Topical agent for onychomycosis

Abstract

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

[Technical Field]

[0001] This case relates to a topical onychomycosis treatment or prevention of its worsening. [Related application reference]

[0002] This patent application claims priority to Japanese Patent Application No. 2023-125977, filed on August 2, 2023, the entire disclosure of which is incorporated herein by reference. [Previous Technology]

[0003] The compound represented by the following formula (1) (hereinafter referred to as "compound (1)") is described as Compound No. 6 (manufacturing example 6) in Patent Document 1, and is known to be a compound used as an antifungal agent for human use. Furthermore, as a related technology of this compound (1), it is also known that the hydrate crystals of compound (1) have properties such as high stability to changes in temperature or humidity and the ability to reduce triboelectricity, which can be advantageously utilized in the effective manufacture 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 indicate the formulation of a topical onychomycosis preparation.

[0004] Onychomycosis is a disease caused by infection of the nails with Trichophyton mentagrophytes. Treatment commonly involves oral or topical medications. Currently, oral medications are primarily used; however, they have been repeatedly cited for the following problems: requiring long-term use; interactions with other medications; and side effects such as liver damage. Therefore, the development of effective topical medications has been sought since ancient times. The main challenge with topical medications is the difficulty in delivering sufficient quantities to the affected area to achieve a therapeutic effect. Research has focused on improving penetration into the nail, inhibiting crystallization during storage or application, and stabilizing the active ingredients.

[0005] As one of the studies, there are known topical pharmaceutical compositions with ruliconazole or lanokonazole as active ingredients (see Patent Documents 3-5).

[0006] According to Patent Document 3, it describes how by blending α-hydroxycarboxylic acid or its salt, the instantaneous precipitation of fine crystals of luriconazole during application can be suppressed, thereby hindering the characteristic phenomenon of luriconazole's penetrating and absorbing properties into biological tissues. Dicarboxylic acid diesters are cited as an example of any component, and have been described as components that promote penetration into the nail.

[0007] According to Patent Document 4, N-methyl-2-pyrrolidone has the effect of inhibiting the precipitation of crystals or insoluble substances on the surface after 20 to 40 seconds of application. This effect is believed to be due to the interaction with the surface structure of the skin or nail, or the interaction with substances present on the surface. Patent Document 4 also cites a diester of a dicarboxylic acid as one of the ingredients, describing it as a component that promotes penetration into the nail.

[0008] According to Patent Document 5, it describes that by containing at least one of the groups selected from higher alcohols and diesters, and at least one of the groups selected from polyoxyethylene alkyl ethers and polyoxyethylene alkenyl ethers, desired properties such as inhibiting the isomerization of the active ingredient, transparency at 20°C after manufacturing, and preventing precipitation during low-temperature storage can be obtained. One reason for blending diesters is to inhibit crystallization in low-temperature regions. When used with a specific ratio of a predetermined higher alcohol, it is also described that it can inhibit crystallization caused by impact, such as crystallization during nail application.

[0009] Furthermore, topical antifungal preparations using iriconazole as the active ingredient are also known (see Patent Document 6). According to Patent Document 6, effective trans-nail penetration can be achieved by containing iriconazole, a monohydric alcohol, a diol, and a predetermined excipient. Dimethyl sulfoxide and diesters are among the many exemplified excipients, and their mixing purpose, as is understood in relation to the overall purpose of the invention, is to promote penetration into the nail.

[0010] As mentioned above, although some people have conducted formulation studies on topical medicines for various active ingredients, no one has conducted any research on topical onychomycosis preparations with at least one of the group consisting of compound (1) and its salt as active ingredients.

[0011] Although the above-mentioned literature records the mixing of dimethyl sulfoxide or diester, in general, the optimal formulation varies with the differences in active ingredients, etc. Therefore, the above-mentioned literature that records active ingredients different from those in this case cannot show the formulation of the following proposed solvent mixed with at least one of the active ingredients selected from the group consisting of compound (1) and its salt as active ingredients in the topical onychomycosis preparation.

[0012] In this regard, paragraph 0029 of Patent Document 3 describes an evaluation of the degree of crystallization after coating Example 5 (a detergent containing luriconazole, diisopropyl adipate, lactic acid, and ethanol) onto a glass slide, comparing it with Comparative Example 6 (a detergent containing luriconazole, diisopropyl adipate, and ethanol, in which lactic acid was replaced with ethanol in the formulation of Example 5). The latter showed that crystallization could not be suppressed (see Figures 4 and 5 of Patent Document 3). [Prior Art Documents] [Patent Documents]

[0013] [Patent Document 1] International Publication No. 2021 / 246455 [Patent Document 2] International Publication No. 2023 / 106320 [Patent Document 3] International Publication No. 2007 / 102241 [Patent Document 4] International Publication No. 2007 / 102243 [Patent Document 5] International Publication No. 2010 / 117091 [Patent Document 6] International Publication No. 2020 / 231800 [Summary of the Invention]

[0014] [The problem that the invention aims to solve]

[0015] This case concerns the provision of a topical onychomycosis preparation that uses at least one of the compounds (1) and their salts as active ingredients, inhibits crystallization in the preparation and crystallization after application, thereby increasing nail penetration and thus fully exerting the effect of the aforementioned active ingredients on onychomycosis. [Means of Solving the Problem]

[0016] The inventors of this case have devoted themselves to research in order to solve the above-mentioned problems and have found that when a certain solvent is used, the crystal precipitation in the preparation and the crystal precipitation after application can be inhibited, thereby increasing the nail penetration rate and fully exerting the effect on onychomycosis, thus completing the present invention.

[0017] That is, this case is a topical preparation for onychomycosis, which contains at least one of the compounds selected from the group consisting of the compounds represented by the following formula (1) and their salts as active ingredients, and contains at least one of the solvents selected from the group consisting of the following solvents (a) to (g) as solvents.

[0018]

[0019] Solvent (a): Dicarboxylic acid diester; Solvent (b): Lower alcohol and dicarboxylic acid diester; Solvent (c): Lower alcohol and dimethyl sulfoxide; Solvent (d): Dimethyl sulfoxide and dicarboxylic acid diester; Solvent (e): Lower alcohol, dimethyl sulfoxide and dicarboxylic acid diester; Solvent (f): Lower alcohol and glycols; and Solvent (g): Lower alcohol, glycols and dicarboxylic acid diester. [Effects of the Invention]

[0020] According to this case, the effective ingredient is selected from at least one compound in the group consisting of compound (1) and its salt, which can inhibit crystallization in the preparation and crystallization after application, thereby increasing nail penetration and fully exerting the effect on onychomycosis.

Implementation Method

[0022] [Form of Invention]

[0023] The following describes in detail the topical preparation for onychomycosis in this case (hereinafter referred to as "the topical preparation in this case"). However, the scope of this case is not limited by such description. Except as exemplified below, appropriate changes may be made to the implementation without prejudice to the intent of this case.

[0024] The topical preparation of this case contains at least one compound selected from the group consisting of compound (1) and its salt as an active ingredient. Compound (1) is a known compound as described above, and is represented by the chemical name 5-chloro-4-(3-chloro-4-tolyl)-1H-imidazol-2-carbamate. As for the salt of compound (1), there are no particular limitations as long as it is a pharmaceutically permissible salt, and examples 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 p-toluenesulfonate. Furthermore, examples of basic salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts.

[0025] In addition, at least one compound selected from the group consisting of compound (1) and its salt may have the following tautomers, except that at least one compound selected from the group consisting of compound (1) and its salt in this case includes both the presence of any one of these tautomers and the coexistence of the tautomers (coexisting in equilibrium).

[0026]

[0027] Furthermore, compound (1) or its salts often absorb moisture when exposed to the atmosphere or undergo recrystallization, thus acquiring adsorbed water or forming hydrates; in this case, compound (1) or its salts also include various such hydrates, solvates and polymorphic compounds. Preferred examples include, for instance, the hydrates and polymorphic compounds disclosed in International Publication No. 2023 / 106320. The proportion of at least one compound selected from the group consisting of compound (1) and its salts relative to the total amount of the adjuvant in this case 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.

[0028] The external application agent of this invention, as a solvent, contains at least one solvent selected from the group consisting of solvents (a) to (g) below (hereinafter referred to as "the solvent defined in this invention"). Solvent (a): dicarboxylic acid diester; Solvent (b): lower alcohol and dicarboxylic acid diester; Solvent (c): lower alcohol and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dicarboxylic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dicarboxylic acid diester; Solvent (f): lower alcohol and glycols; and solvent (g): lower alcohol, glycols and dicarboxylic acid diester.

[0029] The aforementioned diacid diester in the solvent specified in this case is a compound formed by diesterization of a diacid and an alcohol. The aforementioned diacid is not particularly limited, but aliphatic or aromatic diacids are preferred. Examples of aliphatic diacids include saturated aliphatic diacids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, octanoic acid, azelaic acid, and sebacic acid, as well as unsaturated aliphatic diacids such as maleic acid and fumaric acid. Preferably, they are aliphatic diacids with 2 to 10 carbon atoms, more preferably aliphatic diacids with 2 to 6 carbon atoms, and most preferably at least one selected from the group consisting of adipic acid, fumaric acid, and maleic acid. Examples of aromatic diacids include phthalic acid, isophthalic acid, and terephthalic acid. The alcohols resulting from the diesterization of the aforementioned dicarboxylic acids are not particularly limited, but are preferably alcohols with 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and tributanol. More preferably, they are selected from at least one alcohol in the group consisting of ethanol, isopropanol, butanol, and isobutanol. Examples of the diesters of the aforementioned dicarboxylic acids are not particularly limited, but are preferably diisopropyl adipate, diisobutyl adipate, dibutyl fumarate, and diethyl maleate, with diisopropyl adipate being particularly preferred.

[0030] The aforementioned lower alcohols in the solvents defined in this case are not particularly limited, but are preferably alcohols with 1 to 4 carbons such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tributanol, and are particularly preferably selected from at least one of the groups consisting of ethanol and isopropanol.

[0031] The diols used as solvents in this application are not particularly limited, but examples include, for instance, ethylene glycol, propylene glycol, 1,3-propanediol, 1,4-butanediol, or dehydration condensates thereof. Examples of dehydration condensates include diethylene glycol, triethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, and polypropylene glycol. Among the diols used as dehydration condensates, the molecular weight is preferably, for example, 200 to 600, more preferably 200 to 400. Propylene glycol and polyethylene glycol are particularly preferred.

[0032] The proportion of the solvent in this case relative to the total amount of the agent used outside this case is not particularly limited, but it is preferably 60 to 99.9% by mass, more preferably 70 to 99.9% by mass, and especially preferably 80 to 99.9% by mass relative to the total amount of the agent used outside this case.

[0033] In solvent (b), the blending ratio of the lower alcohol and the diester of the diacid, based on mass, is preferably 99.9:0.1 to 10:90 for the lower alcohol to the diester of the diacid, more preferably 75:25 to 50:50. In solvent (c), the blending ratio of the lower alcohol and the dimethyl sulfoxide, based on mass, is preferably 99.9:0.1 to 10:90 for the lower alcohol to the dimethyl sulfoxide, more preferably 75:25 to 50:50. In solvent (d), the blending ratio of the dimethyl sulfoxide and the diester of the diacid, based on mass, is preferably 99.9:0.1 to 10:90 for the dimethyl sulfoxide to the diester of the diacid, more preferably 75:25 to 50:50. In solvent (e), the blending ratio of lower alcohol, dimethyl sulfoxide, and diester of diacid is set to a total of 100% by mass, preferably a ratio of 0.1–99.8% by mass of lower alcohol, 0.1–99.8% by mass of dimethyl sulfoxide, and 0.1–99.8% by mass of diester of diacid, more preferably a ratio of 10–75% by mass of lower alcohol, 5–75% by mass of dimethyl sulfoxide, and 10–75% by mass of diester of diacid. In solvent (f), the blending ratio of lower alcohol and glycols, based on mass, is preferably 99.9:0.1–10:90 for lower alcohol: glycol, more preferably 75:25–50:50. In the solvent (g), the blending ratio of lower alcohols, glycols, and diesters of diacids is set to a total of 100% by mass. Preferably, the ratio is 0.1-99.8% by mass of lower alcohols, 0.1-99.8% by mass of glycols, and 0.1-99.8% by mass of diesters of diacids. More preferably, the ratio is 55-90% by mass of lower alcohols, 5-35% by mass of glycols, and 5-35% by mass of diesters of diacids.

[0034] In the external agent of this case, the mixing ratio of at least one compound selected from the group consisting of compound (1) and its salts with the solvent of this case is not particularly limited, but based on mass, it is preferably 0.1:99.9 to 40:60, more preferably 0.1:99.9 to 20:80, and especially preferably 1:99 to 10:90.

[0035] The topical preparation of this invention may also contain any solvent used in the pharmaceutical composition other than the solvent specified in this invention. Examples of such other solvents include triglycerides such as olive oil, fatty acids such as stearic acid and oleic acid, and polyols other than glycols (such as glycerol). In addition, although 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 help to inhibit crystallization and may even hinder the crystallization inhibition effect of this invention. Therefore, it is not mixed, or if it is mixed, it is advisable to use a small amount. The amount of mixing is preferably 10% by mass or less, more preferably 5% by mass or less, and particularly preferably 1% by mass or less, relative to the total amount of the topical preparation of this invention.

[0036] The topical agents in this case may also contain any ingredients other than those mentioned above. Such arbitrary ingredients may include, for example, common pharmaceutical additives used in topical agents such as expanders, diluents, pH adjusters, dispersants, emulsifiers, preservatives, stabilizers, antioxidants, colorants, UV absorbers, humectants, and thickeners.

[0037] The following are specific examples of preferred ingredients. A specific example of a suitable ingredient is polyvinylpyrrolidone. Polyvinylpyrrolidone has the effect of inhibiting crystallization after coating. It is presumed that this effect is due to the amorphization of at least one compound selected from the group consisting of compound (1) and its salt by polyvinylpyrrolidone. The molecular weight of polyvinylpyrrolidone is not particularly limited, and for example, a weight average molecular weight of 10,000 to 360,000 can be used. The amount of polyvinylpyrrolidone blended is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, relative to the total amount of the topical agent in this invention. Ingredients that can achieve the same effect as polyvinylpyrrolidone (inhibition of crystallization by amorphization) (crystallization inhibitors) include polymers such as ethylene / maleic anhydride copolymers and polyalkylene glycols (polyethylene glycol, polyoxyethylene polyoxypropylene glycol, etc.), which can be used as any ingredient in the topical agent in this invention.

[0038] Furthermore, it is preferable to use an acid as a pH adjuster. By using an acid as a pH adjuster, the stability of at least one compound selected from the group consisting of compound (1) and its salt can be improved, thereby increasing its permeability in organisms. Specific pH adjusters preferably include lactic acid, acetic acid, citric acid (including monohydrate), ascorbic acid, phosphoric acid, etc., more preferably lactic acid and citric acid, and especially preferably lactic acid. The amount of acid used as a pH adjuster is not particularly limited, but is preferably 0.1 to 10% by mass relative to the total amount of the external agent in this invention, more preferably 0.5 to 5% by mass. In particular, when lactic acid is used as an acid, the upper limit is preferably 8% by mass or less, more preferably 4% by mass or less, and especially preferably 0.5 to 2% by mass.

[0039] Furthermore, as a preservative, it is preferable to blend in, for example, benzyl alcohol, benzoic acid or its salts (sodium salt, etc.), sebacic acid, sorbic acid, etc., with benzyl alcohol being particularly preferred. The amount of preservative blended is not particularly limited, but is preferably 0.1 to 10% by mass relative to the total amount of the other agents used in this invention, and more preferably 0.1 to 5% by mass.

[0040] By combining the above-mentioned essential ingredients and any other ingredients as needed, and by formulating them according to common methods, the topical preparation of this invention can be obtained. The form of the preparation can be a form commonly used for topical preparations, such as a lotion, cream, emulsion, suspension, gel, patch, etc., with a lotion being particularly suitable.

[0041] The topical preparation of this invention can be used to treat onychomycosis or prevent its worsening. It can be applied topically to the affected nails of the target animal species (e.g., humans) by means of application, rubbing, or sticking, depending on its specific formulation. In the topical preparation of this invention, the effective amount of at least one compound selected from the group consisting of compound (1) and its salts and the frequency of application of the topical preparation are not particularly limited. Since they vary depending on the species, sex, age, weight, condition, or other reasons of the target animal, it is difficult to generalize. For example, the dosage when applied topically to the affected area of ​​a human is based on the amount of at least one compound selected from the group consisting of compound (1) and its salts. For each adult weighing 60 kg, the daily dosage is usually 500 to 3,000 μg / day per nail, and the appropriate weekly dosage is 3.5 to 15 mg / week per nail.

[0042] According to another aspect of this case, a method for treating onychomycosis is provided, comprising applying an effective amount of a topical onychomycosis agent topically to the affected nail of the subject, wherein the topical onychomycosis agent contains at least one active ingredient selected from the group consisting of compounds represented by formula (1) and their salts, and contains at least one solvent selected from the group consisting of solvents (a) to (g). This method is also referred to as the "treatment method" below.

[0043] Furthermore, according to another aspect of this case, a method is provided for preventing the worsening of onychomycosis in a subject, comprising applying an effective amount of a topical onychomycosis agent topically to the affected nail of the subject, wherein the topical onychomycosis agent contains at least one active ingredient selected from the group consisting of compounds represented by formula (1) and their salts, and contains at least one solvent selected from the group consisting of solvents (a) to (g). This method will also be referred to as the "prevention method" below.

[0044] In the treatment and prevention methods of this case, "treatment of onychomycosis" includes stopping, alleviating or delaying the progression or worsening of onychomycosis through medical or non-medical means. In addition, "preventing the worsening of onychomycosis" includes taking precautions against the worsening of onychomycosis in advance, preventing its occurrence or recurrence before it happens through medical or non-medical means.

[0045] In the treatment and prevention methods of this case, since the "effective amount of topical onychomycosis medication" varies depending on the animal species, sex, age, weight, condition or other reasons of the subject, it is difficult to generalize. For example, the dosage when applied topically to the affected area of ​​a person is preferably 500 to 3,000 μg / (person / day / tablet) per day per nail for an adult weighing 60 kg, and preferably 3.5 to 15 mg / (person / week / tablet) per nail per week.

[0046] In the treatment and prevention methods of this case, the topical preparation for onychomycosis can correspond to its specific formulation and be applied topically to the affected nails of the target animal species (such as humans) by means of application, rubbing, or sticking.

[0047] In the treatment and prevention methods of this case, the above-mentioned topical onychomycosis preparation may contain, for example, at least one solvent selected from the group consisting of the above-mentioned solvents (a), (b), (d), and (e). Furthermore, it may contain at least one solvent selected from the group consisting of the above-mentioned solvents (c), (d), and (e). Moreover, it may also contain at least one solvent selected from the group consisting of the above-mentioned solvents (d) and (e).

[0048] In the treatment and prevention methods of this case, the aforementioned dicarboxylic acid diester is preferably a diester of a dicarboxylic acid and an alcohol having 1 to 4 carbon atoms.

[0049] In the treatment and prevention methods of this case, the above-mentioned topical onychomycosis treatment agent preferably contains polyvinylpyrrolidone.

[0050] In the treatment and prevention methods of this case, the above-mentioned topical onychomycosis treatment agent preferably 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.

[0051] The content of at least one of the compounds selected from the group represented by the above formula (1) and their salts in the above-mentioned topical onychomycosis preparation is 0.1 to 20% by mass, and the content of at least one of the solvents selected from the group (a) to (g) is preferably 60 to 99.9% by mass.

[0052] Furthermore, according to another aspect of this case, a combination of at least one compound selected from the group consisting of compounds represented by formula (1) and their salts, and at least one solvent selected from the group consisting of solvents (a) to (g) is provided for use in the manufacture of a topical agent for onychomycosis or for the treatment of onychomycosis or the prevention of its aggravation. This use is also referred to below as "use of a combination of compounds" or "combination use of compounds".

[0053] Furthermore, according to another aspect of this case, a composition is provided containing at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and containing at least one of the solvents selected from the group consisting of solvents (a) to (g) as a solvent, which is used to manufacture a topical agent for onychomycosis or a medicine for treating onychomycosis or preventing its aggravation. Hereinafter, this use will also be referred to as "use of the composition".

[0054] In the use of the combination of compounds and the use of the composition in this case, "treatment of onychomycosis" and "prevention of the aggravation of onychomycosis" are as described above.

[0055] In the use of the combination of compounds and the use of the composition in this case, the above-mentioned topical onychomycosis treatment and the above-mentioned medicine may contain, for example, at least one solvent selected from the group consisting of the above-mentioned solvents (a), (b), (d) and (e). Furthermore, it may contain at least one solvent selected from the group consisting of the above-mentioned solvents (c), (d) and (e). Moreover, it may also contain at least one solvent selected from the group consisting of the above-mentioned solvents (d) and (e).

[0056] In the use of the combination of compounds and the use of the composition in this case, the above-mentioned dicarboxylic acid diester is preferably a diester of a dicarboxylic acid and an alcohol having 1 to 4 carbon atoms.

[0057] In the use of the combination of compounds and the use of the composition in this case, the above-mentioned topical onychomycosis treatment and the above-mentioned medicine preferably further contain polyvinylpyrrolidone.

[0058] In the use of the combination of compounds and the use of the composition in this case, the above-mentioned onychomycosis topical agent and the above-mentioned medicine 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.

[0059] The content of at least one of the compounds selected from the group consisting of the compound represented by the above formula (1) and its salt in the above-mentioned topical onychomycosis preparation and the above-mentioned medicine is 0.1 to 20% by mass, and the content of at least one of the solvents selected from the group consisting of the above-mentioned solvents (a) to (g) is preferably 60 to 99.9% by mass.

[0060] Furthermore, according to another aspect of the present invention, a composition is provided containing at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and containing at least one of the solvents selected from the group consisting of solvents (a) to (g) below as a solvent, which is used to treat onychomycosis or prevent its aggravation. Hereinafter referred to simply as "composition".

[0061] The components of this case are as described above: "treatment of onychomycosis" and "prevention of the aggravation of onychomycosis".

[0062] The composition of this case can correspond to its specific formulation form and be applied topically to the affected nail of the target animal species (such as human) by means of coating, rubbing, or sticking.

[0063] The composition of this invention may contain at least one solvent selected from the group consisting of solvents (a), (b), (d), and (e) above. Furthermore, it may contain at least one solvent selected from the group consisting of solvents (c), (d), and (e) above. Moreover, it may also contain at least one solvent selected from the group consisting of solvents (d) and (e) above.

[0064] In the composition of this case, the aforementioned dicarboxylic acid diester is preferably a diester of a dicarboxylic acid and an alcohol having 1 to 4 carbon atoms.

[0065] The composition of this case preferably contains polyvinylpyrrolidone.

[0066] The composition of this invention 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.

[0067] The composition of this case contains at least one of the compounds selected from the group consisting of the compounds represented by the above formula (1) and their salts in a proportion of 0.1 to 20% by mass, and preferably contains at least one of the solvents selected from the group consisting of the above solvents (a) to (g) in a proportion of 60 to 99.9% by mass.

[0068] Also, according to the same form of this case, the following is provided: [1] A topical onychomycosis preparation containing at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and containing at least one of the solvents selected from the group consisting of the following solvents (a) to (g) as a solvent: solvent (a): diester of a dicarboxylic acid; solvent (b): lower alcohol and diester of a dicarboxylic acid; solvent (c): lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and diester of a dicarboxylic acid; solvent (e): lower alcohol, dimethyl sulfoxide and diester of a dicarboxylic acid; solvent (f): lower alcohol and glycols; and solvent (g): lower alcohol, glycols and diester of a dicarboxylic acid. [2] The topical onychomycosis preparation of [1] contains at least one of the solvents selected from the group consisting of the above solvents (a), (b), (d) and (e) as a solvent. [3] The onychomycosis topical preparation of [1] or [2] contains at least one solvent selected from the group consisting of solvents (c), (d) and (e) above. [4] The onychomycosis topical preparation of any one of [1] to [3] contains at least one solvent selected from the group consisting of solvents (d) and (e) above. [5] The onychomycosis topical preparation of [1] to [4], wherein the dicarboxylic acid diester is a diester of a dicarboxylic acid and an alcohol having 1 to 4 carbon atoms. [6] The onychomycosis topical preparation of any one of [1] to [5] further contains polyvinylpyrrolidone. [7] The onychomycosis topical preparation of any one of [1] to [6] further contains an acid as a pH adjuster. [8] The onychomycosis topical preparation of [7], wherein the pH adjuster is lactic acid or citric acid. [9] The onychomycosis preparation of any one of [1] to [8] contains at least one of the compounds selected from the group consisting of the compound represented by formula (1) and its salt in a proportion of 0.1 to 20% by mass, and at least one of the solvents selected from the group consisting of (a) to (g) in a proportion of 60 to 99.9% by mass.

[10] The use of at least one compound selected from the group consisting of compounds represented by formula (1) and their salts, and at least one solvent selected from the group consisting of solvents (a) to (g) below, for the manufacture of a topical agent for onychomycosis or for the treatment of onychomycosis or for the prevention of its aggravation; solvent (a): dicarboxylic acid diester; solvent (b): lower alcohol and dicarboxylic acid diester; solvent (c): lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and dicarboxylic acid diester; solvent (e): lower alcohol, dimethyl sulfoxide and dicarboxylic acid diester; solvent (f): lower alcohol and diols; and solvent (g): lower alcohol, diols and dicarboxylic acid diester.

[11] A composition comprising at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and comprising at least one of the solvents selected from the group consisting of solvents (a) to (g) below as a solvent, used for manufacturing a topical agent for onychomycosis or for treating onychomycosis or preventing its aggravation; solvent (a): diester of a dicarboxylic acid; solvent (b): a lower alcohol and diester of a dicarboxylic acid; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and diester of a dicarboxylic acid; solvent (e): a lower alcohol, dimethyl sulfoxide and diester of a dicarboxylic acid; solvent (f): a lower alcohol and diols; and solvent (g): a lower alcohol, diols and diester of a dicarboxylic acid.

[12] A composition comprising at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and comprising at least one of the solvents selected from the group consisting of solvents (a) to (g) below as a solvent, for use in treating onychomycosis or preventing its aggravation; solvent (a): dicarboxylic acid diester; solvent (b): lower alcohol and dicarboxylic acid diester; solvent (c): lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and dicarboxylic acid diester; solvent (e): lower alcohol, dimethyl sulfoxide and dicarboxylic acid diester; solvent (f): lower alcohol and diols; and solvent (g): lower alcohol, diols and dicarboxylic acid diester.

[13] A method for treating onychomycosis of a subject, comprising applying an effective amount of a topical onychomycosis agent topically to the affected nail of the subject, the topical onychomycosis agent containing at least one active ingredient selected from the group consisting of compounds represented by formula (1) and their salts, and containing at least one solvent selected from the group consisting of solvents (a) to (g); solvent (a): dicarboxylic acid diester; solvent (b): lower alcohol and dicarboxylic acid diester; solvent (c): lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and dicarboxylic acid diester; solvent (e): lower alcohol, dimethyl sulfoxide and dicarboxylic acid diester; solvent (f): lower alcohol and diols; and solvent (g): lower alcohol, diols and dicarboxylic acid diester.

[14] A method for preventing the aggravation of onychomycosis in a subject, comprising applying an effective amount of a topical onychomycosis agent to the affected nail of the subject, wherein the topical onychomycosis agent contains at least one active ingredient selected from the group consisting of compounds represented by formula (1) and their salts, and contains at least one solvent selected from the group consisting of solvents (a) to (g); solvent (a): dicarboxylic acid diester; solvent (b): lower alcohol and dicarboxylic acid diester; solvent (c): lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and dicarboxylic acid diester; solvent (e): lower alcohol, dimethyl sulfoxide and dicarboxylic acid diester; solvent (f): lower alcohol and diols; and solvent (g): lower alcohol, diols and dicarboxylic acid diester.

[0069] Also, according to another form of this case, the following is provided: [T1] The use of at least one compound selected from the group consisting of compounds represented by formula (1) and their salts, and at least one solvent selected from the group consisting of solvents (a) to (g) below, for the manufacture of a topical agent for onychomycosis or for the treatment of onychomycosis or for the prevention of its aggravation; solvent (a): diester of a dicarboxylic acid; solvent (b): a lower alcohol and a diester of a dicarboxylic acid; solvent (c): a lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (e): a lower alcohol, dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (f): a lower alcohol and diols; and solvent (g): a lower alcohol, diols and a diester of a dicarboxylic acid. [T2] ​​A composition comprising at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and comprising at least one of the solvents selected from the group consisting of solvents (a) to (g) below as a solvent, used for manufacturing a topical onychomycosis preparation or for treating or preventing the aggravation of onychomycosis; solvent (a): a diester of a dicarboxylic acid; solvent (b): a lower alcohol and a diester of a dicarboxylic acid; solvent (c): a lower alcohol and a dimethyl sulfoxide; solvent (d): a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (e): a lower alcohol, a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (f): a lower alcohol and a diol; and solvent (g): a lower alcohol, a diol and a diester of a dicarboxylic acid. [T3] As used in [T1] or [T2], wherein the aforementioned topical onychomycosis preparation or the aforementioned medicine contains at least one solvent selected from the group consisting of the aforementioned solvents (a), (b), (d), and (e). [T4] As used in any of [T1] to [T3], wherein the aforementioned topical onychomycosis preparation or the aforementioned medicine contains at least one solvent selected from the group consisting of the aforementioned solvents (c), (d), and (e). [T5] As used in any of [T1] to [T4], wherein the aforementioned topical onychomycosis preparation or the aforementioned medicine contains at least one solvent selected from the group consisting of the aforementioned solvents (d) and (e). [T6] As used in any of [T1] to [T5], wherein the aforementioned dicarboxylic acid diester is a diester of a dicarboxylic acid and an alcohol having 1 to 4 carbon atoms. [T7] As described in any of [T1] to [T6], wherein the above-mentioned topical onychomycosis preparation or the above-mentioned medicine further contains polyvinylpyrrolidone. [T8] As described in any of [T1] to [T7], wherein the above-mentioned topical onychomycosis preparation or the above-mentioned medicine further contains an acid as a pH adjuster. [T9] As described in [T8], wherein the pH adjuster is lactic acid or citric acid.[T10] As in any of [T1] to [T9], the content of at least one of the compounds selected from the group consisting of the above-mentioned topical onychomycosis preparation or the above-mentioned medicine is 0.1 to 20% by mass, and the content of at least one of the compounds selected from the group consisting of the above-mentioned formula (1) and their salts is 60 to 99.9% by mass. [Example].

[0070] Hereinafter, examples and comparative examples are shown in order to provide a more specific description of the external application agent in this case, but this case is not limited to these examples. In addition, the compound (1) used in the following examples is a monohydrate crystal prepared based on the description of Manufacturing Example 2 in International Publication No. 2023 / 106320.

[0071] [Example 1] According to the following formulation, at room temperature (approximately 25°C), the ingredients of each formulation are mixed in a glass screw-cap bottle (10mL to 30mL in size), and the mixture is shaken by hand until the solids dissolve to prepare the external application agent of Example 1. Compound (1) 5 parts by weight Isopropanol 47.5 parts by weight Diisopropyl adipate 47.5 parts by weight

[0072] [Evaluation Test: Inhibition of Crystallization Precipitation] For each example and comparative example of the topical application, the following evaluation items were tested. [Examples 2-81, Comparative Examples 1-6] Except that the formulation was changed to the formulation shown in Tables 1-23 in the evaluation tests described below, the topical applications of Examples 2-81 and Comparative Examples 1-6 were prepared in the same manner as in Example 1.

[0073] <Inhibition of Crystallization in Formulation> The obtained topical preparation was left to stand at room temperature (approximately 25°C) for 24 ± 1 hours, and the presence or absence of crystallization was visually confirmed based on the following criteria. A: After 24 ± 1 hours, no crystallization was confirmed, and the appearance was clear. X: Crystallization occurred during the period ending after 24 ± 1 hours. For reference, for Example 1 and Comparative Example 3, photographs showing the state of each topical preparation after standing for 24 hours, representing the test item "Inhibition of Crystallization in Formulation", are shown in Figures 1 and 2, respectively. Example 1 is an example rated "A", with good solubility. As shown in Figure 1, no crystallization was observed, and the appearance was clear. Comparative Example 3 is an example rated "X". As shown in Figure 2, small crystal fragments were confirmed to have precipitated at the bottom in Comparative Example 3.

[0074] <Inhibition of Crystallization After Coating> One drop (approximately 1 μL to 10 μL) of the obtained topical agent was quietly placed on a glass plate using a pipette to form a spot. The presence or absence of crystallization after a predetermined time was visually confirmed, and the following criteria were used for judgment: A: No crystallization was observed in the spot on the glass plate 24 ± 1 hours after coating. X: Crystallization occurred before 24 ± 1 hours after coating. For reference, for Examples 22, Comparative Examples 1 and 2, photographs showing the state of each topical agent on the glass plate after a predetermined time following coating, representing the test item "Inhibition of Crystallization After Coating," are shown in Figures 3 to 5. Example 22 is an example rated "A." After coating, the droplet expanded, as shown in Figure 3, confirming that no crystals appeared even after time. Comparative Examples 1 and 2 are examples rated as "X". As shown in Figure 4, Comparative Example 1 can be confirmed as a state in which white crystals precipitate along the shape of the drug spot; as shown in Figure 5, Comparative Example 2 can be confirmed as a state in which needle-shaped crystals precipitate.

[0075] [Evaluation Test Results: Crystallization Inhibition] Tables 1-17 show the evaluation test results related to crystallization inhibition for each formulation and comparative example of the external agent. In addition, in each table, "IPA" represents isopropanol, "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 (PVP) was Polyvinylpyrrolidone K 30 (weight average molecular weight 40,000) manufactured by Tokyo Chemical Industry Co., Ltd. Polyethylene glycol (PEG) was polyethylene glycol 300 (number average molecular weight 300) manufactured by FUJIFILM Wako Pure Chemical Co., Ltd. The same notation is used in the tables from Table 18 onwards.

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] The results shown in Table 1 were examined. Example 1 was a formulation using isopropanol and diisopropyl adipate as solvents (the solvent is included in the concept of "solvent (b)"). The active ingredient in the formulation showed good solubility, and no crystallization was observed, nor was any crystallization observed after coating. Example 2 was a formulation using only diisopropyl adipate as a solvent (the solvent is included in the concept of "solvent (a)"). However, like Example 1, it was confirmed that the effect of this invention could be achieved. Thus, it can be seen that diisopropyl adipate alone can also achieve the effect of this invention when used as a solvent. Comparative Example 1 was a formulation using only isopropanol as a solvent, and Comparative Example 2 was a formulation using only N-methyl-2-pyrrolidone as a solvent. In these formulations, the active ingredient in the formulation showed good solubility and no crystallization was observed, but crystallization occurred after coating. Thus, it can be seen that the inhibition of crystallization after coating is not solely due to the good solubility produced by the solvent. Furthermore, Comparative Example 3, which used isopropanol and N-methyl-2-pyrrolidone as solvents, showed insufficient solubility of the active ingredient in the formulation, resulting in crystallization. Crystallization also occurred after coating. When N-methyl-2-pyrrolidone was combined with other solvents, crystallization occurred in the formulation. Therefore, this illustrates that N-methyl-2-pyrrolidone should not be used as a solvent in this case.

[0094] The results shown in Table 2 were examined. Example 3 was a formulation using ethanol and diisopropyl adipate as solvents (the solvent is included in the concept of "solvent (b)"), but it was the same as Example 1 using isopropanol, confirming that the effect of this invention could be achieved. Comparative Example 4 was a formulation using only ethanol as a solvent. The active ingredient in the formulation was well soluble and no crystallization was observed, but crystallization occurred after coating. This result was the same as the result shown in Table 1, indicating that the inhibition of crystallization after coating was not solely due to the good solubility produced by the solvent. Furthermore, Comparative Example 5 was a formulation using ethanol and N-methyl-2-pyrrolidone as solvents. The active ingredient in the formulation was not sufficiently soluble and crystallization was observed, and crystallization also occurred after coating. This result also showed the same trend as the result shown in Table 1, indicating that in this invention, it is not advisable to mix N-methyl-2-pyrrolidone as a solvent.

[0095] The results shown in Table 3 were examined. Examples 4 and 6 are formulations using isopropanol 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)"); Example 7 is a formulation using dimethyl sulfoxide and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (d)"); it was confirmed that the effects of this invention could be achieved with these various combinations of solvents.

[0096] The results shown in Tables 4 and 5 were examined. Examples 8-11 were formulations using isopropanol, dimethyl sulfoxide, and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (e)"). For various mixing ratios, it was confirmed that the effects of this invention could be achieved. Examples 12-15 were formulations using ethanol, dimethyl sulfoxide, and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (e)"). For these examples, for various mixing ratios, it was confirmed that the effects of this invention could be achieved.

[0097] The results shown in Tables 6-9 were examined. Examples 16-29 were for verification based on a formulation using diisopropyl adipate, with the diisopropyl adipate replaced by various dicarboxylic acid diesters (the solvent is included in the concept of "solvent (b)" or "solvent (e)"); for various dicarboxylic acid diesters other than diisopropyl adipate, the same as diisopropyl adipate, it was confirmed that they could achieve the effect of this invention.

[0098] The results shown in Tables 10 and 11 were examined. Examples 30-33 were formulations using isopropanol or ethanol, dimethyl sulfoxide, and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (e)"); Examples 34-37 were formulations using isopropanol or ethanol and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (b)"). As suitable optional components, polyvinylpyrrolidone, benzyl alcohol, lactic acid, etc. were respectively mixed in; the active ingredients in the formulations had good solubility, and no crystallization was observed, nor was any crystallization observed after application. These results indicate that the above optional components do not hinder the effect of this product, but help to further improve the physical properties of the topical onychomycosis preparation itself.

[0099] The results shown in Table 12 were examined. Examples 38-40 are formulations using ethanol and various diols as solvents (solvents are included in the concept of "solvent(f)"). It was confirmed that the combination of lower alcohols and various diols could achieve the effect of this invention.

[0100] The results shown in Tables 13-17 were examined. Examples 41-66 are various combinations of the concepts of solvent (b), solvent (f) or solvent (g), and it was confirmed that the effect of this invention can be achieved, especially by mixing various arbitrary components without hindering the effect of this invention, and the effect of this invention can be achieved at various mixing ratios.

[0101] [Evaluation Test: A Substitute Effectiveness Test] <Preparation of Conidial Solution> The cells of *Trichopyton rubrum* (CBS118892 strain) cultured on saprolol dextrose agar were peeled off and placed in a tube. 500 μL of physiological saline was added to disperse the cells. The mixture was filtered through a cell filter (40 μm mesh). The filtrate was centrifuged (13,000 rpm × 5 minutes), and the precipitate was collected. The collected precipitate was washed with physiological saline and dispersed in physiological saline to prepare a bacterial suspension. The bacterial suspension was spread on rye agar and incubated at 28°C. 5 mL of physiological saline was added to the formed colonies, and the surface was scraped with a spatula to collect the bacterial solution. The bacterial solution was stirred using a vortex mixer and filtered through a 100 μm filter to obtain the conidial solution. The number of conidia was examined under a microscope before being used for testing. <Preparation of Human Nails> Nails were sterilized and cleaned with 70% ethanol, then soaked in 100% ethanol for 1 hour to remove moisture. They were then air-dried for 1 hour under a germicidal lamp in a biosafety cabinet. <Treatment of Human Nails with Medication> Each of the above-mentioned human nails was placed in a petri dish (35 mm in diameter). 0.5 μL of the medication was applied from the top layer of the nail, ensuring it remained only on the upper surface and did not drip from the sides. After the surface dried, the nails were kept in a constant temperature incubator at 25°C to allow the medication to penetrate into the nail. This process was repeated once to seven times daily. The topical onychomycosis medications from Examples 3, 5, 7, 27, 38-40, 50, 51, 53, 59, 60, and 67-71 were used for testing. <Preparation of Test Culture Medium> A culture medium for the subungual efficacy test was prepared by adding ampicillin to physiological saline containing 1.5% agarose. <Subungual Efficacy Test> The above-mentioned conidial solution (1×10⁵ cells / 1μL) was spot-inoculated onto the above-mentioned test culture medium. Human fingernails treated with the above-mentioned solution were placed on it with the subungual side (the opposite side of the nail plate coated with the solution) in contact with the conidia and the culture medium, and incubated at 28°C in an incubator. After 7-10 days of incubation, the growth of Trichophyton mentagrophytes was observed and judged based on the following criteria: A: No hyphae growth X: Hyphae growth For reference, for Examples 68 and 69, and the corresponding placebo control groups that did not treat the nails with the solution, photographs showing the state of the nail periphery in the test culture medium after 7 treatments (once a day) in the above-mentioned "Subungual Efficacy Test" are shown in Figure 6. In Examples 68 and 69 of Figure 6, no hyphae were observed and the results were rated "A". However, hyphae were observed in the placebo and control groups and the results were rated "X". Thus, the evaluation of "A" and "X" can be performed more easily and objectively based on appearance.

[0102] [Evaluation Test Results: Subungual Efficacy Test] For the onychomycosis topical preparations used as test solutions in each example, the evaluation test results for each formulation and its subungual efficacy on human fingernails are shown in Tables 18-21. Furthermore, Examples 3, 5, 7, 27, 38-40, 50, and 60 show the results after three treatments, Example 67 shows the results after seven treatments, and the others show the results after one treatment.

[0103]

[0104]

[0105]

[0106]

[0107] [Examination: Subungual Effectiveness Test] As can be seen from the results of each embodiment, the subungual effectiveness of the topical onychomycosis preparation using compound (1) with the solvent specified in this case can be confirmed. Since the drug solution is applied in a manner that allows the drug solution to remain only on the upper surface of the nail, the above test results show that the topical onychomycosis preparation of this case not only has the effect of inhibiting the growth of hyphae under the nail, but also has nail penetration.

[0108] [Evaluation Test: Antifungal Activity Test of Human Nails] Except for the following changes, the procedure was the same as the "Evaluation Test: Subungual Efficacy Test" described above. <Treatment of Human Nails with Drug Solution> Each human nail was placed in a petri dish (35 mm in diameter), and 0.5 μL of the drug solution was applied to the upper layer of each nail, as in the test described above. After the surface dried, the nails were kept in a constant temperature incubator at 25°C to allow the drug solution to penetrate into the nail. The above operation was considered as one operation, and the penetration time was set at 7 days after application. The drug solution used in the test was the topical onychomycosis preparation of Example 68. <Cultivation Experiment> Place cellophane (10 mm long × 10 mm wide × 50 μm thick) on the experimental culture medium, and spot-inoculate the conidial solution (1 × 10⁵ cells / 1 μL) onto it. Then, place human fingernails that have been permeated by the drug solution on the cellophane with the underside of the nail in contact with the conidia and cellophane. After incubating at 28°C for 24 hours, stain the conidia with 4',6-dimethylamidine-2-phenylindole dihydrochloride (DAPI) solution and determine their viability.

[0109] [Evaluation of Test Results: Antifungal Activity Test on Human Nails] The results of Example 68 are shown in Figure 7. Furthermore, as a comparison, Figure 7 also shows the results of commercially available nail topical solutions, namely Sato Pharmaceutical Co., Ltd.'s "LUCONAC" (registered trademark) 5% topical solution and Kenshin Pharmaceutical Co., Ltd.'s "Clenafin" (registered trademark) 10% topical solution, and the placebo corresponding to Example 68.

[0110] [Examination: Antifungal Activity Test of Human Nails] DAPI does not penetrate the cell membrane in living cells, but it can penetrate dead cells due to changes in the cell membrane. In this test, this principle was used to determine the viability of subungual meristems. With the topical onychomycosis treatment of Example 68, DAPI staining of subungual meristems was observed under dark-field microscopy. On the other hand, no staining of meristems was observed with the placebo and the commercially available drug used as comparisons. Therefore, it can be confirmed that the topical onychomycosis treatment of Example 68 kills fungi on subungual meristems, and that the placebo and the commercially available drug allow meristems to survive. Under bright-field microscopy, some degree of growth, such as continuous swelling, was observed in the placebo and the commercially available drug; however, no meristem growth was observed with the topical onychomycosis treatment of Example 68. Thus, while conventional topical onychomycosis preparations have antifungal activity, they do not have antifungal activity. In contrast, the topical onychomycosis preparation in this case not only has antifungal activity but also antifungal activity; therefore, it has superior effects not found in conventional techniques.

[0111] [Reference Experiment: Effect of the Amount and Type of Acid Added by Any Component on Storage Stability] <Effect of Difference in Lactic Acid Addition Amount on Storage Stability> The effects of differences in lactic acid addition amount on storage stability were investigated using the topical formulations of Examples 72-76 (Base Group of Example 49) with varying amounts of lactic acid added (including cases without addition) based on Example 49, and the topical formulations of Examples 77-81 (Base Group of Example 59) with varying amounts of lactic acid added (including cases without addition) based on Example 59. The formulations are shown in Tables 22 and 23 below.

[0112]

[0113]

[0114] Next, the prepared sample solution (approximately 6 mL) was placed into a glass screw-cap vial (10 mL container size), and sealed with VALQUA TAPE and vinyl tape to cover the cap and the vial body. It was stored at 60°C and 80% RH for 4 weeks. The stored sample solution was diluted with acetonitrile and analyzed by liquid chromatography. The results were calculated as a percentage of the sum of the peak areas obtained from the chromatogram and the peak areas of the hydrolysates of the main decomposition product of compound (1). The results are shown in Figure 8.

[0115] <The effect of the difference in the type of acid on the storage stability> The sample solutions of Reference Examples 1 to 11 were prepared in the same manner as in Example 1, using the formulations in Tables 24 to 26 below, which consist of compound (1), lower alcohol and acid.

[0116]

[0117]

[0118]

[0119] Next, the analysis was performed by liquid chromatography in the same manner as the experiment on "the effect of the difference in lactic acid addition on storage stability". The sum of the peak areas obtained from the chromatogram and the peak area of ​​the hydrolysate of the main decomposition product of compound (1) were calculated based on the area percentage. The results are shown in Figure 9.

[0120] <Investigation> Based on the results of the above reference experiments, it can be seen that adding an acid is beneficial to improving the storage stability of compound (1), especially adding lactic acid or citric acid. Regarding the amount added, more is not necessarily better. For example, when using lactic acid, it is known that the preferred mass percentage relative to the total mass of the topical agent is 8% by mass or less, more preferably 4% by mass or less, and particularly preferably 0.5% to 2% by mass. [Industrial Applicability]

[0121] This case is applicable to the treatment of onychomycosis or the prevention of its worsening. [Simplified Explanation of the Diagram]

[0021] [Figure 1] is a photograph showing the state of the topical agent after standing for 24 hours in the evaluation test "Inhibition of Crystallization in Formulation" of Example 1. [Figure 2] is a photograph showing the state of the topical agent after standing for 24 hours in the evaluation test "Inhibition of Crystallization in Formulation" of Comparative Example 3. [Figure 3] is a photograph showing the state of the topical agent on a glass plate after a predetermined time following application in the evaluation test "Inhibition of Crystallization after Application" of Example 22. [Figure 4] is a photograph showing the state of the topical agent on a glass plate after a predetermined time following application in the evaluation test "Inhibition of Crystallization after Application" of Comparative Example 1. [Figure 5] is a photograph showing the state of the topical agent on a glass plate after a predetermined time following application in the evaluation test "Inhibition of Crystallization after Application" of Comparative Example 2. [Figure 6] is a photograph showing the state of the periungual nail during the subungual efficacy test performed on the placebo and control groups of Examples 68 and 69. [Figure 7] is a photograph showing the fluorescence staining results of the fungicidal activity test performed on Example 68, its placebo, and two doses of the commercially available drug. [Figure 8] is a graph showing the change in the amount of hydrolysate generated when the concentration of lactic acid was changed in the formulations of Example 49 or Example 59. [Figure 9] is a graph showing the differences in the amount of hydrolysate generated for Reference Examples 1-11, where the type and amount of acid added differ.

Claims

1. A topical onychomycosis preparation comprising at least one active ingredient selected from the group consisting of compounds represented by formula (1) and their salts, and comprising at least one solvent selected from the group consisting of solvents (a) to (g): solvent (a): dicarboxylic acid diester; solvent (b): lower alcohol and dicarboxylic acid diester; solvent (c): lower alcohol and dimethyl sulfoxide; solvent (d): dimethyl sulfoxide and dicarboxylic acid diester; solvent (e): lower alcohol, dimethyl sulfoxide and dicarboxylic acid diester; solvent (f): lower alcohol and glycols; and solvent (g): lower alcohol, glycols and dicarboxylic acid diester.

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

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

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

5. The topical onychomycosis treatment as requested in item 1, wherein the aforementioned dicarboxylic acid diester is a diester of a dicarboxylic acid and an alcohol having 1 to 4 carbon atoms.

6. The topical onychomycosis treatment described in claim 1 further contains polyvinylpyrrolidone.

7. The topical onychomycosis treatment described in claim 1 further contains an acid as a pH adjuster.

8. For the topical onychomycosis treatment in claim 7, the aforementioned pH adjuster is lactic acid or citric acid.

9. The topical onychomycosis preparation of claim 1, wherein the content of at least one of the compounds selected from the group consisting of the aforementioned formula (1) and their salts is 0.1 to 20% by mass, and the content of at least one of the aforementioned solvents (a) to (g) is 60 to 99.9% by mass.

10. The use of at least one compound selected from the group consisting of compounds represented by formula (1) and their salts, in combination with at least one solvent selected from the group consisting of solvents (a) to (g) below, for the manufacture of a topical onychomycosis preparation or for the treatment of onychomycosis or the prevention of its aggravation; solvent (a): a diester of a dicarboxylic acid; solvent (b): a lower alcohol and a diester of a dicarboxylic acid; solvent (c): a lower alcohol and a dimethyl sulfoxide; solvent (d): a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (e): a lower alcohol, a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (f): a lower alcohol and a diol; and solvent (g): a lower alcohol, a diol and a diester of a dicarboxylic acid.

11. A composition comprising at least one of a compound selected from the group consisting of a compound represented by formula (1) and its salts as an active ingredient, and comprising at least one of a solvent selected from the group consisting of solvents (a) to (g) below as a solvent, for use in manufacturing a topical onychomycosis preparation or a medicament for treating or preventing the aggravation of onychomycosis; solvent (a): a diester of a dicarboxylic acid; solvent (b): a lower alcohol and a diester of a dicarboxylic acid; solvent (c): a lower alcohol and a dimethyl sulfoxide; solvent (d): a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (e): a lower alcohol, a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (f): a lower alcohol and a diol; and solvent (g): a lower alcohol, a diol and a diester of a dicarboxylic acid.

12. A composition comprising at least one of a compound selected from the group consisting of a compound represented by formula (1) and its salts as an active ingredient, and comprising at least one of a solvent selected from the group consisting of solvents (a) to (g) below as a solvent, for use in treating onychomycosis or preventing its aggravation; solvent (a): a diester of a dicarboxylic acid; solvent (b): a lower alcohol and a diester of a dicarboxylic acid; solvent (c): a lower alcohol and a dimethyl sulfoxide; solvent (d): a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (e): a lower alcohol, a dimethyl sulfoxide and a diester of a dicarboxylic acid; solvent (f): a lower alcohol and a diol; and solvent (g): a lower alcohol, a diol and a diester of a dicarboxylic acid.

13. A method for treating onychomycosis, wherein, The treatment comprises applying an effective amount of a topical onychomycosis preparation topically to the affected nail of the aforementioned object, wherein the aforementioned topical onychomycosis preparation contains at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and contains at least one of the solvents selected from the group consisting of solvents (a) to (g) as a solvent; solvent (a): diester of a dicarboxylic acid; Solvent (b): lower alcohols and diesters of dicarboxylic acids; Solvent (c): lower alcohols and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and diesters of dicarboxylic acids; Solvent (e): lower alcohols, dimethyl sulfoxide and diesters of dicarboxylic acids; Solvent (f): lower alcohols and glycols; and solvent (g): lower alcohols, glycols and diesters of dicarboxylic acids.

14. A method for preventing the worsening of onychomycosis in a subject, wherein, The treatment comprises applying an effective amount of a topical onychomycosis preparation topically to the affected nail of the aforementioned object, wherein the aforementioned topical onychomycosis preparation contains at least one of the compounds selected from the group consisting of compounds represented by formula (1) and their salts as an active ingredient, and contains at least one of the solvents selected from the group consisting of solvents (a) to (g) as a solvent; solvent (a): diester of a dicarboxylic acid; Solvent (b): lower alcohols and diesters of dicarboxylic acids; Solvent (c): lower alcohols and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and diesters of dicarboxylic acids; Solvent (e): lower alcohols, dimethyl sulfoxide and diesters of dicarboxylic acids; Solvent (f): lower alcohols and glycols; and solvent (g): lower alcohols, glycols and diesters of dicarboxylic acids.

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