WO2019151282A1 - Liquid agent for external use for prevention and treatment of onychomycosis - Google Patents

Abstract

This liquid agent for external use for prevention and treatment of onychomycosis contains a drug with anti-onychomycotic activity, a volatile alcohol, and a delivery enhancer.

Description

External solution for prevention or treatment of onychomycosis

The present invention relates to an external preparation for preventing or treating onychomycosis.

Onychomycosis is a nail disease caused by dermatophytes, which is said to be more than 90% of the causative agents of onychomycosis in Japan, and is a disease with symptoms such as cloudiness, thickening, destruction and deformation of the nail plate. Currently, it is said that there are about 12 million patients, one in 10 Japanese. It is a disease common to the elderly, and there are concerns that the number of patients will increase further in the future, and there are reports that diabetic patients are likely to be affected, and it has been pointed out that they may cause serious complications.

Currently, in Japan, as a method for treating onychomycosis, antifungal agents (such as itraconazole, terbinafine, efinaconazole, and luliconazole) are approved for internal use and topical use. However, oral antifungal agents have been pointed out to have drug interactions, liver damage, and side effects caused by long-term administration. In addition, elderly people with high incidence of onychomycosis, diabetics, etc. often take a plurality of drugs, and it is often difficult to orally administer antifungal drugs for the treatment of onychomycosis.

Regarding external anti-tinea agent, in order to exert its medicinal effect, in addition to the drug itself having strong anti-tinea activity, the drug concentration should be reduced in the horny and internal areas of the nail, which is the infection site, and in the nail plate. It is necessary to reach a high level.

So far, for example, a 2- (1H-pyrazol-1-yl) phenol derivative has been found as a drug having strong anti-tinea fungi activity, and an external liquid preparation containing this drug as an active ingredient has been proposed ( For example, see Patent Documents 1 and 2).
However, existing drugs with anti-tinea activity are difficult to dissolve in a solvent, and there is a problem that it is difficult to prepare a high-concentration preparation. In addition, when the drug concentration is high, it is often observed that a drug film is formed on the nail or the drug is deposited on contact with water or sweat when the preparation is applied to the nail. There is also the problem that it is difficult to deliver drugs under the nail plate.

In addition, external liquids for prevention or treatment of onychomycosis are excellent in applicability, remove previously administered drugs remaining at the time of administration, or remove drugs attached to non-infected sites. Therefore, it is also required that the wiping removal property is excellent.

Therefore, for the prevention or treatment of onychomycosis, which has anti-tinea fungus activity, is excellent in drug delivery to the nail plate, can contain a high concentration of drug, and is excellent in applicability and wiping removal properties At present, it is strongly desired to provide a liquid preparation for external use promptly.

International Publication No. 2012/102404 International Publication No. 2014/021282

This invention makes it a subject to solve the said various problems in the past and to achieve the following objectives. That is, the present invention has anti-tinea fungus activity, is excellent in drug delivery to the nail plate, can contain a high concentration of drug, and is excellent in applicability and wiping removal properties. An object is to provide an external solution for prevention or treatment.

As a result of intensive studies to solve the above problems, the present inventors have included a delivery enhancer in an external liquid preparation containing a drug having anti-tinea fungi activity and a volatile alcohol, thereby providing a subnail plate. It has been found that it can be used as an externally applied liquid preparation that has excellent drug delivery to the skin, has high anti-tinea fungus activity, can contain a high concentration of drug, and is excellent in applicability and wiping off. Completed the invention.

Means for solving the problems are as follows. That is,
<1> An external liquid for prevention or treatment of onychomycosis comprising a drug having anti-tinea activity, a volatile alcohol, and a delivery accelerator.

ADVANTAGE OF THE INVENTION According to this invention, the said various problems in the past can be solved, the said objective can be achieved, it has an anti- ringworm fungus activity, it is excellent in the delivery property of the drug to a nail plate, and a high concentration drug It is possible to provide a liquid for external use for the prevention or treatment of onychomycosis that is excellent in applicability and wiping off properties.

(External solution for prevention or treatment of onychomycosis)
The topical solution for preventing or treating onychomycosis of the present invention contains at least a drug having anti-tinea fungi activity, a volatile alcohol, and a delivery accelerator, and further contains other components such as a wetting agent as necessary. .

<Drug with anti-tinea activity>
The drug having anti-tinea activity (hereinafter sometimes referred to as “main drug”) is not particularly limited and may be appropriately selected from known drugs having anti-tinea activity according to the purpose. Examples thereof include compounds having antifungal activity, particularly compounds effective for the treatment of onychomycosis.

Specific examples of the drug having anti-tinea activity include, for example, a compound represented by the following general formula (I) or a salt thereof.
<< Compound Represented by Formula (I) >>

In the general formula (I),
R ¹ represents a hydrogen atom, C _1-6 alkyl, or trifluoromethyl,
R ² represents a hydrogen atom, C _1-6 alkyl, halogen, —COO (C _1-6 alkyl), or (CH ₂ ) _1-3 COOR (R represents a hydrogen atom or C _1-6 alkyl). Represent,
R ³ represents a hydrogen atom, C _1-6 alkyl, amino, trifluoromethyl, or OR (R represents a hydrogen atom or C _1-6 alkyl);
R ⁴ represents a hydroxyl group,
R ⁵ represents a hydrogen atom, C _1-6 alkyl, hydroxyl group, or halogen,
R ⁶ represents a hydrogen atom, C _1-6 alkyl, trifluoromethyl, halogen, amino, —NR ^a R ^b , nitro, hydroxy C _1-6 alkyl, —CONR ^a R ^b , —COO (C _1-6 alkyl) ), —COOH, — (CH ₂ ) _1-3 COOR, or OR ^a (R represents a hydrogen atom or C _1-6 alkyl, R ^a and R ^b may be the same or different, and a hydrogen atom Represents C _1-6 alkyl, or C _1-6 acyl),
R ⁷ represents a hydrogen atom, C _1-6 alkyl, —OR (R represents a hydrogen atom or C _1-6 alkyl), or halogen;
R ⁸ represents a hydrogen atom, C _1-6 alkyl, hydroxyl group, amino, or nitro.

The terms used in Formula (I) "C _1-6 alkyl", "C _1-6 alkyl" portion of the group, an alkyl group having from 1 to 6 carbon atoms. The alkyl group may be chain, branched or cyclic. For example, C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, and C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like Group and the like.

The terms used in Formula (I) "C _1-6 acyl", "C _1-6 acyl" part of the group, an acyl group having from 1 to 6 carbon atoms. The acyl group may be chain, branched or cyclic. Examples include formyl, acetyl, propionyl, butyryl, isobutyryl and the like.

The term “halogen” used in the general formula (I) includes fluorine, chlorine, bromine, iodine and the like.

“—OR (R represents a hydrogen atom or C _1-6 alkyl)” which is a group or a part of the group used in the general formula (I) represents a hydroxyl group or C _1-6 alkyloxy. Here, “C _1-6 alkyl” has the same _{meaning as} the above “C _1-6 alkyl”.

In “—OR ^a ” which is ^a group or a part of the group used in the general formula (I), R ^a represents a hydrogen atom, C _1-6 alkyl, or C _1-6 acyl, and “—OR “ ^a ” represents a hydroxyl group, C _1-6 alkyloxy, or C _1-6 acyloxy. Here, “C _1-6 alkyl” has the same _{meaning as} the above “C _1-6 alkyl”.

Specific examples of the compound represented by the general formula (I) include the following compounds.
2- (3,5-Dimethyl-1H-pyrazol-1-yl) phenol 2- (3,5-Dimethyl-1H-pyrazol-1-yl) -4-fluorophenol 2- (1H- Pyrazol-1-yl) phenol 2- (5-hydroxy-3-methyl-1H-pyrazol-1-yl) phenol 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) Phenol-2- (3,5-Bistrifluoromethyl-1H-pyrazol-1-yl) phenol-2- (3-Methyl-1H-pyrazol-1-yl) phenol-2- (5-Methyl-1H-pyrazole -1-yl) phenol ・ 2- (3,4,5-trimethyl-1H-pyrazol-1-yl) phenol ・ 2- (5-amino-3-tert-butyl-1H-pyrazol-1-yl) phenol 4-chloro-2- (3,5-dimethyl-1H-pyrazol-1-yl) phenol 2-chloro-6- (3,5-dimethyl-1H-pyrazol-1-yl) phenol 2- ( 4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl) phenol 2- (3,5-di Tyl-1H-pyrazol-1-yl) phenol ・ 3- (3,5-dimethyl-1H-pyrazol-1-yl) benzene-1,2-diol ・ 2- (3,5-dimethyl-1H-pyrazol- 1-yl) benzene-1,4-diol 2- (4-ethyl-3,5-dimethyl-1H-pyrazol-1-yl) phenol 5-fluoro-2- (3,4,5, -trimethyl -1H-pyrazol-1-yl) phenol 2- (4-chloro-3,5-dimethyl-1H-pyrazol-1-yl) benzene-1,4-diol4-fluoro-2- (3,4 , 5, -Trimethyl-1H-pyrazol-1-yl) phenol 2- (4-chloro-3,5-dimethyl-1H-pyrazol-1-yl) -5-fluorophenol 1- (2-hydroxyphenyl) ) Ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylatemethyl 3- (1- (2-hydroxyphenyl) -3,5-dimethyl-1H-pyrazol-4-yl) propanoate 2- (4-Butyl-3,5-dimethyl-1H-pyrazol-1-yl) phenol 2- (3,5-dimethyl-1H-pyrazol-1- Yl) -5-fluorophenol 5-chloro-2- (3,5-dimethyl-1H-pyrazol-1-yl) phenol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -3 -Nitrophenol 2- (3,5-Dimethyl-1H-pyrazol-1-yl) -5-nitrophenol 3- (1- (2-hydroxyphenyl) -3,5-dimethyl-1H-pyrazole-4 -Yl) propionic acid ・ 5-chloro-2- (3,4,5-trimethyl-1H-pyrazol-1-yl) phenol ・ 5-amino-2- (3,5-dimethyl-1H-pyrazol-1- Yl) phenol 5-nitro-2- (3,4,5-trimethyl-1H-pyrazol-1-yl) phenol 4- (3,5-dimethyl-1H-pyrazol-1-yl) benzene-1, 3-diol 5-amino-2- (3,4,5-trimethyl-1H-pyrazol-1-yl) phenol 4- (3,5-dimethyl-1H-pyrazol-1-yl) -3-hydroxy Benzenecarboxylate methyl 3-amino-2- (3,5-dimethyl-1H-pyrazol-1-yl) phenol 4- (3,5- Methyl-1H-pyrazol-1-yl) -3-hydroxybenzenecarboxylic acid ・ 4- (3,5-dimethyl-1H-pyrazol-1-yl) -3-hydroxy-N, N-dimethylbenzamide 4- ( 3,5-dimethyl-1H-pyrazol-1-yl) -3-hydroxybenzamide 3-hydroxy-4- (3,4,5-trimethyl-1H-pyrazol-1-yl) benzenecarboxylic acid -4- (3,4,5-trimethyl-1H-pyrazol-1-yl) benzamide 4- (4-chloro-3,5-dimethyl-1H-pyrazol-1-yl) -3-hydroxybenzamide 2 -(3,5-dimethyl-1H-pyrazol-1-yl) benzene-1,3-diol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol 2- ( 3,5-dimethyl-1H-pyrazol-1-yl) -5-methoxyphenol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -3-methylphenol 2- (3,5- Dimethyl-1H-pyrazol-1-yl) -5-hydroxymethylphenol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylaminophenol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -4-methylphenol 2- ( 3,5-dimethyl-1H-pyrazol-1-yl) -5-trifluoromethylphenol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -6-methylphenol 2- (3, 5-dimethyl-1H-pyrazol-1-yl) -5-ethylphenol 2- (4-fluoro-3,5-dimethyl-1H-pyrazol-1-yl) phenol 5-bromo-2- (3, 5-Dimethyl-1H-pyrazol-1-yl) phenol 5-bromo-2- (4-chloro-3,5-dimethyl-1H-pyrazol-1-yl) phenol 5-bromo-2- (3, 4,5-trimethyl-1H-pyrazol-1-yl) phenol 4- (3,5-dimethyl-1H-pyrazol-1-yl) -3-hydroxyphenyl acetate 4- (4-chloro-3,5 -Dimethyl-1H-pyrazol-1-yl) -3-hydroxyphenyl acetate 3-hydroxy-4- ( 3,4,5-trimethyl-1H-pyrazol-1-yl) phenyl acetate 2- (3,5-dimethyl-1H-pyrazol-1-yl) -4-methoxy-5-methylphenol 4-chloro- 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -4,5-dimethylphenol 4- (4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl) -benzene-1,3-diol

There is no restriction | limiting in particular as a salt of the compound represented by the said general formula (I), According to the objective, it can select suitably from the salt accept | permitted pharmaceutically, For example, an inorganic acid, organic acid Or a pharmaceutically acceptable salt derived from a base.

“Pharmaceutically acceptable salts” are known in the art. For example, S. M. Berge et al. Describe pharmaceutically acceptable salts in detail in Journal of Pharmaceutical Sciences, 66 p.1 et seq. (1977).

Typical acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, etc .; acetate, trifluoroacetate, lactate, citric acid Organic carboxylic acids such as acid, oxalate, succinate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, nicotinate, phthalate Salts; organic sulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate, 2-naphthalenesulfonate, camphorsulfonate, and the like; Examples include, but are not limited to, acidic amino acid salts such as aspartate and glutamate. The acid addition salt is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; a salt with an organic acid such as oxalic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid or citric acid Is mentioned. More preferred are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, and methanesulfonic acid.

The base addition salt can be produced in situ by reacting a carboxylic acid or phenolic hydroxyl group-containing moiety with an appropriate base during the final isolation and purification process of the compound represented by the general formula (I).
Examples of pharmaceutically acceptable base addition salts include alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt, ammonium salt, methylamine salt, Dimethylamine salt, ethylamine salt, diethylamine salt, trimethylamine salt, triethylamine salt, tetramethylammonium salt, tetraethylammonium salt, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, trishydroxymethylaminomethane salt, Organic base salts such as piperidine salts, piperazine salts, dicyclohexylamine salts, N, N-dibenzylethylenediamine salts; basic amino acid salts such as arginine salts, lysine salts, ornithine salts, etc., but are not limited thereto. Not. Preferred base addition salts include addition salts with sodium, potassium, calcium, ethanolamine, and trishydroxymethylaminomethane. More preferable examples include addition salts with sodium, potassium, and trishydroxymethylaminomethane.

The compound represented by the general formula (I) can also be used as a solvate. As used herein, the term “solvate” means a complex of various stoichiometry formed by a solute (the compound represented by the general formula (I) or a salt thereof) and a solvent. . The solvent is preferably a pharmaceutically acceptable solvent that does not interfere with the biological activity of the solute. Examples of suitable solvents for solvates include, but are not limited to water, methanol, ethanol, ethylene glycol, propylene glycol, ethyl acetate, butyl acetate and the like. The solvent for the solvate preferably includes water, ethanol, ethyl acetate.

There is no restriction | limiting in particular as a manufacturing method of the compound represented by the said general formula (I), or its salt, According to the objective, it can select suitably, For example, the method of international publication 2014/021282, etc. Is mentioned.

Other examples of the drug having anti-tinea activity include polyene antifungal agents such as natamycin, rimocidin, Philippines, nystatin, amphotericin B; miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butconazole Imidazole compounds such as fluconazole, itraconazole, labconazole, posaconazole, voriconazole, efinaconazole, terconazole, etc .; Allylamine compounds such as amorolfine, naphthifine, butenafine; anidurafungin, cas Fangin, echinocandin compounds such as micafungin; ciclopirox, flucytosine, griseofulvin, gentian violet, Haropirojin, tolnaftate, and the like other anti-fungal agents such as undecylenic acid.

The drug having anti-tinea fungi activity may be used alone or in combination of two or more.
Among the drugs having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof is included in that the anti-tinea activity is more excellent. preferable.

The content of the drug having anti-tinea fungi activity in the external solution for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose. The content is preferably 30% by mass, more preferably 5 to 20% by mass, still more preferably 8 to 20% by mass, and 12 to 20% by mass. It is particularly preferable to contain it. When the content is within the preferred range, it is advantageous in that the anti-tinea fungus activity of the solution for external use can be further enhanced.

<Volatile alcohol>
In the present invention, the volatile alcohol refers to one that evaporates from the surface of a nail or the like when an external liquid is applied to the nail or the like.
The volatile alcohol is not particularly limited and can be appropriately selected according to the purpose of those usually used in the pharmaceutical field. Examples thereof include lower alcohols, higher alcohols, and polyhydric alcohols. .
Specific examples of the lower alcohols include ethanol, propanol, isopropanol and the like.
Specific examples of the higher alcohols include oleyl alcohol, dioleic acid propylene glycol, polyethylene glycol and the like.
Specific examples of the polyhydric alcohols include glycerin, sorbitol, ethylene glycol, polyethylene glycol and the like.
The said volatile alcohol may be used individually by 1 type, and may use 2 or more types together.
Moreover, although the said volatile alcohol may be anhydrous and may contain water, at least 90 mass% or more alcohol is preferable.

The content of the volatile alcohol in the external preparation for preventing or treating onychomycosis is not particularly limited and can be appropriately selected according to the purpose. The amount is preferably 50 to 90% by mass. When the content is within a preferable range, it is advantageous in that the precipitation of the drug can be suppressed even when the external liquid preparation is stored at a low temperature.

<Delivery accelerator>
In general, an external preparation for preventing or treating onychomycosis penetrates from the nail plate to the inside of the nail and from the gap between the nail plate and the skin to the nail plate (hereinafter sometimes referred to as “nail bed”). By reaching, a therapeutic effect is produced. In the present invention, delivery refers to allowing a drug to reach the nail bed through the gap between the nail plate and the skin.

The delivery accelerator is not particularly limited and may be appropriately selected depending on the intended purpose. For example, isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate, stearyl alcohol, glycerin, sorbitol, ethylene glycol Polyethylene glycol, octyl myristate, oleyl oleate, diethyl phthalate, dibutyl phthalate, malic acid and the like. These may be used individually by 1 type and may use 2 or more types together. Among these, it is preferable to include at least one selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate, and stearyl alcohol in terms of better delivery, and isopropyl myristate More preferably.

The content of the delivery enhancer in the external solution for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose, but it is 2.0 to 10. It is preferably contained in a proportion of 0% by mass, particularly preferably in a proportion of 5.0 to 7.0% by mass. When the content is within a preferable range, it is advantageous in that the deliverability is more excellent.

<Other ingredients>
The other components are not particularly limited as long as the effects of the present invention are not impaired, and components that are usually used in preparations such as external liquid preparations can be appropriately selected according to the purpose. For example, wetting agents, low volatility An organic solvent, a preservative, and an antioxidant. These may be used individually by 1 type and may use 2 or more types together. Among these, a moistening effect such as a moisturizing effect and tissue softening property can be obtained on the nail, and it is preferable that a wetting agent is included in that the feel at the time of application and / or after application can be further improved.

<< wetting agent >>
The wetting agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include PPG-higher alcohol ether derivatives, organic acid esters, hydrophobized hydroxypropylcellulose, and poloxamer.
The PPG-higher alcohol ether derivative is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone. Etc.
The organic acid esters are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include alkyl lactate, diisobutyl adipate, isopropyl adipate, oleyl oleate, and decyl oleate.
The alkyl lactate is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include C12-C15 alkyl lactate (“C12-15 alkyl lactate”, “alkyl lactate (C12-C15)”). And alkyl lactate (C12, C13).
The said wetting agent may be used individually by 1 type, and may use 2 or more types together.
Among these, 1 selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropyl cellulose, and poloxamer in that the effect of the present invention can be further improved in combination with the delivery accelerator. It preferably contains at least one species, more preferably contains at least one selected from the group consisting of PPG-15 stearyl ether and alkyl lactate, and particularly preferably contains PPG-15 stearyl ether.

The content of the humectant in the external preparation for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose, but it is 3.0 to 10.0 with respect to the entire external preparation. It is preferably contained in a proportion of mass%, particularly preferably in a proportion of 4.0 to 7.0 mass%. When the content is within the preferred range, it is advantageous in that the effect of the present invention can be further improved in combination with a delivery accelerator.

<< Low volatile solvent >>
There is no restriction | limiting in particular as said low-volatile solvent, According to the objective, it can select suitably, For example, diisopropyl adipate, benzyl alcohol, myristyl alcohol etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together.
There is no restriction | limiting in particular as content in the external preparation for the prevention or treatment of the onychomycosis of the said low-volatile solvent, According to the objective, it can select suitably.

<< antiseptic >>
The preservative is not particularly limited and may be appropriately selected depending on the purpose. For example, organic preservatives such as cationic activators, phenols, sorbates, salicylates, dehydroacetates, benzoates, etc. Agents: Inorganic antiseptics such as antibacterial zeolite obtained by ion exchange of antibacterial metal ions such as silver, copper and zinc with zeolite. These may be used individually by 1 type and may use 2 or more types together.
There is no restriction | limiting in particular as content in the external preparation for the prevention or treatment of the onychomycosis of the said preservative, and it can select suitably according to the objective.

<< Antioxidant >>
The antioxidant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, 1,3-butylene glycol, citric acid hydrate (monohydrate), tocopherol, tocopherol acetate, Examples include palmitic acid, ascorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), and propyl gallate. These may be used individually by 1 type and may use 2 or more types together.
There is no restriction | limiting in particular as content in the external preparation for the prevention or treatment of the onychomycosis of the said antioxidant, According to the objective, it can select suitably.

In addition to the above-described other components, additives that improve the feeling of use and the like can be appropriately selected within a range that does not impair the effects of the present invention. For example, silicon-based solvents such as cyclomethicone and dimethicone Terpene solvents such as D-limonene, pinene, terpineol and terpineol; glycol ether solvents such as diethylene glycol monoethyl ether and diethylene glycol; dimethyl isosorbide and the like can also be used.

<Manufacture of topical solution for prevention or treatment of onychomycosis>
The method for producing the external liquid for prevention or treatment of onychomycosis is not particularly limited, and a known method for producing the external liquid can be selected as appropriate. For example, the anti- ringworm bacteria may be added to a part of the volatile alcohol. Examples include a method of dissolving an active drug, the delivery accelerator, and, if necessary, the other components in order and adjusting the amount with a volatile alcohol to obtain a liquid for external use.

<Viscosity>
The viscosity of the external solution for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.5 to 11 mPa · s, more preferably 1 to 8 mPa · s. 1.5 to 5 mPa · s is particularly preferable. Within the preferable range, it is advantageous in terms of more excellent usability such as applicability and delivery of drugs to the nail bed.
The viscosity in the present invention refers to a viscosity measured using a rotational viscometer under normal temperature conditions.

<Use>
Onychomycosis is caused by the invasion of ringworm from the tip of the nail into the nail bed. Nail plate detachment is seen in the affected area of the nail. Therefore, it is necessary to supply sufficient drugs not only to the affected part but also to the boundary part with the healthy part to suppress the growth of ringworm and / or sterilize the ringworm.

The topical solution for preventing or treating onychomycosis of the present invention is used as a first-line drug for patients with mild to moderate onychomycosis, and for patients who cannot administer oral medicine such as patients with hepatic disorder Can be used.

The use mode of the external preparation for preventing or treating onychomycosis of the present invention is not particularly limited and may be appropriately selected depending on the intended purpose. For example, it is applied or dropped on the nails and / or skin of hands and feet. , Spraying, rubbing lightly, etc.

There is no restriction | limiting in particular as a frequency and a period using the external preparation for prevention or treatment of the onychomycosis of this invention, According to the symptom etc., it can select suitably, For example, as a general use frequency, it is 1 per day. From twice to once a week, preferably once a day.

External liquid preparations for the prevention or treatment of onychomycosis are required to facilitate the delivery and / or permeation of drugs to the affected area. For example, when volatile alcohol evaporates or the external liquid application part comes into contact with water, etc. Therefore, it is important to design the formulation so that the drug does not become cloudy or precipitate.
The liquid preparation for external use for prevention or treatment of onychomycosis of the present invention has an appropriate combination of additives, thereby preventing stickiness at the time of application, formation of a film after application, white turbidity and precipitation, and an appropriate viscosity. And has excellent drug delivery. Therefore, a sufficient amount of drug can be delivered to the affected area under the nail plate, and excellent anti-tinea fungi activity is exhibited even in the subnail infection.
In addition, the liquid for external use for prevention or treatment of onychomycosis of the present invention can contain a drug at a high concentration, and when it adheres to a non-infected site or when a preparation previously administered at the time of administration remains. The preparation can be easily removed by wiping off the preparation.
Further, since it has an appropriate surface tension and viscosity, it can be held well on the nail surface, and the drug can be exposed to the affected area by permeation from the nail plate into the nail. In addition, the drug can be exposed to the affected area of the nail mother by absorption through the skin. Therefore, also in these respects, a preventive or therapeutic effect against onychomycosis can be obtained.

Hereinafter, the present invention will be described with reference to production examples and examples, but the present invention is not limited to these production examples and examples.

(Production Example 1: Production of 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol)
a) Synthesis of 2-amino-5-methylphenyl 4-methylbenzenesulfonate Dissolve 400 mg of 2-amino-5-methylphenol in 6.5 mL of dichloromethane, add 476 μL of triethylamine and 619 mg of p-toluenesulfonyl chloride, and add 1 at room temperature. Stir for hours. 60 mL of water was added to the reaction mixture, and the mixture was extracted with 60 mL of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 730.1 mg of the title compound.
The physicochemical properties of the obtained compound were as follows and were confirmed to be the title compound.
¹ H-NMR (CDCl ₃ ); δ (ppm) 2.15 (3H, s), 2.46 (3H, s), 3.63 (2H, brs), 6.61-6.63 (1H, m), 6.67 (1H, s), 6.82-6.85 (1H, m), 6.33 (2H, d, J = 8.4Hz), 7.78 (2H, d, J = 8.4Hz).
MS (ESI); m / z 278 (M + H) ⁺

b) Synthesis of 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenyl 4-methylbenzenesulfonate 2-amino-5-methylphenyl 4-methylbenzenesulfonate 453 mg with 5N hydrochloric acid 1.6 A solution of 146 mg of sodium nitrite dissolved in 1 mL of water was added dropwise at 0 ° C. and stirred for 30 minutes. Next, a solution prepared by dissolving 736 mg of stannous chloride in 0.8 mL of 5N hydrochloric acid was added dropwise at 0 ° C. and stirred for 1 hour. The solvent was distilled off under reduced pressure, ethanol (3.2 mL) and acetylacetone (167 μL) were added, and the mixture was heated to reflux for 2 hours. 50 mL of water was added to the reaction mixture, neutralized with saturated sodium hydrogen carbonate solution, and extracted with 80 mL of ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 199.6 mg of the title compound.
The physicochemical properties of the obtained compound were as follows and were confirmed to be the title compound.
¹ H-NMR (CDCl ₃ ); δ (ppm) 2.09 (3H, s), 2.11 (3H, s), 2.41 (3H, s), 2.43 (3H, s), 5.82 (1H, s), 7.15- 7.21 (4H, m), 7.36-7.38 (3H, m).
MS (ESI); m / z 357 (M + H) ⁺

c) Synthesis of 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenyl 4- A solution prepared by dissolving 314 mg of potassium hydroxide in 4 mL of ethanol and 4 mL of water was added to 199.6 mg of methylbenzenesulfonate, and the mixture was heated to reflux for 1 hour. 20 mL of water was added to the reaction mixture, and the mixture was extracted with 20 mL of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and purified using preparative thin layer silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired fraction. Was dissolved in 1,4-dioxane and freeze-dried to obtain 66.2 mg of the title compound.
The physicochemical properties of the obtained compound were as follows and were confirmed to be the title compound.
¹ H-NMR (CDCl ₃ ); δ (ppm) 2.29 (3H, s), 2.33 (3H, s), 2.37 (3H, s), 6.01 (1H, s), 6.70 (1H, d, J = 8.0 Hz), 6.90 (1H, s), 7.07 (1H, d, J = 8.0Hz), 9.64 (1H, brs).
MS (ESI); m / z 203 (M + H) ⁺

(Example 1: Production of liquid for external use)
C12-C15 alkyl lactate 5g, isopropyl myristate 6.3g, diisopropyl adipate 5g, benzyl alcohol 2.7g, PPG-15 stearyl ether 5g are mixed with absolute ethanol 60g, dissolved in 1g myristyl alcohol, A formulation of Example 1 was obtained by dissolving 15 g of 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol.

(Example 2: Production of liquid for external use)
A preparation of Example 2 was obtained in the same manner as in Example 1 except that the blending amounts of isopropyl myristate, PPG-15 stearyl ether, diisopropyl adipate and C12-C15 alkyl lactate were changed to those shown in Table 1. .

(Example 3: Production of liquid for external use)
The preparation of Example 3 in the same manner as in Example 1, except that the amounts of benzyl alcohol, isopropyl myristate, PPG-15 stearyl ether, diisopropyl adipate and C12-C15 alkyl lactate were changed to those shown in Table 1. Got.

(Example 4: Production of liquid for external use)
C12-C15 alkyl lactate (2 g), isopropyl myristate (1.2 g), D-limonene (1.6 g), and cyclomethicone (0.2 g) are mixed with anhydrous ethanol (12 g), and the active ingredient 2- (3,5-dimethyl-1H-pyrazole-1- I) 3 g of 5-methylphenol was dissolved to obtain the preparation of Example 4.

(Example 5: Production of liquid for external use)
2- (3,5-dimethyl-1H-pyrazol-1-yl), the active ingredient, is mixed with 1 g of isopropyl myristate, 2.8 g of diethyl glycol monoethyl ether (Transcutol P) and 0.2 g of cyclomethicone in 12 g of absolute ethanol. The preparation of Example 5 was obtained by dissolving 4 g of -5-methylphenol.

(Example 6: Production of liquid for external use)
C12-C15 alkyl lactate 2.1 g, isopropyl myristate 5.9 g, diisopropyl adipate 7 g, benzyl alcohol 2.7 g, PPG-15 stearyl ether 6.3 g are mixed with absolute ethanol 65 g and dissolved by adding myristyl alcohol 1 g, further effective 10 g of 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol as a component was dissolved to obtain a preparation of Example 6.

(Comparative Example 1: Production of liquid for external use)
C2-C15 alkyl lactate 2g, diethyl sebacate 1g, diethyl glycol monoethyl ether (Transcutol P) 4.46g, benzyl alcohol 0.54g are mixed with absolute ethanol 9g, 2- (3,5-dimethyl-1H, which is the active ingredient -Pyrazol-1-yl) -5-methylphenol (3 g) was dissolved to obtain a preparation of Comparative Example 1.

(Comparative Example 2: Production of liquid for external use)
C12-C15 alkyl lactate 5 g, dimethyl isosorbide 11 g, cyclomethicone 5 g, oleyl alcohol 3 g, isopropanol 30 g are mixed with absolute ethanol 30 g, dissolved by adding 1 g of myristyl alcohol, and active ingredient 2- (3,5-dimethyl -1H-pyrazol-1-yl) -5-methylphenol was dissolved to obtain a preparation of Comparative Example 2.

Table 1 shows the formulations of the external liquid preparations of Examples 1 to 6 and Comparative Examples 1 and 2.

Table 2 shows the product names and manufacturer names of the components used in Examples 1 to 6 and Comparative Examples 1 and 2.

(Comparative Example 3: Production of liquid for external use)
As the preparation of Comparative Example 3, the preparation described in Example 1 of International Publication No. 2014/021282 was produced.
Specifically, 10 g of the compound produced in Production Example 1 and 10 g of copolyvidone (Prasudone S-630) were dissolved in order in a part of ethanol to make a total of 100 mL with ethanol to obtain a preparation. In addition, the density | concentration of the main ingredient in the comparative example 3 is 11.4 w / w%.

(Test Example 1)
The viscosity, precipitation, and removability of the prepared preparation were evaluated as follows.

<Viscosity>
The viscosity of the preparation was measured using a rotational viscometer (B-type viscometer, model B8L, manufactured by Tokyo Keiki Seisakusho Co., Ltd.), and the rotor used was a BL adapter attached to the apparatus. The results are shown in Table 3.

<Precipitation>
The drug precipitation when the formulation was in contact with water, sweat, etc. was tested as follows. The results are shown in Table 3.
-Additive precipitation test method for water (1)-
After 20 μL of the prepared preparation was dropped on a slide glass and allowed to stand for 1 hour, 20 μL of purified water was added, and the presence or absence of precipitation was visually observed after 30 minutes.
-Water addition precipitation test method (2)-
20 μL of the prepared preparation was dropped onto an artificial nail (Vitro-Nails (registered trademark), IMS Inc.) and allowed to stand for 1 hour, then 20 μL of purified water was added, and the presence or absence of precipitation was visually observed after 30 minutes. did.

<Wipe removal property>
50 μL of the prepared preparation is dropped onto an artificial nail (Vitro-Nails (registered trademark), IMS Inc.), and about 0.5 mm is quickly applied using a coating jig (Bird Applicator, Gardco, Model No. AP-B5363). Apply to a thickness. After swabbing horizontally with cotton containing 3 drops of water, it was swabbed with dry cotton, and the properties of the wiped portion were visually observed and classified according to the following criteria.
[Standard]
・ Level-1: Can be easily removed and no residue is observed.
・ Level-2 ... It can be easily removed, but a slight residue is observed.
・ Level-3 ... It is difficult to remove. A slight residue is observed.

From the results in Table 3, since the preparation of the present invention does not become cloudy or precipitate even when exposed to water or the like, the drug on the nail and / or skin when applied to the nail and / or skin. Can be prevented from becoming clouded or precipitated. Moreover, the formulation of this invention is excellent also in removability, and also is excellent in delivery property and applicability | paintability from a low viscosity.

(Test Example 2: Subnail-like gap delivery test)
Evaluation method reported by Dr. Bhatt et al. (V. Bhatt, R. Pillai. Efinaconazole topical solution, 10%: formulation development program of a new topical treatment of toenail onychomycosis. Journal of Pharmaceutical Sciences 2015; 104: 2177-82) The test was carried out with some changes. Using a glass slide, wheat clay and aluminum foil, a gap imitating the nail and sub-nail gap was created. Add 1/100 volume of fluorescent dye dissolved in ethanol to each external solution, drop 16 μL of each prepared fluorescent material-containing external solution into the gap created with aluminum foil, and deliver it in the space of each solution using a fluorescence microscope The area was observed and measured, and evaluated according to the following criteria. The results are shown in Table 4.
[Standard]
A: The difference from the sub-nail-like gap delivery area of the preparation of Comparative Example 3 is +40 mm ² or more.
B: The difference from the sub-nail-like gap delivery area of the preparation of Comparative Example 3 is +30 mm ² or more and less than +40 mm ² .
C: The difference from the sub-nail-like gap delivery area of the preparation of Comparative Example 3 is +20 mm ² or more and less than +30 mm ² .
D: The difference from the sub-nail-like gap delivery area of the preparation of Comparative Example 3 is 0 mm ² or more and less than +20 mm ² .

From the results shown in Table 4, it was confirmed that the preparation of the present invention was superior in deliverability to the nail plate.

(Test Example 3: Anti- ringworm fungus activity test of external solution)
The anti-tinea activity of the prepared preparation was evaluated as follows.

Create a total of 4 hair loss sites with a diameter of about 2 cm under the anesthesia on the back of the guinea pig. Elicited (approximately 1 × 10 ⁶ CFU / site). From 3 days after bacterial inoculation, the preparation was applied to the infected site once a day for 14 days by 0.1 mL. Before the drug application on each day, the drug remaining on the skin surface at the site of infection was wiped off. Three days after administration of the final drug, the guinea pig was euthanized, the drug remaining on the skin surface was wiped off, and the skin at the four infected sites was peeled off. After removing the remaining drug by washing the peeled skin, the peeled skin was cut into 10 pieces each, cultured on a Mycosel agar plate at 28 ° C for 2 weeks, and mycelia were confirmed on the skin pieces visually. Was determined to be culture positive. The bacterial positive rate was calculated from the number of culture-positive skin pieces according to the following formula, and the therapeutic effect was determined according to the following criteria. The results are shown in Table 5.
Bacteria positive rate (%) = number of skin pieces showing bacteria positive / total number of skin pieces x 100
[Standard]
A: The average bacteria positive rate is 0% or more and less than 25%.
B: The average bacteria positive rate is 25% or more and less than 50%.
C: The average bacteria positive rate is 50% or more and less than 75%.
D: The average bacteria positive rate is 75% or more and less than 100%.

From the above results, the preparation of the present invention has a strong anti-tinea fungus activity without forming a film even when it contains a drug at a high concentration or is applied to the skin, etc. It was confirmed that it has a delivery property, an effect of suppressing the precipitation of active ingredients upon contact with water after coating, ease of removal such as wiping, and excellent coating properties.
Therefore, according to the present invention, it is possible to provide a nail and / or skin external solution that is easy to handle at a high concentration and has a high preventive or therapeutic effect.

Examples of the aspect of the present invention include the following.
<1> An external liquid for prevention or treatment of onychomycosis comprising a drug having anti-tinea activity, a volatile alcohol, and a delivery accelerator.
<2> Prevention of onychomycosis according to the above <1>, wherein the drug having anti-tinea activity is 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof Alternatively, it is a therapeutic external solution.
<3> Any one of <1> to <2>, wherein the delivery accelerator includes one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate, and stearyl alcohol. For external use for preventing or treating onychomycosis.
<4> The external preparation for preventing or treating onychomycosis according to any one of <1> to <3>, further including a wetting agent.
<5> For preventing or treating onychomycosis according to the above <4>, wherein the wetting agent comprises one or more selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropylcellulose, and poloxamer. It is a liquid for external use.
<6> As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
As the delivery accelerator, one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate and stearyl alcohol,
Furthermore, for the prevention or treatment of onychomycosis according to the above <1>, which may contain one or more selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropylcellulose, and poloxamer as a wetting agent. It is a liquid for external use.
<7> As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
As the delivery accelerator, one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate and stearyl alcohol,
Further, as wetting agents, PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone, diisobutyl adipate, isopropyl adipate, oleyl oleate, decyl oleate, C12-C15 alkyl lactate And the liquid for external use for prevention or treatment of onychomycosis according to the above <1>, which may contain at least one selected from the group consisting of alkyl lactate (C12, C13).
<8> As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
And as the delivery accelerator, isopropyl myristate,
Furthermore, the external preparation for preventing or treating onychomycosis according to the above <1>, which may further contain PPG-15 stearyl ether as a wetting agent.
<9> As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
As the delivery enhancer, isopropyl myristate and
The external preparation for preventing or treating onychomycosis according to the above <4>, which contains PPG-15 stearyl ether as the wetting agent.
<10> The drug having anti-tinea activity includes 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
Furthermore, the low-volatility solvent may be one or more selected from the group consisting of diisopropyl adipate, benzyl alcohol and myristyl alcohol. The liquid for external use for prevention or treatment of onychomycosis according to the above <1>.
<11> As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
And one or more selected from the group consisting of diisopropyl adipate, benzyl alcohol and myristyl alcohol as a low volatility solvent,
Further, as wetting agents, PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone, diisobutyl adipate, isopropyl adipate, oleyl oleate, decyl oleate, C12-C15 alkyl lactate And the external preparation for the prevention or treatment of onychomycosis according to the above <1>, which may contain one or more selected from the group consisting of alkyl lactate (C12, C13).
<12> Prevention or treatment of onychomycosis according to any one of <1> to <11>, wherein the drug having anti-tinea fungi activity is contained at a ratio of 5 to 20% by mass with respect to the whole external preparation. It is a liquid for external use.

Claims (12)

1. An external liquid for preventing or treating onychomycosis comprising a drug having anti-tinea fungus activity, a volatile alcohol, and a delivery accelerator.
2. 2. The topical use for prevention or treatment of onychomycosis according to claim 1, wherein the drug having anti-tinea activity is 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof. Liquid drug.
3. 3. The onychomycosis of claim 1, wherein the delivery enhancer comprises one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate and stearyl alcohol. An external solution for prevention or treatment.
4. The external preparation for preventing or treating onychomycosis according to any one of claims 1 to 3, further comprising a wetting agent.
5. The external preparation for preventing or treating onychomycosis according to claim 4, wherein the wetting agent comprises one or more selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropylcellulose, and poloxamer.
6. As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
   As the delivery accelerator, one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate and stearyl alcohol,
   The topical use for prevention or treatment of onychomycosis of claim 1, further comprising one or more selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropylcellulose, and poloxamer as a wetting agent. Liquid drug.
7. As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
   As the delivery accelerator, one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate and stearyl alcohol,
   Further, as wetting agents, PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone, diisobutyl adipate, isopropyl adipate, oleyl oleate, decyl oleate, C12-C15 alkyl lactate And an external solution for preventing or treating onychomycosis according to claim 1, which may contain at least one selected from the group consisting of: and alkyl lactate (C12, C13).
8. As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
   And as the delivery accelerator, isopropyl myristate,
   The external preparation for preventing or treating onychomycosis according to claim 1, which may further contain PPG-15 stearyl ether as a wetting agent.
9. As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
   As the delivery enhancer, isopropyl myristate and
   The external preparation for prevention or treatment of onychomycosis according to claim 4, comprising PPG-15 stearyl ether as the wetting agent.
10. The drug having anti-tinea activity includes 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
    Furthermore, the liquid for external use for prevention or treatment of onychomycosis of Claim 1 which may contain 1 or more types selected from the group which consists of diisopropyl adipate, benzyl alcohol, and myristyl alcohol as a low volatility solvent.
11. As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
    And one or more selected from the group consisting of diisopropyl adipate, benzyl alcohol and myristyl alcohol as a low volatility solvent,
    Further, as wetting agents, PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone, diisobutyl adipate, isopropyl adipate, oleyl oleate, decyl oleate, C12-C15 alkyl lactate And an external solution for preventing or treating onychomycosis according to claim 1, which may contain at least one selected from the group consisting of: and alkyl lactate (C12, C13).
12. The external preparation for preventing or treating onychomycosis according to any one of claims 1 to 11, which contains the drug having anti-tinea fungus activity in a proportion of 5 to 20% by mass with respect to the entire external preparation.