Pharmaceutical compositions

Abstract

To provide a pharmaceutical composition excellent in solubility of an azole-based antifungal agent and permeability to nails.SOLUTION: (C) 1 to 18% by mass of water, and (D) 54% by mass or more of ethanol, wherein the components (B) are solvents whose Hansen solubility parameter is located within a Hansen solubility sphere with a radius of 12.6 centered on (δ D = 17.5, δ P = 15.9, δ H = 6.9), and the solvents include at least one or more selected from the group consisting of (B1) benzyl alcohol, 1-phenylethanol, and 2-phenylethanol.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions. [Background technology]

[0002] Azole antifungal drugs inhibit the synthesis of ergosterol, an important component of fungal cell membranes, and are therefore widely used as therapeutic agents for, for example, dermatomycosis, visceral mycosis, and onychomycosis. However, azole antifungal drugs are poorly soluble, and it is difficult to deliver the drug to the site of fungal infection via transdermal administration. Therefore, it is very important to design a formulation that improves the solubility and stability of azole antifungal drugs and ensures their efficient penetration into the site of fungal infection via transdermal administration.

[0003] It has been reported that, for example, mixing luliconazole with a specific organic solvent can suppress the coloration of luliconazole over time due to light irradiation (Patent Document 1). Furthermore, when a pharmaceutical formulation containing luliconazole is applied to a living body, luliconazole microcrystals precipitate, inhibiting its permeability and absorption. Even the inclusion of a permeation enhancer such as benzyl alcohol fails to improve permeability and absorption. However, it has also been reported that the inclusion of an α-hydroxycarboxylic acid and / or a salt thereof inhibits the precipitation of luliconazole microcrystals and improves permeability and absorption (Patent Document 2). Furthermore, since permeability of nails, which are primarily composed of keratin, is enhanced by hydration, including more water in the formulation is advantageous for nail permeability. Therefore, it has been reported that the solubility and nail permeability of an imidazole antifungal drug can be improved by adding lactic acid, tartaric acid, and lauromacrogol together with the imidazole antifungal drug and increasing the water content to 20% by mass or more (Patent Document 3). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2013-253078 [Patent Document 2] International Publication No. 2007 / 102241 [Patent Document 3] International Publication No. 2014 / 17411 Summary of the Invention [Problem to be solved by the invention]

[0005] However, the pharmaceutical compositions of Patent Documents 1 and 2 do not necessarily have sufficient nail penetration and absorption, and there is room for improvement. Furthermore, Patent Document 3 states that a formulation containing more water is advantageous for improving nail penetration, but the present inventors have confirmed that nail penetration is inhibited depending on the formulation. An object of the present invention is to provide a pharmaceutical composition that allows an azole antifungal drug to have excellent solubility and penetration into nails. [Means for solving the problem]

[0006] Patent Document 3 specifically shows that in a pharmaceutical composition containing an antifungal drug, reducing the water content to about 10% by mass results in insufficient permeability, and that permeability can be improved only by increasing the water content to 20% by mass or more. However, the present inventors have unexpectedly discovered that by incorporating a specific amount of ethanol and a specific solvent in combination with an azole antifungal drug and then reducing the water content within a specific range, a pharmaceutical composition can be obtained in which the azole antifungal drug has good solubility and significantly improved permeability into the nail.

[0007] That is, the present invention provides the following [1] to [3]. [1] The following components (A) to (D); (A) Azole antifungal drugs (B) Solvent (C) 1 to 18% by mass of water, and (D) Ethanol 54% by mass or more A pharmaceutical composition comprising: Component (B) is a solvent whose Hansen solubility parameters are (δD=17.5, δP=15.9, δH=6.9) and are located within a Hansen solubility sphere with a radius of 12.6, and the solvent contains at least (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol; Pharmaceutical compositions. [2] The pharmaceutical composition according to [1] above, comprising, as component (B), (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol, or a combination of (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol and (B2) one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, methyl isobutyl ketone, benzophenone, and 2-ethyl-1,3-hexanediol. [3] The pharmaceutical composition according to [1] or [2] above, comprising an imidazole antifungal drug as component (A). [Effects of the Invention]

[0008] According to the present invention, a pharmaceutical composition can be provided which has excellent solubility of an azole antifungal drug and excellent penetration into nails. DETAILED DESCRIPTION OF THE INVENTION

[0009] The pharmaceutical composition of the present invention contains components (A) to (D). Each component will be explained below.

[0010] <Component (A)> The pharmaceutical composition of the present invention contains an azole antifungal drug as component (A). Here, as used herein, the term "azole antifungal drug" refers to a compound having antifungal activity and containing an imidazole ring or a triazole ring in its molecule. Component (A) may be in the form of a physiologically acceptable salt. The salt may be an inorganic salt or an organic salt. Examples of the salt include inorganic salts such as hydrochlorides, nitrates, sulfates, and phosphates; organic salts such as citrates, oxalates, glycolates, lactates, and acetates; and sulfates such as mesylates and tosylates.

[0011] Examples of component (A) include imidazole antifungal drugs such as luliconazole, lanoconazole, ketoconazole, bifonazole, miconazole, isoconazole, clotrimazole, neticonazole, sulconazole, oxiconazole, and econazole; and triazole antifungal drugs such as efinaconazole, fluconazole, fosfluconazole, itraconazole, voriconazole, posaconazole, ravuconazole, and fosravuconazole. Component (A) may contain one or more types, and may be a commercially available product or one prepared according to literature.

[0012] Among these, it is preferable that component (A) contains an imidazole antifungal drug, and it is even more preferable that component (A) contains one or more selected from luliconazole, lanoconazole, ketoconazole, and bifonazole, in order to more easily enjoy the effects of the present invention.

[0013] The content of component (A) in the pharmaceutical composition of the present invention is preferably 0.5% by mass or more, more preferably 1.5% by mass or more, and even more preferably 3.5% by mass or more from the viewpoint of sufficient efficacy, and is preferably 12% by mass or less, more preferably 9% by mass or less, and even more preferably 7% by mass or less from the viewpoint of solubility in the composition. That is, the content of component (A) in the pharmaceutical composition of the present invention is preferably 0.5 to 12% by mass, more preferably 1.5 to 9% by mass, and even more preferably 3.5 to 7% by mass.

[0014] <Ingredient (B)> The pharmaceutical composition of the present invention contains a solvent as component (B), and such a solvent must satisfy the following two requirements. (i) The solvent is located within the Hansen solubility sphere with a radius of 12.6 and a center of (δD=17.5, δP=15.9, δH=6.9) with Hansen solubility parameters (hereinafter referred to as "HSP values"). (ii) It contains at least (B1) one or more solvents selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol (hereinafter also referred to as "component (B1)").

[0015] In (i), the "HSP value" is the solubility parameter decomposed into three elements: dispersion term (δD), polar term (δP), and hydrogen bond term (δH). These three parameters can be regarded as coordinates in a three-dimensional space (Hansen space). The HSP value and Hansen solubility sphere can be calculated using, for example, HSPiP 5th Edition software. In (ii), it is preferable that component (B1) contains at least benzyl alcohol, also known as phenylmethanol, which increases the solubility of component (A) in the composition and further improves penetration into nails.

[0016] If the pharmaceutical composition of the present invention contains component (B1) as component (B), it may contain, as component (B2), a solvent other than component (B1) that is located within the Hansen sphere of radius 12.6, with the HSP value centered at (δD=17.5, δP=15.9, δH=6.9). Component (B2) is not particularly limited as long as it can dissolve component (A), but from the viewpoint of improving the nail penetration of component (A), it preferably contains one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, methyl isobutyl ketone, benzophenone, and 2-ethyl-1,3-hexanediol, and more preferably contains one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, and methyl isobutyl ketone. From the viewpoint of improving the solubility of component (A) in the composition and the nail penetration, the polyethylene glycol preferably has a number average molecular weight of 150 or more, more preferably 190 or more, and even more preferably 230 or more, and preferably 650 or less, more preferably 550 or less, and even more preferably 450 or less. That is, the number average molecular weight of polyethylene glycol is preferably 150 to 650, more preferably 190 to 550, and even more preferably 230 to 450. Here, the "number average molecular weight" refers to the number average molecular weight in terms of polystyrene measured by gel permeation chromatography (GPC).

[0017] Preferred embodiments of component (B) are as follows: (i) (B1) Contains one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol (ii) (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol, and (B2) one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, methyl isobutyl ketone, benzophenone, and 2-ethyl-1,3-hexanediol. (iii) (B1) a combination of one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol, and (B2) a combination of one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, and methyl isobutyl ketone.

[0018] In the case of the above-mentioned embodiment (i), the content of component (B1) in the pharmaceutical composition of the present invention is preferably 1.5% by mass or more, more preferably 2.5% by mass or more, and even more preferably 3.5% by mass or more, from the viewpoint of improving the penetration of component (A) into the nail and the ease of spreading the composition, and is preferably 30% by mass or less, more preferably 20% by mass or less, and even more preferably 10% by mass or less, from the viewpoint of preventing damage to components when filled in a container. That is, the content of component (B1) in the pharmaceutical composition of the present invention is preferably 1.5 to 30% by mass, more preferably 2.5 to 20% by mass, and even more preferably 3.5 to 10% by mass.

[0019] In the case of the above-mentioned embodiment (ii) or (iii), the total content of component (B1) and component (B2) in the pharmaceutical composition of the present invention is preferably 3.5% by mass or more, more preferably 8% by mass or more, and even more preferably 15% by mass or more, from the viewpoint of improving the penetration of component (A) into the nail and the ease of spreading the composition, and is preferably 30% by mass or less, more preferably 28% by mass or less, and even more preferably 26% by mass or less, from the viewpoint of preventing damage to components when filled in a container. That is, the total content of components (B1) and (B2) in the pharmaceutical composition of the present invention is preferably 3.5 to 30% by mass, more preferably 8 to 28% by mass, and even more preferably 15 to 26% by mass.

[0020] In the case of the above-mentioned embodiment (ii) or (iii), the mass ratio of component (B1) to component (B2) [(B2) / (B1)] is preferably 0.5 or more, more preferably 1.5 or more, and even more preferably 3 or more, from the viewpoint of improving the penetration of component (A) into the nail, and from the viewpoint of preventing damage to components when filled in a container, it is preferably 15 or less, more preferably 11 or less, and even more preferably 9 or less. That is, the mass ratio [(B2) / (B1)] is preferably 0.5 to 15, more preferably 1.5 to 11, even more preferably 1.5 to 9, and still more preferably 3 to 9.

[0021] The mass ratio of component (A) to component (B1) [(B1) / (A)] is preferably 0.125 or more, more preferably 0.2 or more, and even more preferably 0.5 or more, from the viewpoints of improving the solubility of component (A) in the composition, penetrability into nails, and ease of spreading the composition, and is preferably 6 or less, more preferably 2.5 or less, and even more preferably 1.2 or less, from the viewpoint of preventing damage to components when filled in a container. That is, the mass ratio [(B1) / (A)] is preferably 0.125 to 6, more preferably 0.2 to 2.5, and even more preferably 0.5 to 1.2.

[0022] <Ingredient (C)> The pharmaceutical composition of the present invention contains water as component (C), such as tap water, pure water, ion-exchanged water, purified water, and distilled water. The content of component (C) in the pharmaceutical composition of the present invention must be 1 to 18% by mass. When the content of component (C) is within this range, the penetration of component (A) into the nail is good. The content of component (C) in the pharmaceutical composition of the present invention is 1 to 18% by mass, but from the viewpoint of improving the penetration of component (A) into the nail, particularly the swelling property of keratin, it is preferably 1.5% by mass or more, more preferably 2.5% by mass or more, even more preferably 3.5% by mass or more, even more preferably 6% by mass or more, and especially preferably 8% by mass or more, and from the viewpoint of improving the penetration of component (A) into the nail, particularly the wettability of the nail surface, it is preferably 16% by mass or less, more preferably 14% by mass or less, and even more preferably 12% by mass or less. That is, the content of component (C) in the pharmaceutical composition of the present invention is preferably 1.5 to 18% by mass, more preferably 2.5 to 18% by mass, even more preferably 3.5 to 16% by mass, still more preferably 6 to 16% by mass, even more preferably 8 to 14% by mass, and especially especially preferably 8 to 12% by mass.

[0023] The mass ratio of component (C) to component (B1) [(B1) / (C)] is preferably 0.15 or more, more preferably 0.25 or more, and even more preferably 0.33 or more, from the viewpoints of improving the penetration of component (A) into nails and improving the ease of spreading the composition, and from the viewpoints of improving the penetration of component (A) into nails and preventing damage to components when filled in a container, it is preferably 6 or less, more preferably 2.6 or less, even more preferably 1.6 or less, even more preferably 1.1 or less, and especially preferably 0.9 or less. That is, this mass ratio [(B1) / (C)] is preferably 0.15 to 6, more preferably 0.15 to 2.6, even more preferably 0.25 to 1.6, still more preferably 0.25 to 1.1, and especially preferably 0.33 to 0.9.

[0024] <Ingredient (D)> The pharmaceutical composition of the present invention contains ethanol as component (D). The content of component (D) in the pharmaceutical composition of the present invention must be 54% by mass or more. When the content of component (D) is within this range, the proportion of water can be adjusted to the above range, thereby improving the penetration of component (A) into the nail. The content of component (D) in the pharmaceutical composition of the present invention is 54% by mass or more, and from the viewpoint of further improving the penetration of component (A) into the nail and the ease of spreading the composition, it is preferably 55% by mass or more, more preferably 57% by mass or more, and even more preferably 59% by mass or more. The upper limit of the content of component (D) in the pharmaceutical composition of the present invention is not particularly limited as long as it is equal to or less than the remainder excluding the total content of components (A) to (C), and is, for example, preferably 90% by mass or less, more preferably 87% by mass or less.

[0025] The mass ratio of component (D) to component (B1) [(B1) / (D)] is preferably 0.025 or more, more preferably 0.035 or more, even more preferably 0.050 or more, and even more preferably 0.059 or more, from the viewpoints of improving the penetration of component (A) into nails and improving the ease of spreading the composition, and is preferably 0.075 or less, more preferably 0.072 or less, and even more preferably 0.068 or less, from the viewpoints of improving the penetration of component (A) into nails and preventing damage to components when filled in a container. That is, this mass ratio [(B1) / (D)] is preferably 0.025 to 0.075, more preferably 0.035 to 0.075, even more preferably 0.050 to 0.072, and even more preferably 0.059 to 0.068.

[0026] From the viewpoint of improving the penetration of component (A) into the nail, the mass ratio of component (C) to component (D) [(D) / (C)] is preferably 3.1 or more, more preferably 3.4 or more, even more preferably 4.1 or more, even more preferably 4.9 or more, and is preferably 100 or less, more preferably 50 or less, even more preferably 30 or less, even more preferably 20 or less, and especially preferably 10 or less. That is, the mass ratio [(D) / (C)] is preferably 3.1 to 100, more preferably 3.4 to 50, even more preferably 3.4 to 30, still more preferably 4.1 to 20, and especially especially preferably 4.9 to 10.

[0027] <Other ingredients> The pharmaceutical composition of the present invention may contain, in addition to components (A) to (D), components commonly used in topical skin preparations. Examples of such components include solvents other than components (B) and (D), oils that are liquid at 25°C, pH adjusters, surfactants, thickeners, preservatives, powders, antioxidants, UV absorbers, antioxidants, chelating agents, pigments, fragrances, moisturizers, blood circulation promoters, cooling agents, antiperspirants, disinfectants, whitening agents, anti-inflammatory agents, and skin activators. The content of these components can be appropriately determined within a range that does not impair the effects of the present invention.

[0028] [Form of preparation] The pharmaceutical composition of the present invention is usually used as an external preparation and can take the form of a pharmaceutical or quasi-drug. Examples of dosage forms include liquids, creams, gels, foams, ointments, propellants, and wipes. Among these, liquids are preferred, and non-aerosol liquids are more preferred. Examples of wipes include those in which the pharmaceutical composition of the present invention is impregnated into a substrate such as a fiber; those in which the pharmaceutical composition of the present invention is attached, sprinkled, sprayed, or the like onto the surface of a substrate such as a fiber; and those in which the pharmaceutical composition of the present invention is attached, sprinkled, sprayed, or the like onto the object to be wiped.

[0029] The pharmaceutical composition of the present invention is effective for treating or preventing, for example, mycoses of the body such as tinea corporis, mycoses of the hands and feet such as tinea pedis, and onychomycoses such as tinea unguium. More specifically, the pharmaceutical composition is effective for treating or preventing mycoses and onychomycoses caused by, for example, the genera Tricophyton, Aspergillus, Candida, Cryptococcus, and Malassezia, and is particularly effective for treating or preventing hyperkeratotic tinea and onychophytic disease, especially tinea and onychophytic disease caused by the genus Tricophyton.

[0030] [Application] The pharmaceutical composition of the present invention is applied in an appropriate amount to the target site. It may be taken in the hand and spread on the target site, or it may be applied directly to the affected area and then spread by hand. The application to the target site may be carried out once or multiple times a day. The amount applied per time may be appropriately set, but is, for example, about 20 μL per target site.

[0031] [Manufacturing method] The pharmaceutical composition of the present invention can be produced, for example, by mixing components (A) to (D) and, if necessary, other components. The order in which the components are added when producing the pharmaceutical composition is not particularly limited, and they may be added in any order or simultaneously.

[0032] In relation to the above-described embodiment, the present invention further discloses the following aspects.

[0033] <1> The following components (A) to (D): (A) Azole antifungal drugs (B) Solvent (C) 1 to 18% by mass of water, and (D) Ethanol 54% by mass or more A pharmaceutical composition comprising: Component (B) is a solvent whose Hansen solubility parameters are (δD=17.5, δP=15.9, δH=6.9) and lie within a Hansen solubility sphere of radius 12.6, the center of which is at least (B1) one or more solvents selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol.

[0034] <2> The component (A) preferably contains one or more selected from imidazole antifungal drugs and triazole antifungal drugs, more preferably contains an imidazole antifungal drug, even more preferably contains one or more selected from luliconazole, lanoconazole, ketoconazole, bifonazole, miconazole, isoconazole, clotrimazole, neticonazole, sulconazole, oxiconazole and econazole, and even more preferably contains one or more selected from luliconazole, lanoconazole, ketoconazole and bifonazole. <1> The pharmaceutical composition described.

[0035] <3> The content of component (A) in the pharmaceutical composition is preferably 0.5% by mass or more, more preferably 1.5% by mass or more, even more preferably 3.5% by mass or more, and preferably 12% by mass or less, more preferably 9% by mass or less, even more preferably 7% by mass or less. <1> or <2> The pharmaceutical composition described.

[0036] <4> The content of component (A) in the pharmaceutical composition is preferably 0.5 to 12% by mass, more preferably 1.5 to 9% by mass, and even more preferably 3.5 to 7% by mass. <1> ~ <3> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0037] <5> The component (B) preferably contains at least benzyl alcohol as component (B1). <1> ~ <4> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0038] <6> Component (B) preferably contains, as component (B2), a solvent whose Hansen solubility parameters are located within a Hansen sphere of radius 12.6 centered at (δD=17.5, δP=15.9, δH=6.9), other than component (B1), more preferably one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, methyl isobutyl ketone, benzophenone, and 2-ethyl-1,3-hexanediol, and even more preferably one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, and methyl isobutyl ketone, <1> ~ <5> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0039] <7> The component (B) is preferably any one of the following embodiments (i) to (iii): <1> ~ <6> 1. The pharmaceutical composition according to any one of claims 1 to 9. (i) (B1) Contains one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol (ii) (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol, and (B2) one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, methyl isobutyl ketone, benzophenone, and 2-ethyl-1,3-hexanediol. (iii) (B1) a combination of one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol, and (B2) a combination of one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, and methyl isobutyl ketone.

[0040] <8> When component (B) is of the above embodiment (i), the content of component (B1) is preferably 1.5% by mass or more, more preferably 2.5% by mass or more, even more preferably 3.5% by mass or more, and preferably 30% by mass or less, more preferably 20% by mass or less, even more preferably 10% by mass or less. <7> The pharmaceutical composition described.

[0041] <9> When the component (B) is the embodiment (i), the content of the component (B1) is preferably 1.5 to 30 mass%, more preferably 2.5 to 20 mass%, and even more preferably 3.5 to 10 mass%. <7> or <8> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0042] <10> When component (B) is the embodiment (ii) or (iii) above, the total content of component (B1) and component (B2) is preferably 3.5% by mass or more, more preferably 8% by mass or more, even more preferably 15% by mass or more, and preferably 30% by mass or less, more preferably 28% by mass or less, even more preferably 26% by mass or less. <7> The pharmaceutical composition described.

[0043] <11> When the component (B) is the embodiment (ii) or (iii), the total content of the component (B1) and the component (B2) is preferably 3.5 to 30 mass%, more preferably 8 to 28 mass%, and even more preferably 15 to 26 mass%. <7> or <10> The pharmaceutical composition described.

[0044] <12> When the component (B) is of the above embodiment (ii) or (iii), the mass ratio of the component (B1) to the component (B2) [(B2) / (B1)] is preferably 0.5 or more, more preferably 1.5 or more, even more preferably 3 or more, and preferably 15 or less, more preferably 11 or less, even more preferably 9 or less. <7> , <10> and <11> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0045] <13> When the component (B) is the above-mentioned embodiment (ii) or (iii), the mass ratio of the component (B1) to the component (B2) [(B2) / (B1)] is preferably 0.5 to 15, more preferably 1.5 to 11, even more preferably 1.5 to 9, and even more preferably 3 to 9. <7> , and <10> ~ <12> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0046] <14> the mass ratio of component (A) to component (B1) [(B1) / (A)] is preferably 0.125 or more, more preferably 0.2 or more, even more preferably 0.5 or more, and is preferably 6 or less, more preferably 2.5 or less, even more preferably 1.2 or less; <1> ~ <13> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0047] <15> The mass ratio of the component (A) to the component (B1) [(B1) / (A)] is preferably 0.125 to 6, more preferably 0.2 to 2.5, and even more preferably 0.5 to 1.2. <1> ~ <14> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0048] <16> The component (C) preferably contains one or more selected from tap water, pure water, ion-exchanged water, purified water, and distilled water. <1> ~ <15> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0049] <17> The content of component (C) in the pharmaceutical composition is preferably 1.5% by mass or more, more preferably 2.5% by mass or more, even more preferably 3.5% by mass or more, even more preferably 6% by mass or more, even more preferably 8% by mass or more, and preferably 16% by mass or less, more preferably 14% by mass or less, even more preferably 12% by mass or less. <1> ~ <16> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0050] <18> The content of component (C) in the pharmaceutical composition is preferably 1.5 to 18% by mass, more preferably 2.5 to 18% by mass, even more preferably 3.5 to 16% by mass, even more preferably 6 to 16% by mass, even more preferably 8 to 14% by mass, and even more preferably 8 to 12% by mass. <1> ~ <17> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0051] <19> the mass ratio of component (C) to component (B1) [(B1) / (C)] is preferably 0.15 or more, more preferably 0.25 or more, even more preferably 0.33 or more, and is preferably 6 or less, more preferably 2.6 or less, even more preferably 1.6 or less, even more preferably 1.1 or less, even more preferably 0.9 or less; <1> ~ <18> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0052] <20> the mass ratio of component (C) to component (B1) [(B1) / (C)] is preferably 0.15 to 6, more preferably 0.15 to 2.6, even more preferably 0.25 to 1.6, even more preferably 0.25 to 1.1, and even more preferably 0.33 to 0.9; <1> ~ <19> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0053] <21> The content of component (D) in the pharmaceutical composition is preferably 55% by mass or more, more preferably 57% by mass or more, and even more preferably 59% by mass or more. <1> ~ <20> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0054] <22> The content of component (D) in the pharmaceutical composition is preferably 54% by mass or more, more preferably 55% by mass or more, even more preferably 57% by mass or more, even more preferably 59% by mass or more, and preferably 90% by mass or less, even more preferably 87% by mass or less. <1> ~ <20> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0055] <23> the mass ratio of component (D) to component (B1) [(B1) / (D)] is preferably 0.025 or more, more preferably 0.035 or more, even more preferably 0.050 or more, even more preferably 0.059 or more, and is preferably 0.075 or less, more preferably 0.072 or less, even more preferably 0.068 or less; <1> ~ <22> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0056] <24> the mass ratio of component (D) to component (B1) [(B1) / (D)] is preferably 0.025 to 0.075, more preferably 0.035 to 0.075, even more preferably 0.050 to 0.072, and still more preferably 0.059 to 0.068; <1> ~ <23> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0057] <25> the mass ratio of component (C) to component (D) [(D) / (C)] is preferably 3.1 or more, more preferably 3.4 or more, even more preferably 4.1 or more, even more preferably 4.9 or more, and is preferably 100 or less, more preferably 50 or less, even more preferably 30 or less, even more preferably 20 or less, even more preferably 10 or less; <1> ~ <24> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0058] <26> the mass ratio of component (C) to component (D) [(D) / (C)] is preferably 3.1 to 100, more preferably 3.4 to 50, even more preferably 3.4 to 30, even more preferably 4.1 to 20, and even more preferably 4.9 to 10; <1> ~ <25> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0059] <27> Preferably, the composition further contains one or more selected from the group consisting of a solvent other than component (B) and component (D), an oil that is liquid at 25°C, a pH adjuster, a surfactant, a thickener, a preservative, a powder, an antioxidant, an ultraviolet absorber, an antioxidant, a chelating agent, a colorant, a fragrance, a moisturizer, a blood circulation promoter, a cooling agent, an antiperspirant, a disinfectant, a whitening agent, an anti-inflammatory agent, and a skin activator. <1> ~ <26> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0060] <28> Preferably, the above-mentioned is an external preparation. <1> ~ <27> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0061] <29> The dosage form is preferably a liquid, cream, gel, foam, ointment, propellant or wipe, more preferably a liquid, and even more preferably a non-aerosol liquid. <1> ~ <28> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0062] <30> Preferably, the pharmaceutical composition is for the treatment or prevention of mycoses of the body such as tinea corporis, mycoses of the hands and feet such as tinea pedis, and onychomycoses such as tinea unguium, more preferably for the treatment or prevention of mycoses and onychomycosis caused by the genus Tricophyton, Aspergillus, Candida, Cryptococcus, or Malassezia, even more preferably for the treatment or prevention of hyperkeratotic tinea and tinea unguium, and even more preferably for the treatment or prevention of tinea and tinea unguium caused by the genus Tricophyton. <1> ~ <28> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0063] <31> Preferably, the composition is applied by applying an appropriate amount to a target site. <1> ~ <30> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0064] <32> Preferably, the composition is applied to the target area one to several times a day. <1> ~ <31> 1. The pharmaceutical composition according to any one of claims 1 to 9.

[0065] <33> The amount applied per time is preferably about 20 μL per target site. <1> ~ <32> 1. The pharmaceutical composition according to any one of claims 1 to 9. [Example]

[0066] 1. Reagents The reagents used in this example are as follows: Benzyl alcohol: Fujifilm Wako Pure Chemical Industries, Ltd. HSP value(δD,δP,δH)=(18.4,6.3,13.7) N-methyl-2-pyrrolidone: Fujifilm Wako Pure Chemical Industries, Ltd. HSP value(δD,δP,δH)=(18.6,12.3,7.2) Diisopropyl adipate: Tokyo Chemical Industry Co., Ltd. HSP value(δD,δP,δH)=(15.9,3.9,4.6) Methyl ethyl ketone (2-butanone): Fujifilm Wako Pure Chemical Industries, Ltd. HSP value(δD,δP,δH)=(16.0,9.0,5.1) Propylene carbonate: Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(20.0,18.0,4.1) Acetone: Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(15.5,10.4,7.0) Triethylene glycol: Fujifilm Wako Pure Chemical Industries, Ltd. HSP value(δD,δP,δH)=(16.0,12.5,18.6) Polyethylene Glycol (Polyethylene Glycol 400): Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(15.7,7.5,9.7) Dipropylene glycol: ADEKA Corporation HSP value(δD,δP,δH)=(16.5,10.6,17.7) Methyl isobutyl ketone: Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(15.3,6.1,4.1) Benzophenone: Tokyo Chemical Industry Co., Ltd. HSP value(δD,δP,δH)=(19.5,7.2,5.1) 2-Ethyl-1,3-hexanediol: Tokyo Chemical Industry Co., Ltd. HSP value(δD,δP,δH)=(16.4,5.8,13.7) Ethanol: Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(15.8,8.8,19.4) Glycerin: Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(17.4,11.3,27.2) Normal hexane: Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(14.9,0,0) Water (pure water): Fujifilm Wako Pure Chemical Corporation HSP value(δD,δP,δH)=(15.5,16.0,42.3) Luliconazole: Tokyo Chemical Industry Co., Ltd. Lanoconazole: Fujifilm Wako Pure Chemical Corporation Ketoconazole: Tokyo Chemical Industry Co., Ltd. Bifonazole: Tokyo Chemical Industry Co., Ltd.

[0067] 2. Evaluation (1) Evaluation of the solubility of component (A) The components in the proportions shown in the table were mixed in a borosilicate glass vial (Mighty Vial No. 4, manufactured by Maruemu Co., Ltd.) so that the total weight of the pharmaceutical composition was 5 g, and the mixture was sonicated for 30 minutes using an ultrasonicator (ASUCLEANER: AS ONE). The appearance of the pharmaceutical compositions of each Example and Comparative Example was then visually observed at room temperature (25°C) according to the following evaluation criteria.

[0068] Evaluation criteria 〇: The appearance is transparent △: Appearance is slightly cloudy or cloudy ×: Some residue remains and precipitate is present

[0069] (2) Evaluation of permeability The present inventors have focused on the fact that the epidermis and nails contain a large amount of keratin, and have conducted detailed studies on the permeability of compounds. As a result, they have found that the swelling degree of keratin and the wettability (contact angle) with respect to the nail surface are closely related to the permeability of compounds into the nail. That is, even if only one of the swelling degree of keratin and the wettability (contact angle) with respect to the nail surface is good, the permeability into the nail is insufficient. However, it has been confirmed that when both the swelling degree of keratin and the wettability (contact angle) with respect to the nail surface are good, the permeability into the nail is excellent. Then, using the swelling degree of keratin and the wettability (contact angle) with respect to the nail surface as indicators, the permeability of compounds into the nail was evaluated by the following method.

[0070] (i) Evaluation of keratin swelling 20 mg of wool keratin (Tokyo Chemical Industry Co., Ltd.) was filled into an NMR tube (Optima Corporation, 5 mm Sample tubes, φ5 mm × 178 mm), and 980 μL of the pharmaceutical composition was added and dispersed. The mixture was then infiltrated and stirred for 1 minute using a vortex mixer (Scientific Industries, VORTEX GENIE2) and allowed to stand. The swelling ratio of the keratin after 24 hours was calculated using the following formula:

[0071] Keratin swelling rate (%) = X / Y x 100 (wherein X represents the keratin filling height (mm) before the formulation was added, and Y represents the keratin filling height (mm) after 24 hours of standing.)

[0072] (3) Evaluation of wettability on the nail surface At 25°C, 2 μL of the pharmaceutical composition filled in a syringe was dropped onto the surface of a thinly sliced ​​cow's hoof, and the contact angle 10 seconds after the drop landed was measured using an automatic contact angle meter ("DM-501i" manufactured by Kyowa Chemical Industry Co., Ltd.) and evaluated according to the following criteria.

[0073] Evaluation criteria A: 0 to 10° (however, if it immediately spreads after dripping, it is considered 0°) B: 11~20° C: 21~30° D: 31° or more

[0074] Examples 1 to 7 and Comparative Examples 1 to 2 Pharmaceutical compositions were obtained by mixing the components shown in Table 1. Each pharmaceutical composition was then evaluated. The results are also shown in Table 1.

[0075] [Table 1]

[0076] Examples 8 to 19 and Comparative Examples 3 to 4 Pharmaceutical compositions were obtained in the same manner as in Example 1, except that the components shown in Table 2 were used. Each pharmaceutical composition was then evaluated. The results are also shown in Table 2.

[0077] [Table 2]

[0078] Examples 20 to 24 and Comparative Examples 5 to 7 Pharmaceutical compositions were obtained in the same manner as in Example 1, except that the components shown in Table 3 were used. Each pharmaceutical composition was then evaluated. The results are also shown in Table 3.

[0079] [Table 3]

[0080] Examples 25 to 27 Pharmaceutical compositions were obtained in the same manner as in Example 1, except that the components shown in Table 4 were used. Each pharmaceutical composition was then evaluated. The results are shown in Table 4, along with the results of Example 6.

[0081] [Table 4]

[0082] Examples 28 to 30 Pharmaceutical compositions were obtained in the same manner as in Example 1, except that the components shown in Table 5 were used. Each pharmaceutical composition was then evaluated. The results are shown in Table 5 together with the results of Example 6.

[0083] [Table 5]

[0084] Tables 1 to 5 show that by incorporating a specific amount of ethanol and at least benzyl alcohol in combination with an azole antifungal drug and then controlling the water content within a specific range, a pharmaceutical composition that is excellent in solubility of the azole antifungal drug and in penetration into nails can be obtained.

Claims

1. The following components (A) to (D): (A) Azole antifungal drug (B) Solvent (C) 1 to 18% by mass of water, and (D) Ethanol 54% by mass or more A pharmaceutical composition comprising: Component (B) is a solvent whose Hansen solubility parameters are (δD = 17.5, δP = 15.9, δH = 6.9) and located within a Hansen sphere of radius 12.6, and the solvent contains at least (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol; Pharmaceutical compositions.

2. The pharmaceutical composition according to claim 1, comprising, as component (B), (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol, or a combination of (B1) one or more selected from benzyl alcohol, 1-phenylethanol, and 2-phenylethanol and (B2) one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, methyl ethyl ketone, propylene carbonate, acetone, triethylene glycol, polyethylene glycol, dipropylene glycol, methyl isobutyl ketone, benzophenone, and 2-ethyl-1,3-hexanediol.

3. 3. The pharmaceutical composition according to claim 1, comprising an imidazole antifungal drug as component (A).

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