into the skin region. It is presumed that it acts on the fungi 5 existing inside 10 and inactivates or kills the fungus 5 lurking inside the skin. In this way, the mycosis caused by the fungus 5 is treated and a remarkably excellent antibacterial effect is obtained.

  Such an antifungal composition for external use is repeatedly applied to the surface of the skin region 10 every predetermined time, so that the fungus 5 which has further moved to the back of the skin tissue 20 or the subcutaneous tissue 40 and propagated is repeatedly used. As a result, the skin state-modifying action of salicylic acid and the antifungal effect action of the terbinafine antifungal agent are exhibited, and the action effect of completely deactivating or killing the fungus 5 is exhibited.

Generally, when an antifungal composition containing terbinafine antifungal agent and salicylic acid is applied to the surface of the skin region 10, the skin tissue increases as the content of salicylic acid contained in the antifungal composition increases. The state of No. 20 was “a state in which no change was observed in the state of the skin tissue 20 in the macroscopic observation, and a state in which the state changed to wet, softening, and swelling in the microscopic observation”, and the content of salicylic acid further increased. In this case, the skin region 10 changes to “a state in which destruction of the skin tissue 20 such as damage and dissolution of the stratum corneum 2a is observed even in macroscopic observation”.
In such a state, in the present invention, “salicylic acid does not alter the state of the skin tissue 20 in the macroscopic observation, does not dissolve the stratum corneum 2a, and alters the state of the skin tissue 20 in the microscopic observation. "Constitution contained in a range of concentrations that exhibit a skin condition alteration effect" is particularly desirable.
When an antifungal external composition containing such a salicylic acid concentration range is applied to the surface of the skin region 10, the skin tissue 20 is in a state of the skin tissue 20 in macroscopic observation due to the skin state alteration action of salicylic acid. No alteration is observed, and the sample is altered to a wet, softened, or swollen state in microscopic observation. In this skin alteration state, the terbinafine antifungal agent acts on the fungus 5 present on the surface of the skin region 10, and further penetrates into the skin tissue 20 that has been altered by the skin state alteration action of salicylic acid. It penetrates at least one skin region 10 of the skin tissue 20 and the subcutaneous tissue 40 and acts on the fungus 5 present in the skin region 10. In this way, the terbinafine antifungal agent acts on the fungus 5 existing in the surface of the skin region 10, at least one of the skin tissue 20 and the subcutaneous tissue 40, and loses the fungus 5. The effect of activating or dying and treating mycosis caused by the fungus 5 is further remarkably exhibited.

  The phenomenon in which salicylic acid exerts the “skin penetration promoting effect of promoting the skin penetration of terbinafine antifungal agents” has not been clearly clarified scientifically, but the possible view will be explained. That is, when the antifungal composition for external application is applied to the surface of the skin region 10, the skin region 10 and its surroundings are not affected by the skin state alteration action of salicylic acid, and the state of the skin tissue 20 is not observed by macroscopic observation. However, in microscopic observation, the state of the skin tissue 20 is altered due to wetting, softening, swelling, etc., and the pore groups organized in the skin region 10 are also softened. In this state, the terbinafine antifungal The agent is likely to be delivered to the skin tissue 20 and the subcutaneous tissue 40 through the softened pore group. Alternatively, the terbinafine antifungal agent and salicylic acid exhibit some chemical interaction, so that the terbinafine antifungal agent easily penetrates the skin tissue 20 and is delivered to the skin tissue 20 and the subcutaneous tissue 40.

  As described above, salicylic acid has the effect of altering the skin tissue 20 when applied to the skin surface. As the salicylic acid content increases, the skin tissue 20 is destroyed and dissolved. Become harmful. Therefore, the content of salicylic acid contained in the antifungal composition for external use is desirably the minimum content that can exert the effect of promoting the skin penetration of the terbinafine antifungal agent.

  In the present invention, it is desirable that salicylic acid is contained in an amount of 0.1 to 0.8% by weight based on the total amount of the antifungal composition for external use. The content of salicylic acid is more preferably 0.2% by weight to 0.5% by weight based on the total amount of the antifungal external composition.

When the content of salicylic acid contained in the antifungal composition for external use is less than 0.1% by weight based on the total amount of the antifungal composition, the skin penetration promoting effect of promoting the skin penetration of the terbinafine antifungal agent There is little effect which inactivates and kills the fungus 5 which exists in the skin tissue 20 and the subcutaneous tissue 40.
In particular, when salicylic acid is not contained in the antifungal composition for external use, the state of the skin tissue 20 does not change to softening / swelling, without exhibiting the effect of promoting skin penetration of the terbinafine antifungal agent, The effect of inactivating / killing the fungus 5 existing in the skin tissue 20 and the subcutaneous tissue 40 is small.

  When the content of salicylic acid contained in the antifungal composition for external use exceeds 0.8% by weight based on the total amount of the antifungal composition, the skin tissue 20 is destroyed and the stratum corneum is dissolved, causing damage to the skin. The tendency to do is recognized. Moreover, it tends to harm the health of the human body within the blood vessels present in the subcutaneous tissue 40.

  When the content of salicylic acid contained in the antifungal external composition is 0.1 wt% to 0.8 wt% per antifungal external composition, the salicylic acid does not dissolve the stratum corneum 2a, Without destroying the skin tissue 20, without changing the state of the skin tissue 20 by macroscopic observation, the skin tissue 20 is softened and swollen, and in the state of skin condition alteration, the terbinafine antifungal agent is used. A fungus in which the skin penetration promoting effect that exhibits the effect of promoting skin penetration is exhibited, the terbinafine antifungal agent penetrates into the skin tissue 20 and the subcutaneous tissue 40, and the terbinafine antifungal agent exists in the skin tissue 20 and the subcutaneous tissue 40 The effect of inactivating and killing 5 is recognized.

  In particular, when the content of salicylic acid is 0.2% by weight to 0.5% by weight based on the total amount of the antifungal external composition, “the stratum corneum without changing the state of the skin tissue 20 in visual observation” Without dissolving 2a, without destroying the skin tissue, the state of the skin tissue 20 is transformed into softening and swelling, and the skin penetration promoting effect is exerted to promote the skin penetration of the terbinafine antifungal agent. In addition, the effect of inactivating and killing the fungus 5 existing in the skin tissue 20 and the subcutaneous tissue 40 is remarkably improved.

  In general, when a medicinal component such as a terbinafine antifungal agent is ingested in the human body, it exhibits an antifungal effect by appropriately selecting the amount of ingestion. As it increases, it tends to be harmful to human health. Accordingly, the terbinafine antifungal content contained in the antifungal composition is desirably the minimum content that allows the terbinafine antifungal agent to penetrate the skin and exert its antifungal action.

  The terbinafine antifungal agent is desirably contained in an amount of 0.5% by weight to 10.0% by weight based on the total amount of the antifungal external composition. The content of the terbinafine antifungal agent is more preferably 0.8% to 2.0% by weight based on the total amount of the antifungal composition.

  When the content of the terbinafine antifungal agent contained in the antifungal external composition is less than 0.5% by weight based on the total amount of the antifungal external composition, the terbinafine antifungal inactivates or kills the fungus 5. Less effective.

  When the content of the terbinafine antifungal agent contained in the antifungal external composition exceeds 10.0% by weight based on the total amount of the antifungal external composition, the antifungal external composition was applied to the surface of the skin region 10. Occasionally, abnormalities in the skin or abnormalities in the concentration of terbinafine antifungal agents in the blood may be observed, and a tendency to impair human health may be observed.

When the terbinafine antifungal agent is contained in an amount of 0.5% to 10.0% by weight based on the total amount of the antifungal composition, it effectively exhibits the skin penetration promoting effect of the terbinafine antifungal agent of salicylic acid, A terbinafine antifungal agent acts on the fungus 5 present in the skin tissue 20 and the subcutaneous tissue 40 to inactivate and kill the fungus 5.
In particular, when the content of the terbinafine antifungal agent is 0.8% to 2.0% by weight based on the total amount of the antifungal composition, the antifungal effect of the terbinafine antifungal agent and the terbinafine type of salicylic acid Due to the synergistic effect with the skin penetration promoting effect of the antifungal agent, the effect of further remarkably improving the “efficacy to inactivate and kill the fungus 5 existing in the skin tissue 20 and the subcutaneous tissue 40” is exhibited.

  The salicylic acid contained in the antifungal topical composition contains 0.1% by weight to 0.8% by weight per total amount of the antifungal topical composition, and the terbinafine antifungal agent is 0.5% by weight per total amount of the antifungal topical composition. It is desirable to contain 10.0% by weight. More preferably, the salicylic acid contained in the antifungal composition for external use contains 0.2 wt% to 0.5 wt% of the antifungal composition for external use, and the terbinafine antifungal agent is added in an amount of 0. 8 to 2.0% by weight is contained.

  When such an antifungal composition for external application is applied to the surface of the skin region 10, the synergistic effect of the antifungal effect of the terbinafine antifungal agent described above and the skin penetration promoting effect of the terbinafine antifungal agent of salicylic acid Thus, the terbinafine antifungal agent acts on the fungus 5 existing on the surface of the skin region 10 to inactivate and kill the fungus 5, and further, salicylic acid alters the state of the skin tissue 20 in macroscopic observation. In addition, without dissolving the stratum corneum 2a, without destroying the skin tissue 20, the state of the skin tissue 20 is softened and swollen in the microscopic observation, and the terbinafine antifungal in the state of skin state alteration The skin permeation promoting effect that the agent has the effect of promoting skin permeation is exhibited, and the terbinafine antifungal agent is applied to the skin tissue 20 and subcutaneously. Penetrates into weave 40, terbinafine antifungal agent is inactivated fungal 5 present in the skin tissue 20 and subcutaneous tissue 40, it exhibits a potency to kill. In this way, the fungus 5 present on the surface of the skin region 10 and the subcutaneous tissue 40 is inactivated and killed.

Moreover, the application method of the antifungal external composition which repeats and apply | coats the antifungal external composition of this invention demonstrated above on the surface of the skin area | region 10 for every predetermined time can be implemented.
As described above, when the antifungal composition for external application is applied to the surface of the skin region 10, the surface of the skin region 10 and the fungus present on the subcutaneous tissue 40 are inactivated and killed. However, a part of the fungus 5 moves deeper into the skin tissue 20 and the subcutaneous tissue 40 without being deactivated or killed. In such a state that a part of the fungus 5 remains and moves deep inside the skin region 10, the antifungal topical composition is repeatedly applied to the surface of the skin region 10 every predetermined time, whereby terbinafine The system antifungal agent penetrates into the skin tissue 20 that has been further altered by the skin condition alteration action of salicylic acid, and further penetrates into at least one skin region 10 of the skin tissue 20 and the subcutaneous tissue 40. It acts on the fungus 5 moving or existing deeper inside or deeper inside the subcutaneous tissue 40 to exert an antifungal effect, and the fungus 5 is completely inactivated or killed. Thus, the mycosis caused by the fungus 5 is treated by repeatedly applying the antifungal composition to the surface of the skin region 10 every predetermined time.

That is, when the antifungal composition for external application is applied to the surface of the skin region 10, it acts on the fungi 5 present on the skin tissue surface and inside the skin tissue to deactivate or kill some fungi 5, however, Some fungi 5 may move further into the skin tissue 20 or the subcutaneous tissue 40 without being inactivated or killed, and the fungus 5 may be propagated.
Such an antifungal composition for external use is repeatedly applied to the surface of the skin region 10 every predetermined time, so that the fungus 5 which has further moved to the back of the skin tissue 20 or the subcutaneous tissue 40 and propagated is repeatedly used. As a result, the skin state-modifying action of salicylic acid and the antifungal effect action of the terbinafine antifungal agent are exhibited, and the action effect of completely deactivating or killing the fungus 5 is exhibited.

  The form of the antifungal composition for external use of the present invention is not particularly limited, and may be a cream, ointment, liquid, lotion, spray, gel, patch, etc. It is used in the form used by applying to. In particular, it is desirable that the antifungal external composition is in the form of a cream. More preferably, the antifungal composition for external use contains at least water, and at least a part of terbinafine hydrochloride is dissolved in water and emulsified in the form of a cream.

  When the antifungal composition for external use of the present invention contains water and is in the form of an emulsified cream, a part of terbinafine hydrochloride is dissolved in water, and the antifungal composition for external use is a cream. The water containing the terbinafine hydrochloride enters the skin tissue 20 whose state has been altered by the skin state alteration action of salicylic acid and is easily delivered to the skin tissue 20 or the subcutaneous tissue 40. As a result, the skin tissue 20 or The amount of terbinafine hydrochloride delivered to the subcutaneous tissue 40 increases, and the above-mentioned actions and effects can be optimally exhibited.

  In the antifungal composition for external use of the present invention, in addition to the terbinafine antifungal agent and salicylic acid, base materials such as alcohols, water, fats and oils, emulsifiers, stabilizers, and antioxidants that are usually blended in skin external preparations Agents, preservatives, preservatives, moisturizers, cleansing agents, other additives, excipients, etc. can be added as appropriate, and the preparation conditions for ordinary external preparations for skin can also be applied. .

Hereinafter, the antifungal composition for external use of the present invention will be described specifically by way of examples.
Example A
An antifungal composition A comprising the following components is prepared.
Salicylic acid (0.35g)
Terbinafine hydrochloride (1.0 g)
1,3-butylene glycol (1.0 g)
Stearyl alcohol (5.0 g)
Cetanol (4.0 g)
Cetyl palmitate (4.0 g)
Polysorbate 60 (1.0 g)
Polyoxyethylene stearyl ether (1.0 g)
Self-emulsifying glyceryl monostearate (1.0 g)
Sodium edetate (0.1g)
Purified water (81.55g)
Total amount (100g)
Predetermined amounts of all components other than purified water among the above components are weighed, placed in a beaker, heated to 80 ° C. and stirred. After each component is uniformly dissolved, purified water heated to 80 ° C. is added with stirring. Then, it is cooled to room temperature while stirring. Thus, emulsified creamy antifungal composition A for external use was prepared.

  Next, with respect to the prepared antifungal composition A, the method for determining the skin permeation promoting effect of salicylic acid that has the effect of promoting skin permeation of the terbinafine antifungal agent and the results of the skin permeation promoting effect will be described.

By measuring the amount of terbinafine antifungal agent that permeates the skin using the Franz diffusion cell test method as a transdermal absorption tester and membrane permeation test device, the skin penetration promoting effect of salicylic acid that promotes skin penetration of terbinafine hydrochloride is demonstrated. judge.
That is, hairless mouse-extracted skin (refrigerated product, male, 7 weeks old) is set in the Franz diffusion cell test, and an appropriate amount of the prepared antifungal external composition prepared is applied to the surface of the hairless mouse-extracted skin. . Thereafter, over time, the receptor liquid (PEG-400, 40% aqueous solution) is sampled from the diffusion cell (diffusion cell temperature is 32 ° C.) using a syringe. To each sampled receptor solution, the same amount of methanol or acetonitrile as the receptor solution is added, and the content of terbinafine hydrochloride is quantified by a high performance liquid chromatography (HPLC) method. In this manner, the amount of terbinafine hydrochloride that has permeated through the skin removed from the hairless mouse is measured. The amount of terbinafine hydrochloride (μg / 10 ml) permeated through the hairless mouse isolated skin was measured as the content (μg) of terbinafine hydrochloride per 10 ml of the diffusion cell after 8 hours and 24 hours.
As a result, the content of terbinafine hydrochloride that permeated the skin after 8 hours was 0.21 μg / diffusion cell 10 ml, and the content of terbinafine hydrochloride that permeated the skin 24 hours later was 5.91 μg / 10 ml of diffusion cell. Met.

  Separately from the above Franz diffusion cell test method, the prepared antifungal composition was applied to the surface of the hairless mouse-extracted skin, and then the state of the skin 24 hours later was observed with the naked eye. As a result, no alteration of the skin tissue 20 was observed, and no phenomena such as destruction and dissolution of the stratum corneum were observed.

Example B
In the antifungal composition for external use of Example A, the content of purified water was adjusted so that the salicylic acid content was 0.5 g, the other components were the same, and the total amount was 100 g. Then, a creamy antifungal composition B was prepared in the same manner as in Example A.
For antifungal composition B, the amount of terbinafine antifungal agent that permeates the skin is measured by the same Franz-type diffusion cell test method as in Example A to promote skin penetration of terbinafine hydrochloride. Efficacy was determined. As a result, the content of terbinafine hydrochloride permeating the skin after 8 hours was 0.38 μg / diffusion cell 10 ml, and the content of terbinafine hydrochloride permeating the skin 24 hours later was 6.19 μg / diffusion cell 10 ml. there were.
Moreover, after applying the prepared antifungal composition for external application to the surface of the hairless mouse-extracted skin, the state of the skin 24 hours later was observed with the naked eye. As a result, no alteration of the skin tissue 20 was observed, and no phenomena such as destruction and dissolution of the stratum corneum were observed.

Reference Example In the antifungal composition for external use of Example A, the salicylic acid is not contained, the content of other components is the same, and the amount of purified water is adjusted so that the total amount becomes 100 g. By the same method as in Example A, a creamy antifungal composition C was prepared.
About the antifungal composition C, the amount of terbinafine hydrochloride permeating the skin was measured by the same Franz diffusion cell test method as in Example A. As a result, the content of terbinafine hydrochloride that permeated the skin after 8 hours was less than 0.1 μg / diffusion cell 10 ml.

  Thus, like Example A and Example B, when the antifungal composition for external use containing both salicylic acid and terbinafine hydrochloride is applied to the surface of the skin region 10, the hydrochloric acid that permeates and penetrates the skin tissue 20 High amount of terbinafine. In contrast, as in Reference Example, when the antifungal composition C containing only terbinafine hydrochloride and not containing salicylic acid is applied to the surface of the skin, terbinafine hydrochloride that permeates and penetrates the skin tissue 20 is used. The amount is significantly reduced.

  That is, in an antifungal composition for external use containing both salicylic acid and a terbinafine antifungal agent, salicylic acid exerts a skin state alteration action to alter the state of the skin tissue 20, and thereby the skin of the terbinafine antifungal agent. The terbinafine antifungal agent has an effect of promoting penetration, and permeates and penetrates the skin tissue 20 whose state has been altered by the skin state alteration action of salicylic acid, and enters at least one skin region of the skin tissue 20 and the subcutaneous tissue 40. It is demonstrated to penetrate.

  Antifungal containing at least one of terbinafine and terbinafine hydrochloride having an antifungal effect and salicylic acid having an effect of promoting skin penetration of an antifungal agent to promote skin penetration By applying and applying the composition for external application on the surface of the skin region 10 where the fungus 5 is present, the composition for external use on the fungus acts on the fungus 5 existing on the surface of the skin region. It is efficiently delivered to the inside of the skin tissue 20 where the fungus 5 is present, and the medicinal component effectively acts directly on the fungus 5, thereby exhibiting extremely excellent antibacterial performance.

2 epidermis 2a stratum corneum 2b epidermis functional layer 3 dermis 5 fungus 10 skin region 20 skin tissue 40 subcutaneous tissue

Claims (11)

    A terbinafine antifungal agent having at least one antifungal effect of terbinafine and terbinafine hydrochloride, and salicylic acid having a skin permeation promoting effect exhibiting an effect of promoting skin permeation of the terbinafine antifungal agent An antifungal composition for external use. When applied to the surface of a skin region composed of a skin tissue composed of an epidermis including a stratum corneum and a dermis located inside the epidermis, and a subcutaneous tissue located inside the skin tissue,
The salicylic acid has the effect of promoting skin penetration of the terbinafine antifungal agent by altering the state of the skin tissue by exerting a skin state alteration action,
The terbinafine antifungal agent acts on the fungi present on the surface of the skin region, and further penetrates the skin tissue that has been altered by the skin condition alteration action of the salicylic acid, thereby the skin tissue and the subcutaneous tissue. The antifungal composition for external use according to claim 1, which penetrates into the skin region of at least one of them and acts on a fungus existing in the skin region. When applied to the surface of a skin region composed of a skin tissue composed of an epidermis including a stratum corneum and a dermis located inside the epidermis, and a subcutaneous tissue located inside the skin tissue,
The salicylic acid does not alter the state of the skin tissue in the macroscopic observation, dissolves the stratum corneum, and exhibits a skin state alteration effect that alters the state of the skin tissue in the microscopic observation. Contained in
2. The terbinafine antifungal agent penetrates the skin tissue whose state has been changed and penetrates into the skin region, and acts on a fungus existing inside the skin region. Antifungal composition for external use.   The antifungal composition for external use according to claim 1, 2, or 3, wherein the salicylic acid is contained in an amount of 0.1 to 0.8% by weight based on the total amount of the composition.   The antifungal composition for external use according to claim 1, 2, or 3, wherein the terbinafine antifungal agent is contained in an amount of 0.5 to 10.0% by weight based on the total amount of the composition. The salicylic acid is contained in an amount of 0.1% to 0.8% by weight based on the total amount of the composition,
The antifungal composition for external use according to claim 1, 2, or 3, wherein the terbinafine antifungal agent is contained in an amount of 0.5 to 10.0% by weight based on the total amount of the composition. In addition, it contains water
At least a portion of the terbinafine antifungal agent is dissolved in the water,
The antifungal composition for external use according to any one of claims 1 to 6, wherein the composition is in the form of an emulsified cream. (A) a terbinafine antifungal agent having at least one antifungal effect of terbinafine and terbinafine hydrochloride, and salicylic acid having a skin permeation promoting effect having an effect of promoting skin permeation of the terbinafine antifungal agent A step of preparing an antifungal composition for external use,
(B) applying the antifungal composition for external application to the surface of a skin region in which inflammation is caused by a fungus,
Here, the skin region is composed of a skin tissue composed of an epidermis including a stratum corneum and a dermis located inside the epidermis, and a subcutaneous tissue located inside the skin tissue,
(C) When the antifungal topical composition is applied to the surface of the skin region,
The salicylic acid has the effect of promoting skin penetration of the terbinafine antifungal agent by altering the state of the skin tissue by exerting a skin state alteration action,
The terbinafine antifungal agent acts on the fungi present on the surface of the skin region, and further penetrates the skin tissue that has been altered by the skin condition alteration action of the salicylic acid, thereby the skin tissue and the subcutaneous tissue. Penetrates into the skin area of at least one of them, acts on fungi present in the skin area,
Thereby, treating a mycosis caused by a fungus present in at least one skin region of the surface of the skin region, the skin tissue and the subcutaneous tissue,
A method for applying an antifungal composition for external use, comprising: further,
(D) The antifungal composition for external application is applied to the surface of the skin region every predetermined time, and the step (c) is repeated to act on the fungus present in the skin region. Treating mycosis caused by fungi present in the area,
The application method of the antifungal composition for external use of Claim 8 characterized by the above-mentioned. The salicylic acid is contained in an amount of 0.1% to 0.8% by weight based on the total amount of the composition,
The method for applying an antifungal composition for external use according to claim 8 or 9, wherein the terbinafine antifungal agent is contained in an amount of 0.5 to 10.0% by weight based on the total amount of the composition.     The method for applying an antifungal composition for external use according to any one of claims 8 to 10, wherein the antifungal composition for external use is in the form of a cream.

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