Topical agent for onychomycosis

Abstract

A topical agent for onychomycosis according to the present disclosure contains, as an active ingredient, at least one selected from the group consisting of compounds represented by formula (1) and salts thereof, and contains, as a solvent, any of the solvents indicated by solvents (a)-(g). Solvent (a): dibasic acid diester; solvent (b): lower alcohol and dibasic acid diester; solvent (c): lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and dibasic acid diester; solvent (e): lower alcohol, dimethyl sulfoxide, and dibasic acid diester; solvent (f): lower alcohol and glycol; and solvent (g): lower alcohol, glycol, and dibasic acid diester.

Description

Topical agent for nail fungus REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority based on Japanese Patent Application No. 2023-125977, filed on August 2, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates to an external preparation for onychomycosis that is used to treat onychomycosis and prevent its worsening.

[0003] The compound represented by the following formula (1) (hereinafter simply referred to as "compound (1)") is described in Patent Document 1 as Compound No. 6 (Preparation Example 6) and is known to be a useful compound as an antifungal agent for humans. It is also known that, as a related art of compound (1), a hydrate crystal of compound (1) has properties such as high stability against changes in temperature and humidity and the ability to reduce triboelectric charge, and can be advantageously used in the efficient production of formulations. However, Patent Documents 1 and 2 do not specifically describe the use of this compound for the treatment of onychomycosis, and naturally do not describe or suggest a formulation for a topical preparation for onychomycosis.

[0004] Onychomycosis is a disease caused by infection of the nail by Trichophyton fungi, and oral or topical medications are used to treat it. While oral medications are currently primarily used, problems with oral medications include the need for long-term administration, interactions with other drugs, and side effects such as liver dysfunction. Therefore, the development of effective topical medications has long been desired. A major challenge with topical medications is the difficulty of delivering a sufficient amount of the drug to the affected area to exert a therapeutic effect. Therefore, research has focused on improving penetration (permeability) into the nail, suppressing crystal precipitation during storage or application, and stabilizing the active ingredient.

[0005] As one example of such studies, topical pharmaceutical compositions containing luliconazole or lanoconazole as active ingredients are known (see Patent Documents 3 to 5).

[0006] According to Patent Document 3, by incorporating an α-hydroxycarboxylic acid or a salt thereof, it is possible to suppress a phenomenon specific to luliconazole, in which luliconazole microcrystals are instantaneously precipitated upon application, inhibiting its penetration and absorption into biological tissues. A dibasic acid diester is listed as one of the optional components, and is described as a component that promotes penetration into the nail.

[0007] According to Patent Document 4, N-methyl-2-pyrrolidone is said to have the effect of suppressing the precipitation of crystals or insoluble matter on the application surface, which appears 20 to 40 seconds after administration, presumably due to interaction with the surface structure of the skin or nail or with substances present on the surface. Patent Document 4 also lists a dibasic acid diester as one of the optional components, and describes it as a component that promotes penetration into the nail.

[0008] According to Patent Document 5, by incorporating at least one selected from the group consisting of predetermined higher alcohols and dibasic acid diesters and at least one selected from the group consisting of polyoxyethylene alkyl ethers and polyoxyethylene alkenyl ethers, desired properties such as suppression of isomerization of the active ingredient, transparency at 20°C after production, and prevention of precipitation during low-temperature storage can be obtained. One of the reasons for incorporating the dibasic acid diester is said to be suppression of crystal precipitation in the low-temperature range, and it is also described that when used in a specific ratio with the predetermined higher alcohol, it also exhibits an effect of suppressing crystal precipitation due to impact, such as crystal precipitation during application to nails.

[0009] Furthermore, topical antifungal preparations containing efinaconazole as an active ingredient are also known (see Patent Document 6). According to Patent Document 6, effective transungual penetration is achieved by incorporating efinaconazole, a monohydric alcohol, a glycol, and a specific excipient. Dimethyl sulfoxide and a dibasic acid diester are listed as examples of the excipients, and the purpose of their inclusion is understood to be to promote penetration into the nail in light of the overall objective of the invention.

[0010] As described above, formulations of topical medications have been investigated for a plurality of active ingredients, but no investigation has been conducted on topical preparations for onychomycosis containing at least one active ingredient selected from the group consisting of compound (1) and a salt thereof.

[0011] Although the above-mentioned documents describe the incorporation of dimethyl sulfoxide and a dibasic acid diester, it is common for the optimal formulation to differ depending on the active ingredient, etc., in formulation studies. Therefore, it cannot be said that the above-mentioned documents, which describe active ingredients different from those in the present disclosure, suggest a formulation for incorporating the specified solvent described below in the present disclosure in an external preparation for onychomycosis containing at least one active ingredient selected from the group consisting of compound (1) and salts thereof.

[0012] In relation to this point, paragraph 0029 of Patent Document 3 evaluates the degree of crystal precipitation after application onto a slide glass for Example 5 (a lotion containing luliconazole, diisopropyl adipate, lactic acid, and ethanol) and Comparative Example 6 (i.e., a lotion containing luliconazole, diisopropyl adipate, and ethanol) in which lactic acid in the formulation of Example 5 was replaced with ethanol, and shows that crystal precipitation could not be suppressed in the latter (see also Figures 4 and 5 of Patent Document 3).

[0013] International Publication No. WO 2021 / 246455 International Publication No. WO 2023 / 106320 International Publication No. WO 2007 / 102241 International Publication No. WO 2007 / 102243 International Publication No. WO 2010 / 117091 International Publication No. WO 2020 / 231800

[0014] An object of the present disclosure is to provide an external preparation for onychomycosis that contains at least one compound selected from the group consisting of compound (1) and a salt thereof as an active ingredient, suppresses crystal precipitation in the preparation and after application, and improves nail transmittance, thereby enabling the active ingredient to fully exert its effect on onychomycosis.

[0015] The present inventors have conducted extensive research to solve the above problems and have found that when a specific solvent is used, crystal precipitation in the formulation and after application is suppressed, nail transmittance is improved, and the effect on onychomycosis can be fully exerted, thereby completing the present invention.

[0016] That is, the present disclosure relates to an external preparation for onychomycosis, which contains, as an active ingredient, at least one selected from the group consisting of compounds represented by the following formula (1) and salts thereof, and further contains, as a solvent, at least one selected from the group consisting of the following solvents (a) to (g):

[0017]

[0018] Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohol and glycols; and Solvent (g): lower alcohol, glycols and dibasic acid diester.

[0019] According to the present disclosure, for at least one compound selected from the group consisting of compound (1) and a salt thereof, which is an active ingredient, crystal precipitation in a formulation and after application can be suppressed, nail transmittance can be improved, and the effect on onychomycosis can be fully exerted.

[0020] 1 is a photograph showing the state of the topical preparation after standing for 24 hours in the evaluation test "inhibition of crystal precipitation in the formulation" in Example 1. 2 is a photograph showing the state of the topical preparation after standing for 24 hours in the evaluation test "inhibition of crystal precipitation in the formulation" in Comparative Example 3. 3 is a photograph showing the state of the topical preparation on a glass plate after a predetermined period has elapsed since application of the topical preparation in the evaluation test "inhibition of crystal precipitation after application" in Example 22. 4 is a photograph showing the state of the topical preparation on a glass plate after a predetermined period has elapsed since application of the topical preparation in the evaluation test "inhibition of crystal precipitation after application" in Comparative Example 1. 5 is a photograph showing the state of the topical preparation on a glass plate after a predetermined period has elapsed since application of the topical preparation in the evaluation test "inhibition of crystal precipitation after application" in Comparative Example 2. 6 is a photograph showing the state of the topical preparation on a glass plate after a predetermined period has elapsed since application of the topical preparation in the evaluation test "inhibition of crystal precipitation after application" in Comparative Example 2. 7 is a photograph showing the state of the area around the nail when a subungual efficacy test was conducted for each of the placebos and controls of Examples 68 and 69. 8 is a photograph showing the results of fluorescent staining when a subungual fungicidal activity test was conducted for Example 68, its placebo, and two commercially available drugs. 1 is a graph showing the change in the amount of hydrolysate produced when the concentration of lactic acid is changed in the formulation of Example 49 or Example 59. 2 is a graph showing the difference in the amount of hydrolysate produced for Reference Examples 1 to 11, in which the type and / or amount of acid added is different.

[0021] The topical preparation for onychomycosis of the present disclosure (hereinafter, may be simply referred to as the "topical preparation of the present disclosure") will be described in detail below, but the scope of the present disclosure is not limited to these descriptions, and modifications other than those exemplified below may be made as appropriate within the scope that does not impair the spirit of the present disclosure.

[0022] The topical preparation of the present disclosure contains, as an active ingredient, at least one compound selected from the group consisting of compound (1) and salts thereof. As described above, compound (1) is a known compound and is represented by the chemical name 5-chloro-4-(3-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile. The salt of compound (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, and organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate. Examples of basic salts include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt.

[0023] At least one compound selected from the group consisting of compound (1) and salts thereof may have the following tautomers, and the at least one compound selected from the group consisting of compound (1) and salts thereof in the present disclosure may exist as any of these tautomers or may coexist as tautomers (including coexistence in an equilibrium state).

[0024]

[0025] Furthermore, compound (1) or a salt thereof may absorb moisture, adsorb water, or become a hydrate when left in the air or recrystallized. In the present disclosure, compound (1) or a salt thereof also encompasses such various hydrates, solvates, and crystalline polymorphic compounds. Preferred examples include the hydrates and crystalline polymorphic compounds disclosed in International Publication No. 2023 / 106320. The content of at least one compound selected from the group consisting of compound (1) and its salts relative to the total amount of the topical preparation of the present disclosure is not particularly limited, but is preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and particularly preferably 1 to 5% by mass.

[0026] The topical preparation of the present disclosure contains at least one solvent selected from the group consisting of the following solvents (a) to (g) (hereinafter simply referred to as the "prescribed solvent of the present disclosure"). Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohol and glycols; and Solvent (g): lower alcohol, glycols and dibasic acid diester.

[0027] The dibasic acid diester in the specified solvent disclosed herein is a compound obtained by diesterifying a dibasic acid with an alcohol. The dibasic acid is not particularly limited, but it is preferable to use an aliphatic dibasic acid or an aromatic dibasic acid. Examples of the aliphatic dibasic acid include saturated aliphatic dibasic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid, as well as unsaturated aliphatic dibasic acids such as maleic acid and fumaric acid. Aliphatic dibasic acids having 2 to 10 carbon atoms are preferred, aliphatic dibasic acids having 2 to 6 carbon atoms are more preferred, and at least one selected from the group consisting of adipic acid, fumaric acid, and maleic acid is particularly preferred. Examples of the aromatic dibasic acid include phthalic acid, isophthalic acid, and terephthalic acid. The alcohol to be diesterified with the dibasic acid is not particularly limited, but preferred examples include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, and tert-butyl alcohol, and at least one selected from the group consisting of ethanol, isopropyl alcohol, butanol, and isobutyl alcohol is more preferred. Examples of the dibasic acid diester are not particularly limited, but preferred examples include diisopropyl adipate, diisobutyl adipate, dibutyl fumarate, and diethyl maleate, and diisopropyl adipate is particularly preferred.

[0028] The lower alcohol in the specified solvent of the present disclosure is not particularly limited, but preferred examples include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, and tert-butyl alcohol. At least one selected from the group consisting of ethanol and isopropyl alcohol is particularly preferred.

[0029] The glycols in the specified solvent of the present disclosure are not particularly limited, but preferred examples include ethylene glycol, propylene glycol, 1,3-propanediol, 1,4-butanediol, and dehydration condensates thereof. Preferred dehydration condensates include diethylene glycol, triethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, and polypropylene glycol. The molecular weight of glycols as dehydration condensates is preferably, for example, a number average molecular weight of 200 to 600, and more preferably 200 to 400. Propylene glycol and polyethylene glycol are particularly preferred.

[0030] The content ratio of the specified solvent of the present disclosure relative to the total amount of the topical preparation of the present disclosure is not particularly limited, but is preferably 60 to 99.9% by mass, more preferably 70 to 99.9% by mass, and particularly preferably 80 to 99.9% by mass, relative to the total amount of the topical preparation of the present disclosure.

[0031] In solvent (b), the blending ratio of the lower alcohol and the dibasic acid diester is preferably lower alcohol:dibasic acid diester=99.9:0.1 to 10:90, and more preferably 75:25 to 50:50, by mass. In solvent (c), the blending ratio of the lower alcohol and the dimethyl sulfoxide is preferably lower alcohol:dimethyl sulfoxide=99.9:0.1 to 10:90, and more preferably 75:25 to 50:50, by mass. In solvent (d), the blending ratio of the dimethyl sulfoxide and the dibasic acid diester is preferably dimethyl sulfoxide:dibasic acid diester=99.9:0.1 to 10:90, and more preferably 75:25 to 50:50, by mass. In solvent (e), the blending ratio of the lower alcohol, dimethyl sulfoxide, and dibasic acid diester is preferably 0.1 to 99.8% by mass of the lower alcohol, 0.1 to 99.8% by mass of the dimethyl sulfoxide, and 0.1 to 99.8% by mass of the dibasic acid diester, and more preferably 10 to 75% by mass of the lower alcohol, 5 to 75% by mass of the dimethyl sulfoxide, and 10 to 75% by mass of the dibasic acid diester, based on the total of the three. In solvent (f), the blending ratio of the lower alcohol and glycols is preferably lower alcohol:glycols=99.9:0.1 to 10:90, and more preferably 75:25 to 50:50, based on mass. In the solvent (g), the blending ratios of the lower alcohol, glycols, and dibasic acid diester, relative to the total of the three being 100% by mass, are preferably 0.1 to 99.8% by mass of the lower alcohol, 0.1 to 99.8% by mass of the glycol, and 0.1 to 99.8% by mass of the dibasic acid diester, and more preferably 55 to 90% by mass of the lower alcohol, 5 to 35% by mass of the glycol, and 5 to 35% by mass of the dibasic acid diester.

[0032] In the topical preparation of the present disclosure, the blending ratio of at least one compound selected from the group consisting of compound (1) and salts thereof to the specified solvent of the present disclosure is not particularly limited, but is preferably 0.1:99.9 to 40:60 by mass, more preferably 0.1:99.9 to 20:80, and particularly preferably 1:99 to 10:90 by mass.

[0033] The topical preparation of the present disclosure may contain any solvent used in pharmaceutical compositions other than the above-mentioned specified solvent of the present disclosure. Examples of such other solvents include triglycerides such as olive oil, fatty acids such as stearic acid and oleic acid, and polyhydric alcohols other than glycols (e.g., glycerin). While N-methyl-2-pyrrolidone is suitable as a solvent for at least one compound selected from the group consisting of compound (1) and its salts, it does not contribute to the suppression of crystal precipitation and may even inhibit the crystal precipitation-inhibiting effect of the present disclosure. Therefore, it is preferable to not incorporate N-methyl-2-pyrrolidone, or to incorporate it in a small amount. In this case, the amount incorporated is preferably 10% by weight or less, more preferably 5% by weight or less, and particularly preferably 1% by weight or less, based on the total amount of the topical preparation of the present disclosure.

[0034] The topical preparation of the present disclosure may contain optional components other than the above-mentioned components, such as bulking agents, diluents, pH adjusters, dispersants, emulsifiers, preservatives, stabilizers, antioxidants, colorants, UV absorbers, moisturizers, and thickeners, which are commonly used in topical preparations.

[0035] Particularly suitable optional components are specifically exemplified below. A specific example of a suitable optional component is polyvinylpyrrolidone. Polyvinylpyrrolidone has the effect of suppressing crystal precipitation after application. This effect is presumably due to polyvinylpyrrolidone amorphizing at least one compound selected from the group consisting of compound (1) and its salts. The molecular weight of polyvinylpyrrolidone is not particularly limited, but for example, one with a weight-average molecular weight of 10,000 to 360,000 can be used. The amount of polyvinylpyrrolidone to be incorporated is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, of the total amount of the topical preparation of the present disclosure. Examples of components (crystallization inhibitors) that are expected to have the same effect as polyvinylpyrrolidone (inhibition of crystallization by amorphization) include polymeric compounds such as ethylene-maleic anhydride copolymer and polyalkylene glycols (polyethylene glycol, polyoxyethylene polyoxypropylene glycol, etc.), and these may be used as optional components in the topical preparation of the present disclosure.

[0036] It is also preferable to incorporate an acid as a pH adjuster. By incorporating an acid as a pH adjuster, the stability of at least one compound selected from the group consisting of compound (1) and its salts is improved, leading to improved permeability into the body. Specific pH adjusters include lactic acid, acetic acid, citric acid (including monohydrate), ascorbic acid, phosphoric acid, etc., with lactic acid and citric acid being more preferred, and lactic acid being particularly preferred. The amount of acid incorporated as a pH adjuster is not particularly limited, but is preferably 0.1 to 10% by mass, and more preferably 0.5 to 5% by mass, relative to the total amount of the topical preparation of the present disclosure. In particular, when lactic acid is incorporated, the upper limit is preferably 8% by mass or less, more preferably 4% by mass or less, and particularly preferably 0.5 to 2% by mass.

[0037] In addition, as a preservative, for example, benzyl alcohol, benzoic acid or its salt (such as the sodium salt), sebacic acid, sorbic acid, etc. are preferably blended, with benzyl alcohol being particularly preferred. The amount of the preservative to be blended is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.1 to 5% by mass, of the total amount of the topical preparation of the present disclosure.

[0038] The topical preparation of the present disclosure can be obtained by combining the above-mentioned essential components and optional components as needed and formulating them in a conventional manner. The formulation can be in the form of a general topical preparation, such as a lotion, cream, emulsion, suspension, gel, patch, etc., with lotion being particularly suitable.

[0039] The topical preparation of the present disclosure can be used to treat or prevent the worsening of onychomycosis, and can be applied locally to the affected area, the nail, of a target animal species (e.g., human) by painting, rubbing, applying, etc., depending on the specific formulation. In the topical preparation of the present disclosure, the effective amount of at least one compound selected from the group consisting of compound (1) and salts thereof and the number of times the topical preparation is administered are not particularly limited, and vary depending on the target animal species, sex, age, weight, condition, and other factors, making it difficult to specify in general terms. However, for example, the dosage when administered locally to the affected area in a human is, for an adult weighing 60 kg, typically 500 to 3,000 μg / day per nail as the amount of at least one compound selected from the group consisting of compound (1) and salts thereof, and a preferred weekly dose is 3.5 to 15 mg / week per nail.

[0040] According to another aspect of the present disclosure, there is provided a method for treating onychomycosis in a subject, the method comprising topically applying an effective amount of an external preparation for onychomycosis to the affected nail of the subject, the external preparation for onychomycosis comprising, as an active ingredient, at least one selected from the group consisting of the compound represented by formula (1) above and a salt thereof, and further comprising, as a solvent, at least one selected from the group consisting of solvents (a) to (g) above. Hereinafter, this method may also be simply referred to as a "treatment method."

[0041] According to yet another aspect of the present disclosure, there is provided a method for preventing the worsening of onychomycosis in a subject, the method comprising topically applying an effective amount of an external preparation for onychomycosis to the affected nail of the subject, the external preparation for onychomycosis comprising, as an active ingredient, at least one selected from the group consisting of the compound represented by formula (1) above and a salt thereof, and further comprising, as a solvent, at least one selected from the group consisting of solvents (a) to (g) above. Hereinafter, this method will also be referred to simply as a "prevention method."

[0042] In the treatment and prevention methods disclosed herein, "treating onychomycosis" includes stopping, alleviating, or delaying the progression or worsening of onychomycosis by medical or non-medical intervention. Also, "preventing the worsening of onychomycosis" includes preparing in advance for anticipated worsening of onychomycosis and preventing its occurrence or recurrence by medical or non-medical intervention.

[0043] In the treatment and prevention methods of the present disclosure, the "effective amount of the topical preparation for onychomycosis" varies depending on the species, sex, age, weight, condition, and other factors of the animal to be administered, and is therefore difficult to define in general terms. For example, the dosage when administered topically to an affected area in humans is preferably 500 to 3,000 μg / (person-day-nail) per day and 3.5 to 15 mg / (person-week-nail) per week per nail for an adult weighing 60 kg, as the amount of at least one compound selected from the group consisting of compound (1) and its salts.

[0044] In the treatment and prevention methods disclosed herein, the topical preparation for onychomycosis is applied locally to the affected area, the nail, of a target animal species (e.g., human) by painting, rubbing, applying, or the like, depending on the specific formulation.

[0045] In the treatment and prevention methods disclosed herein, the topical preparation for onychomycosis may contain, for example, at least one solvent selected from the group consisting of the solvents (a), (b), (d), and (e). It may also contain, as a solvent, at least one solvent selected from the group consisting of the solvents (c), (d), and (e). It may also contain, as a solvent, at least one solvent selected from the group consisting of the solvents (d) and (e).

[0046] In the treatment and prevention methods of the present disclosure, the dibasic acid diester is preferably a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.

[0047] In the treatment and prevention methods of the present disclosure, the topical preparation for onychomycosis preferably further contains polyvinylpyrrolidone.

[0048] In the treatment and prevention methods of the present disclosure, the topical preparation for onychomycosis preferably further contains an acid as a pH adjuster, and the pH adjuster is more preferably lactic acid or citric acid, and even more preferably lactic acid.

[0049] In the topical preparation for onychomycosis, it is preferred that the content of at least one selected from the group consisting of the compound represented by formula (1) and salts thereof is 0.1 to 20% by mass, and the content of at least one selected from the group consisting of the solvents (a) to (g) is 60 to 99.9% by mass.

[0050] According to another aspect of the present disclosure, there is provided use of a combination of at least one compound selected from the group consisting of the compound represented by formula (1) above and a salt thereof with at least one solvent selected from the group consisting of solvents (a) to (g) above, for the manufacture of an external preparation for onychomycosis or a medicament for treating or preventing the worsening of onychomycosis. Hereinafter, this use is also referred to as "use of a combination of compounds" or "combined use of compounds."

[0051] According to yet another aspect of the present disclosure, there is provided use of a composition comprising, as an active ingredient, at least one compound selected from the group consisting of the compound represented by formula (1) above and salts thereof, and further comprising, as a solvent, at least one solvent selected from the group consisting of the solvents (a) to (g) above, for the manufacture of an external preparation for onychomycosis or a medicament for treating or preventing the worsening of onychomycosis. Hereinafter, this use is also referred to as "use of the composition."

[0052] In the use of the compound combination and composition of the present disclosure, "treatment of onychomycosis" and "prevention of worsening of onychomycosis" are as described above.

[0053] In using the combination of compounds and the composition of the present disclosure, the topical preparation for onychomycosis and the drug may contain, for example, at least one solvent selected from the group consisting of the solvents (a), (b), (d), and (e). They may also contain at least one solvent selected from the group consisting of the solvents (c), (d), and (e). Furthermore, they may also contain at least one solvent selected from the group consisting of the solvents (d) and (e).

[0054] In using the compound combination and composition of the present disclosure, the dibasic acid diester is preferably a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.

[0055] In using the combination of compounds and the composition of the present disclosure, the topical preparation for onychomycosis and the drug preferably further contain polyvinylpyrrolidone.

[0056] In using the combination of compounds and the composition of the present disclosure, the topical preparation for onychomycosis and the drug preferably further contain an acid as a pH adjuster, and the pH adjuster is more preferably lactic acid or citric acid, and even more preferably lactic acid.

[0057] In the topical preparation for onychomycosis and the medicament, it is preferable that the content of at least one selected from the group consisting of the compound represented by formula (1) and salts thereof is 0.1 to 20% by mass, and the content of at least one selected from the group consisting of the solvents (a) to (g) is 60 to 99.9% by mass.

[0058] According to another aspect of the present invention, there is provided a composition for use in treating or preventing the worsening of onychomycosis, the composition comprising, as an active ingredient, at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof, and further comprising, as a solvent, at least one solvent selected from the group consisting of the following solvents (a) to (g). Hereinafter, this composition may also be simply referred to as the "composition."

[0059] In the composition of the present disclosure, "treatment of onychomycosis" and "prevention of worsening of onychomycosis" are as described above.

[0060] The composition of the present disclosure is applied topically to the affected nail of the target animal species (e.g., human) by painting, rubbing, applying, or the like, depending on the specific formulation.

[0061] The composition of the present disclosure may contain, for example, at least one solvent selected from the group consisting of the solvents (a), (b), (d), and (e). It may also contain at least one solvent selected from the group consisting of the solvents (c), (d), and (e). It may also contain at least one solvent selected from the group consisting of the solvents (d) and (e).

[0062] In the composition of the present disclosure, the dibasic acid diester is preferably a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.

[0063] Preferably, the composition of the present disclosure further comprises polyvinylpyrrolidone.

[0064] The composition of the present disclosure preferably further contains an acid as a pH adjuster, and the pH adjuster is more preferably lactic acid or citric acid, and even more preferably lactic acid.

[0065] In the composition of the present disclosure, it is preferred that the content of at least one selected from the group consisting of the compound represented by formula (1) above and salts thereof is 0.1 to 20 mass %, and the content of at least one selected from the group consisting of the solvents (a) to (g) above is 60 to 99.9 mass %.

[0066] According to one aspect of the present disclosure, the following is provided: [1] An external preparation for onychomycosis, comprising, as an active ingredient, at least one selected from the group consisting of compounds represented by the following formula (1) and salts thereof, and further comprising, as a solvent, at least one selected from the group consisting of the following solvents (a) to (g): Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohol and glycols; and Solvent (g): lower alcohol, glycols and dibasic acid diester. [2] The topical preparation for onychomycosis according to [1], which contains at least one solvent selected from the group consisting of solvents (a), (b), (d), and (e). [3] The topical preparation for onychomycosis according to [1] or [2], which contains at least one solvent selected from the group consisting of solvents (c), (d), and (e). [4] The topical preparation for onychomycosis according to any one of [1] to [3], which contains at least one solvent selected from the group consisting of solvents (d) and (e). [5] The topical preparation for onychomycosis according to [1] to [4], wherein the dibasic acid diester is a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms. [6] The topical preparation for onychomycosis according to any of [1] to [5], further comprising polyvinylpyrrolidone. [7] The topical preparation for onychomycosis according to any of [1] to [6], further comprising an acid as a pH adjuster. [8] The topical preparation for onychomycosis according to [7], wherein the pH adjuster is lactic acid or citric acid. [9] The topical preparation for onychomycosis according to any of [1] to [8], wherein the content of at least one selected from the group consisting of the compound represented by formula (1) and a salt thereof is 0.1 to 20% by mass, and the content of at least one selected from the group consisting of the solvents (a) to (g) is 60 to 99.9% by mass.

[10] Use of a combination of at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof and at least one solvent selected from the group consisting of the following solvents (a) to (g) for the manufacture of an external preparation for onychomycosis or a medicament for treating onychomycosis or preventing the worsening of onychomycosis: Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohol and glycols; and Solvent (g): lower alcohol, glycols and dibasic acid diester.

[11] Use of a composition containing at least one compound represented by formula (1) below and a salt thereof as an active ingredient, and further containing at least one solvent selected from the group consisting of solvents (a) to (g) below, for the manufacture of an external preparation for onychomycosis or a medicament for treating or preventing the worsening of onychomycosis.

[12] A composition for use in treating or preventing the worsening of onychomycosis, comprising as an active ingredient at least one selected from the group consisting of a compound represented by the following formula (1) and a salt thereof, and further comprising as a solvent at least one selected from the group consisting of the following solvents (a) to (g):

[13] A method for treating onychomycosis in a subject, comprising topically applying an effective amount of an external preparation for onychomycosis to the affected nail of the subject, wherein the external preparation for onychomycosis contains at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further contains at least one solvent selected from the group consisting of solvents (a) to (g) below:

[16] A method for preventing the worsening of onychomycosis in a subject, the method comprising topically applying an effective amount of an external preparation for onychomycosis to the affected nail of the subject, the external preparation for onychomycosis comprising at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of solvents (a) to (g) below: Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohol and glycols; and Solvent (g): lower alcohol, glycols and dibasic acid diester.

[0067] According to another aspect of the present disclosure, the following is provided: [T1] Use of a combination of at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof and at least one solvent selected from the group consisting of solvents (a) to (g) below, for the manufacture of an external preparation for onychomycosis or a medicament for treating onychomycosis or preventing the worsening of onychomycosis. Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohol and glycols; and Solvent (g): lower alcohol, glycols and dibasic acid diester. [T2] Use of a composition for the manufacture of an external preparation for onychomycosis or a medicament for treating or preventing the worsening of onychomycosis, the composition comprising at least one compound represented by formula (1) below and a salt thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of solvents (a) to (g) below: Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohol and glycols; and Solvent (g): lower alcohol, glycols and dibasic acid diester. [T3] The use according to [T1] or [T2], wherein the topical preparation for onychomycosis or the drug contains at least one solvent selected from the group consisting of solvents (a), (b), (d), and (e). [T4] The use according to any of [T1] to [T3], wherein the topical preparation for onychomycosis or the drug contains at least one solvent selected from the group consisting of solvents (c), (d), and (e). [T5] The use according to any one of [T1] to [T4], wherein the topical preparation for onychomycosis or the medicament contains at least one solvent selected from the group consisting of solvents (d) and (e). [T6] The use according to any one of [T1] to [T5], wherein the dibasic acid diester is a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms. [T7] The use according to any one of [T1] to [T6], wherein the topical preparation for onychomycosis or the medicament further contains polyvinylpyrrolidone. [T8] The use according to any one of [T1] to [T7], wherein the topical preparation for onychomycosis or the medicament further contains an acid as a pH adjuster. [T9] The use according to [T8], wherein the pH adjuster is lactic acid or citric acid. [T10] The use according to any one of [T1] to [T9], wherein the content of at least one selected from the group consisting of the compound represented by formula (1) and salts thereof in the topical preparation for onychomycosis or the medicament is 0.1 to 20% by mass, and the content of at least one selected from the group consisting of the solvents (a) to (g) is 60 to 99.9% by mass.

[0068] In the following, examples and comparative examples will be shown to more specifically explain the topical preparation of the present disclosure, but the present disclosure is not limited to these examples. In addition, as the compound (1) used in each of the following examples, a monohydrate crystal prepared based on the description of Preparation Example 2 of WO 2023 / 106320 was used.

[0069] [Example 1] According to the following formulation, the ingredients were mixed in a glass screw tube (container size: 10 mL to 30 mL) at room temperature (approximately 25°C) and shaken by hand until the solids were dissolved to prepare the topical preparation of Example 1. Compound (1) 5 parts by weight Isopropyl alcohol 47.5 parts by weight Diisopropyl adipate 47.5 parts by weight

[0070] [Evaluation Test: Crystal Precipitation Inhibition] The topical preparations of each Example and Comparative Example were tested for the following evaluation items. [Examples 2 to 81, Comparative Examples 1 to 6] The topical preparations of Examples 2 to 81 and Comparative Examples 1 to 6 were prepared in the same manner as Example 1, except that the formulations were changed to those shown in Tables 1 to 23 in each evaluation test described below.

[0071] <Inhibition of Crystal Precipitation in Preparation> The obtained topical preparation was left to stand for 24±1 hours at room temperature (approximately 25°C), and the presence or absence of crystal precipitation was visually confirmed and rated based on the following criteria. A: After 24±1 hours, no crystal precipitation was observed and the appearance was clear. X: Crystals precipitated within 24±1 hours. For reference, photographs showing the state of each topical preparation after standing for 24 hours in the test item "Inhibition of Crystal Precipitation in Preparation" for Example 1 and Comparative Example 3 are shown in Figures 1 and 2, respectively. Example 1 is an example rated as "A," and has good solubility. As shown in Figure 1, it can be confirmed that no crystal precipitation was observed and the appearance was clear. Comparative Example 3 is an example rated as "X," and as shown in Figure 2, it can be confirmed that small crystals precipitated at the bottom in Comparative Example 3.

[0072] <Inhibition of Crystal Precipitation After Application> A drop (approximately 1 μL to 10 μL) of the obtained topical preparation was gently placed on a glass plate using a pipette to form a patch. After a predetermined time, the presence or absence of crystal precipitation was visually confirmed and rated based on the following criteria. A: 24±1 hours after dropwise application, no crystal precipitation was observed on the patch on the glass plate. X: Crystal precipitation occurred within less than 24±1 hours after dropwise application. For reference, photographs of Example 22 and Comparative Examples 1 and 2 showing the state of each topical preparation on the glass plate after a predetermined period of time has passed since application in the test item "Inhibition of Crystal Precipitation After Application" are shown in Figures 3 to 5, respectively. Example 22 is an example rated "A," in which the droplets spread after application, and it can be confirmed that no crystals were present even after the passage of time, as shown in Figure 3. Comparative Examples 1 and 2 are examples evaluated as "X." As shown in Figure 4, it can be seen that white crystals precipitated along the shape of the drug spot in Comparative Example 1, and as shown in Figure 5, it can be seen that needle-shaped crystals precipitated in Comparative Example 2.

[0073] [Evaluation Test Results: Crystal Precipitation Inhibition] Tables 1 to 17 show the evaluation test results for the crystal precipitation inhibition of each formulation for the topical preparations of each Example and Comparative Example. In each table, "IPA" represents isopropyl alcohol, "EtOH" represents ethanol, "DMSO" represents dimethyl sulfoxide, "NMP" represents N-methyl-2-pyrrolidone, "PVP" represents polyvinylpyrrolidone, "BzOH" represents benzyl alcohol, "PG" represents propylene glycol, "PEG" represents polyethylene glycol, and "TEG" represents triethylene glycol. Polyvinylpyrrolidone K 30 (weight average molecular weight 40,000) manufactured by Tokyo Chemical Industry Co., Ltd. was used as polyvinylpyrrolidone (PVP). Polyethylene glycol 300 (number average molecular weight 300) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. was used as polyethylene glycol (PEG). The same notation is used in Table 18 and subsequent tables described below.

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] The results shown in Table 1 will be discussed. Example 1 is a formulation using isopropyl alcohol and diisopropyl adipate as solvents (the solvent is included in the concept of "solvent (b)"), but the solubility of the active ingredient in the formulation was good and no crystalline precipitation was observed, and no crystalline precipitation occurred after application. Example 2 is a formulation using only diisopropyl adipate as the solvent (the solvent is included in the concept of "solvent (a)"), but similar to Example 1, it was confirmed that the effects of the present disclosure were exhibited. Therefore, it was found that the effects of the present disclosure can be achieved even when diisopropyl adipate is used alone as a solvent. Comparative Example 1 is a formulation using only isopropyl alcohol as the solvent, and Comparative Example 2 is a formulation using only N-methyl-2-pyrrolidone as the solvent. In these formulations, the solubility of the active ingredient in the formulation was good and no crystalline precipitation was observed, but crystals precipitated after application. Therefore, it can be seen that the suppression of crystal precipitation after application is not solely due to the good solubility of the solvent. Furthermore, in Comparative Example 3, which was a formulation using isopropyl alcohol and N-methyl-2-pyrrolidone as solvents, the solubility of the active ingredient in the formulation was insufficient, and crystal precipitation was confirmed, even after application. When N-methyl-2-pyrrolidone was combined with other solvents, crystal precipitation occurred in the formulation, suggesting that it is not desirable to incorporate N-methyl-2-pyrrolidone as a solvent in the present disclosure.

[0092] The results shown in Table 2 will be considered. Example 3 is a formulation using ethanol and diisopropyl adipate as the solvent (the solvent is included in the concept of "solvent (b)"), but it was confirmed that the effects of the present disclosure were exhibited, similar to Example 1, which used isopropyl alcohol. Comparative Example 4 is a formulation using only ethanol as the solvent, and although the solubility of the active ingredient in the formulation was good and no crystal precipitation was observed, crystals precipitated after application. This result, similar to the results shown in Table 1, suggests that the suppression of crystal precipitation after application is not solely due to the good solubility of the solvent. Furthermore, Comparative Example 5 is a formulation using ethanol and N-methyl-2-pyrrolidone as the solvent, but the solubility of the active ingredient in the formulation was insufficient, and crystal precipitation was observed, and crystals also precipitated after application. This result also showed a similar tendency to the results shown in Table 1, suggesting that it is undesirable to incorporate N-methyl-2-pyrrolidone as a solvent in the present disclosure.

[0093] Consider the results shown in Table 3. Examples 4 and 6 are formulations using isopropyl alcohol and dimethyl sulfoxide as solvents (solvents are included in the concept of "solvent (c)"), Example 5 is a formulation using ethanol and dimethyl sulfoxide as solvents (solvents are included in the concept of "solvent (c)"), and Example 7 is a formulation using dimethyl sulfoxide and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (d)"), but it was confirmed that the effects of the present disclosure were also exhibited with these various combinations of solvents.

[0094] The results shown in Tables 4 and 5 will be considered. Examples 8 to 11 are formulations using isopropyl alcohol, dimethyl sulfoxide, and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (e)"), and it was confirmed that the effects of the present disclosure are exhibited at various blend ratios. Examples 12 to 15 are formulations using ethanol, dimethyl sulfoxide, and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (e)"), and it was confirmed that the effects of the present disclosure are exhibited at various blend ratios in these examples as well.

[0095] The results shown in Tables 6 to 9 will now be considered. Examples 16 to 29 were based on formulations using diisopropyl adipate, and examined formulations in which the diisopropyl adipate was replaced with various dibasic acid diesters (the solvents are included in the concept of "solvent (b)" or "solvent (e)"). It was confirmed that the effects of the present disclosure were also exhibited with various dibasic acid diesters other than diisopropyl adipate, similar to diisopropyl adipate.

[0096] The results shown in Tables 10 and 11 are discussed below. Examples 30 to 33 are formulations using isopropyl alcohol or ethanol, dimethyl sulfoxide, and diisopropyl adipate as solvents (the solvents are included in the concept of "solvent (e)"), and Examples 34 to 37 are formulations using isopropyl alcohol or ethanol and diisopropyl adipate as solvents (the solvents are included in the concept of "solvent (b)"). Each formulation contains suitable optional ingredients such as polyvinylpyrrolidone, benzyl alcohol, and lactic acid. However, the solubility of the active ingredient in the formulation was good and no crystalline precipitation was observed, and no crystalline precipitation occurred after application. From these results, it can be said that each of the optional ingredients described above contributes to further improving the physical properties of the topical agent for onychomycosis without inhibiting the effects of the present disclosure.

[0097] The results shown in Table 12 will be considered. Examples 38 to 40 are formulations using ethanol and various glycols as solvents (the solvents are included in the concept of "solvent (f)"), and it was confirmed that the effects of the present disclosure are exhibited in combinations of lower alcohols and various glycols.

[0098] The results shown in Tables 13 to 17 are discussed below. Examples 41 to 66 confirmed that the effects of the present disclosure are exhibited in various combinations encompassed by the concepts of solvent (b), solvent (f), or solvent (g), and in particular that the effects of the present disclosure are not hindered by the inclusion of various optional components, and that the effects of the present disclosure are exhibited in various blending ratios.

[0099] [Evaluation Test: Subungual Efficacy Test] <Preparation of Conidial Solution> Fungal cells of Trichopyton rubrum (CBS118892 strain) cultured on Sabouraud dextrose agar medium were peeled and placed in a tube. 500 μL of saline was added to disperse the fungal cells, which were then filtered through a cell strainer (mesh size 40 μm). The filtrate was centrifuged (13,000 rpm × 5 minutes) to recover the precipitate. The recovered precipitate was washed with saline and dispersed in saline to prepare a fungal cell suspension. The fungal cell suspension was spread on a rye medium and cultured at 28°C. After that, 5 mL of saline was added to the formed mycelium, and the surface was scraped with a scraper to recover the fungal cell solution. The fungal cell solution was stirred with a vortex and then filtered through a 100 μm filter to obtain a conidial solution. The number of conidia was counted under a microscope and used for testing. <Human Nail Preparation> After sterilization and washing with 70% ethanol, the nails were immersed in 100% ethanol for 1 hour to remove moisture and then air-dried for 1 hour under a germicidal lamp in a safety cabinet. <Medicinal Solution Treatment of Human Nails> Each human nail was placed in a dish (35 mm diameter), and 0.5 μL of the medicinal solution was applied to the upper layer of the nail plate, ensuring that the medicinal solution remained on the top surface and did not drip down the sides. After the surface dried, the nail was kept in an incubator at 25°C to allow the medicinal solution to penetrate the human nail. This procedure was repeated once a day, 1 to 7 times. The medicinal solutions tested were the topical agents for onychomycosis in Examples 3, 5, 7, 27, 38-40, 50, 51, 53, 59, 60, and 67-71. <Test Medium Preparation> A medium for the subungual efficacy test was prepared by adding ampicillin to saline containing 1.5% agarose. <Subungual Efficacy Test> The conidial solution (1 x 10 ５A spot inoculation of 1 μL of conidia was performed on the nails, and the human nails treated with the above-mentioned drug solution were placed on top of the inoculated conidia so that the lower nail layer (the side opposite the upper nail layer to which the drug solution was applied) was in contact with the medium. The nails were then cultured at 28°C in an incubator. After culturing for 7 to 10 days, the growth of Trichophyton fungi was observed and rated based on the following criteria: A: No hyphal growth; X: Hyphal growth. For reference, Figure 6 shows photographs of the condition of the nail periphery in the test medium after seven drug solution treatments (once a day) in the above-mentioned "Subungual Efficacy Test" for Examples 68 and 69, their corresponding placebos, and a control in which the nails were not treated with the drug solution. No hyphal growth was observed in Examples 68 and 69 in Figure 6, and they were rated as "A." On the other hand, hyphal growth was observed in each placebo and control, and they were rated as "X." Thus, the "A" and "X" ratings can be relatively easily and objectively determined based on appearance.

[0100] [Evaluation Test Results: Subungual Efficacy Test] The evaluation test results of the subungual efficacy test on human nails for the topical preparations for onychomycosis of each Example used as test solutions, along with each formulation, are shown in Tables 18 to 21. Examples 3, 5, 7, 27, 38 to 40, 50, and 60 show the results after three drug solution treatments, Example 67 shows the results after seven drug solution treatments, and the others show the results after one drug solution treatment.

[0101]

[0102]

[0103]

[0104]

[0105] [Discussion: Subungual Efficacy Test] As can be seen from the results of each example, the topical preparation for onychomycosis of compound (1) using a predetermined solvent according to the present disclosure was confirmed to be subungual effective. Since the chemical solution treatment was performed so that the chemical solution remained only on the upper surface of the nail, the above test results show that the topical preparation for onychomycosis according to the present disclosure not only has an effect of inhibiting mycelium growth under the nail, but also has nail permeability.

[0106] [Evaluation test: human nail fungicidal activity test] This test was carried out in the same manner as the above-mentioned "Evaluation test: subungual efficacy test," except for the following changes. <Medicinal solution treatment on human nails> Human nails were placed one by one in a dish (35 mm diameter), and 0.5 μL of each medicinal solution was applied to the upper layer of the nail plate, as in the above test. After the surface dried, the nail was kept in an incubator at 25°C, and the medicinal solution was allowed to penetrate into the human nail. The above operation was carried out only once, and the penetration time was 7 days after application. The medicinal solution used was the topical agent for onychomycosis of Example 68. <Culture test> Cellophane (10 mm length x 10 mm width x 50 μm thickness) was placed on the test medium, and conidial solution (1 x 10 ５ The conidia were spot-inoculated with 1 μL of each of the conidia (100 conidia / 1 μL), and a human nail soaked in a drug solution was placed on top of the inoculation so that the lower nail layer was in contact with the cellophane. After culturing at 28°C for 24 hours, the conidia were stained with 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) solution to determine whether they were viable or dead.

[0107] [Evaluation Test Results: Human Nail Fungicidal Activity Test] The results of Example 68 are shown in Figure 7. For comparison, the results of commercially available topical nail solutions, "Luconac" (registered trademark) 5% topical solution manufactured by Sato Pharmaceutical Co., Ltd. and "Clenafin" (registered trademark) 10% topical solution manufactured by Kaken Pharmaceutical Co., Ltd., and the placebo corresponding to Example 68, are also shown in Figure 7.

[0108] [Discussion: Human Nail Fungicidal Activity Test] DAPI does not penetrate the cell membrane of live cells, but becomes permeable in dead cells due to changes in the cell membrane. In this test, this principle was used to determine the viability of subungual conidia. In the case of the topical onychomycosis preparation of Example 68, it was observed that the subungual conidia were stained with DAPI in dark field observation. On the other hand, no conidial staining was observed in the placebo and the two commercially available drugs used for comparison. Therefore, it was confirmed that the topical onychomycosis preparation of Example 68 fungicides subungual conidia, and that the placebo and the two commercially available drugs retained viable conidia. Even in bright field observation, some growth, such as swelling of conidia, was observed in the placebo and the two commercially available drugs, but no conidial growth was observed in the topical onychomycosis preparation of Example 68. As described above, conventional topical preparations for onychomycosis have antifungal activity but do not have fungicidal activity, whereas the topical preparation for onychomycosis of the present disclosure has not only antifungal activity but also fungicidal activity, and in this respect, it has excellent effects not seen in the prior art.

[0109] [Reference Test: Effect of Amount and Type of Optional Acid Added on Storage Stability] <Effect of Different Amounts of Lactic Acid Added on Storage Stability> The effect of different amounts of lactic acid added on storage stability was investigated using topical preparations of Examples 72 to 76 (Example 49 base group) in which the amount of lactic acid added was changed (including no addition) based on Example 49, and topical preparations of Examples 77 to 81 (Example 59 base group) in which the amount of lactic acid added was changed (including no addition) based on Example 59. The formulations are shown in Tables 22 and 23 below.

[0110]

[0111]

[0112] Next, the prepared sample solution (approximately 6 mL) was placed in a glass screw tube (container size: 10 mL) and sealed with bulk tape and vinyl tape to cover the cap and body. It was stored for 4 weeks under conditions of 60°C and 80% RH. After storage, the sample solution was diluted with acetonitrile and analyzed by liquid chromatography. Area percentages were calculated from the sum of the peak areas obtained on the chromatogram and the peak area of ​​the hydrolysate, which is the main decomposition product of compound (1). The results are shown in Figure 8.

[0113] <Effect of Different Types of Acid on Storage Stability> Sample solutions of Reference Examples 1 to 11 were prepared in the same manner as in Example 1 using the formulations of Compound (1), a lower alcohol, and an acid shown in Tables 24 to 26 below.

[0114]

[0115]

[0116]

[0117] Next, analysis was performed by liquid chromatography in the same manner as in the test relating to the above-mentioned "Effect of Differences in the Amount of Lactic Acid Added on Storage Stability," and the area percentage was calculated from the sum of the peak areas obtained on the chromatogram and the peak area of ​​the hydrolysate, which is the main degradation product of compound (1). The results are shown in Figure 9.

[0118] <Discussion> From the results of the above-mentioned reference tests, it was found that adding an acid is advantageous for improving the storage stability of compound (1), and that adding lactic acid or citric acid is particularly preferable. The amount of addition does not necessarily have to be increased; for example, in the case of lactic acid, it was found that the mass ratio relative to the entire topical preparation is preferably 8% by mass or less, more preferably 4% by mass or less, and particularly preferably 0.5 to 2% by mass.

[0119] The present disclosure can be suitably used in the field of treating onychomycosis and preventing its worsening.

Claims

1. An external preparation for onychomycosis comprising, as an active ingredient, at least one selected from the group consisting of compounds represented by the following formula (1) and salts thereof, and further comprising, as a solvent, at least one selected from the group consisting of the following solvents (a) to (g): Solvent (a): a dibasic acid diester; solvent (b): a lower alcohol and a dibasic acid diester; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and a dibasic acid diester; solvent (e): a lower alcohol, dimethyl sulfoxide and a dibasic acid diester; solvent (f): a lower alcohol and glycols; and solvent (g): a lower alcohol, glycols and a dibasic acid diester.

2. The topical preparation for onychomycosis according to claim 1, which contains at least one solvent selected from the group consisting of the solvents (a), (b), (d) and (e).

3. The topical preparation for onychomycosis according to claim 1, which contains at least one solvent selected from the group consisting of the solvents (c), (d) and (e).

4. The topical preparation for onychomycosis according to claim 1, which contains at least one solvent selected from the group consisting of solvents (d) and (e).

5. The external preparation for nail tinea according to claim 1, wherein the dibasic acid diester is a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.

6. The topical preparation for onychomycosis according to claim 1, further comprising polyvinylpyrrolidone.

7. The topical preparation for onychomycosis according to claim 1, further comprising an acid as a pH adjuster.

8. The external preparation for nail tinea as described in claim 7, wherein the pH adjuster is lactic acid or citric acid.

9. The topical preparation for onychomycosis according to claim 1, wherein the content of at least one selected from the group consisting of the compound represented by formula (1) and a salt thereof is 0.1 to 20% by mass, and the content of at least one selected from the group consisting of the solvents (a) to (g) is 60 to 99.9% by mass.

10. Use of a combination of at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof and at least one solvent selected from the group consisting of the following solvents (a) to (g) for the manufacture of an external preparation for onychomycosis or a medicament for treating onychomycosis or preventing the worsening of onychomycosis: Solvent (a): a dibasic acid diester; solvent (b): a lower alcohol and a dibasic acid diester; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and a dibasic acid diester; solvent (e): a lower alcohol, dimethyl sulfoxide and a dibasic acid diester; solvent (f): a lower alcohol and glycols; and solvent (g): a lower alcohol, glycols and a dibasic acid diester.

11. Use of a composition comprising at least one compound represented by the following formula (1) and a salt thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of the following solvents (a) to (g), for the manufacture of an external preparation for onychomycosis or a medicament for treating onychomycosis or preventing the worsening of onychomycosis: Solvent (a): a dibasic acid diester; solvent (b): a lower alcohol and a dibasic acid diester; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and a dibasic acid diester; solvent (e): a lower alcohol, dimethyl sulfoxide and a dibasic acid diester; solvent (f): a lower alcohol and glycols; and solvent (g): a lower alcohol, glycols and a dibasic acid diester.

12. A composition for use in treating or preventing the worsening of onychomycosis, comprising as an active ingredient at least one selected from the group consisting of compounds represented by the following formula (1) and salts thereof, and further comprising as a solvent at least one selected from the group consisting of the following solvents (a) to (g): Solvent (a): a dibasic acid diester; solvent (b): a lower alcohol and a dibasic acid diester; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and a dibasic acid diester; solvent (e): a lower alcohol, dimethyl sulfoxide and a dibasic acid diester; solvent (f): a lower alcohol and glycols; and solvent (g): a lower alcohol, glycols and a dibasic acid diester.

13. A method for treating onychomycosis in a subject, comprising topically applying an effective amount of an external preparation for onychomycosis to an affected nail of the subject, wherein the external preparation for onychomycosis contains at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further contains at least one solvent selected from the group consisting of the following solvents (a) to (g): Solvent (a): a dibasic acid diester; solvent (b): a lower alcohol and a dibasic acid diester; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and a dibasic acid diester; solvent (e): a lower alcohol, dimethyl sulfoxide and a dibasic acid diester; solvent (f): a lower alcohol and glycols; and solvent (g): a lower alcohol, glycols and a dibasic acid diester.

14. A method for preventing the worsening of onychomycosis in a subject, comprising topically applying an effective amount of an external preparation for onychomycosis to an affected nail of the subject, wherein the external preparation for onychomycosis contains at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further contains at least one solvent selected from the group consisting of the following solvents (a) to (g): Solvent (a): a dibasic acid diester; solvent (b): a lower alcohol and a dibasic acid diester; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and a dibasic acid diester; solvent (e): a lower alcohol, dimethyl sulfoxide and a dibasic acid diester; solvent (f): a lower alcohol and glycols; and solvent (g): a lower alcohol, glycols and a dibasic acid diester.

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