Pharmaceutical compositions

Abstract

To provide a pharmaceutical composition excellent in solubility of an antifungal agent and permeability to a nail.SOLUTION: A pharmaceutical composition comprising an aerosol stock solution and a propellant, wherein the aerosol stock solution comprises 1 to 18% by mass of the following components (A) to (C), (A) an antifungal agent, (B) a solvent, and (C) water in the aerosol stock solution, the component (B) is a solvent having a Hansen solubility parameter located within a Hansen solubility sphere having a radius of 12.6 centered on (δ D = 17.5, δ P = 15.9, δ H = 6.9), and the propellant comprises carbon dioxide gas.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] 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 and onychomycosis. However, antifungal drugs are poorly soluble, and it is difficult for them to reach the site of fungal infection. Therefore, it is very important to design a pharmaceutical formulation that improves the solubility of antifungal drugs and ensures their efficient penetration into the site of fungal infection.

[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 has excellent solubility of an antifungal drug and excellent 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 only be improved by increasing the water content to 20% by mass or more. However, the present inventors have unexpectedly discovered that by adding a specific solvent together with carbon dioxide gas to an antifungal drug and then reducing the water content within a specific range, a pharmaceutical composition can be obtained in which the solubility of the antifungal drug is good and its permeability into the nail is significantly improved.

[0007] That is, the present invention provides the following [1] to [4]. [1] A pharmaceutical composition containing an aerosol concentrate and a propellant, The aerosol concentrate contains the following components (A) to (C); (A) Antifungal drugs (B) a solvent, and (C) Water: 1 to 18% by mass in the aerosol concentrate Including, Component (B) is a solvent located within the Hansen solubility sphere with a radius of 12.6, whose Hansen solubility parameters are (δD=17.5, δP=15.9, δH=6.9). Contains carbon dioxide gas as a propellant. Pharmaceutical compositions. [2] The pharmaceutical composition according to [1] above, containing, as component (B), one or more selected from benzyl alcohol, 1-phenylethanol and 2-phenylethanol, 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, 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. [4] The pharmaceutical composition according to any one of the above [1] to [3], which contains an imidazole antifungal drug as component (A). [Effects of the Invention]

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

[0009] The pharmaceutical composition of the present invention contains an aerosol concentrate and a propellant, which will be described in detail below.

[0010] [Concentrated aerosol solution] The aerosol concentrate contains components (A) to (C). <Component (A)> The aerosol concentrate contains an antifungal drug as component (A). Here, in this specification, the term "antifungal drug" refers to a substance that has the function of inhibiting or suppressing the growth of fungi or killing fungi, and is used to treat or prevent various diseases and symptoms caused by fungal infections. Examples of component (A) include azole antifungal drugs, amine antifungal drugs, and morpholine antifungal drugs. Component (A) can contain one or more types, and may be a commercially available product or one prepared according to literature. 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 azole antifungal drugs 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, but are not limited to these, as long as they are compounds having an imidazole ring or a triazole ring in the molecule. Examples of amine antifungal drugs include allylamine antifungal drugs such as terbinafine and terbinafine hydrochloride; benzylamine antifungal drugs such as butenafine; and thiocarbamate antifungal drugs such as tolnaftate and liranaftate. An example of a morpholine antifungal drug is amorolfine.

[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 aerosol concentrate 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 15% by mass or less, more preferably 12% by mass or less, and even more preferably 9% by mass or less from the viewpoint of solubility in the composition. That is, the content of component (A) in the aerosol concentrate is preferably 0.5 to 15% by mass, more preferably 1.5 to 12% by mass, and even more preferably 3.5 to 9% by mass.

[0014] <Ingredient (B)> The aerosol concentrate contains a solvent as component (B), and the solvent must have a Hansen solubility parameter (hereinafter referred to as "HSP value") within the Hansen solubility sphere with a radius of 12.6, centered at (δD = 17.5, δP = 15.9, δH = 6.9). Here, the "HSP value" refers to the solubility parameter decomposed into three elements: the dispersion term (δD), the polar term (δP), and the hydrogen bonding term (δH). These three parameters can be considered 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.

[0015] From the viewpoint of improving the nail penetration of component (A), component (B) preferably contains one or more solvents selected from benzyl alcohol, 1-phenylethanol, 2-phenylethanol, 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. This enhances the solubility of component (A) in the composition and further improves nail penetration. Furthermore, from the viewpoint of improving the solubility of component (A) in the composition and 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).

[0016] Preferred embodiments of component (B) are as follows: (i) One or more selected from benzyl alcohol, 1-phenylethanol, 2-phenylethanol, 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 (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.

[0017] In the case of the above-mentioned embodiment (i), the content of component (B) in the aerosol concentrate is preferably 3% by mass or more, more preferably 7% by mass or more, even more preferably 14% by mass or more, and even more preferably 21% by mass or more, from the viewpoint of improving the penetration of component (A) into nails, 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 into a container. That is, the content of such component (B) in the aerosol concentrate is preferably 3 to 30% by mass, more preferably 7 to 28% by mass, even more preferably 14 to 26% by mass, and even more preferably 21 to 26% by mass.

[0018] In the case of the above-mentioned embodiment (ii), the total content of components (B1) and (B2) in the aerosol concentrate is preferably 7% by mass or more, more preferably 14% by mass or more, and even more preferably 21% by mass or more, from the viewpoint of improving the penetration of component (A) into nails, and is preferably 90% by mass or less, more preferably 70% by mass or less, and even more preferably 50% by mass or less, from the viewpoint of preventing damage to components when filled into a container. That is, the total content of components (B1) and (B2) in the aerosol concentrate is preferably 7 to 90% by mass, more preferably 14 to 70% by mass, and even more preferably 21 to 50% by mass.

[0019] In the case of the above-mentioned embodiment (ii), the mass ratio of component (B1) to component (B2) [(B2) / (B1)] is preferably 0.5 or more, more preferably 1 or more, and even more preferably 1.5 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 8 or less. That is, the mass ratio [(B2) / (B1)] is preferably 0.5 to 15, more preferably 1 to 11, and even more preferably 1.5 to 8.

[0020] The mass ratio of component (A) to component (B) [(B) / (A)] is preferably 2 or more, more preferably 3 or more, and even more preferably 4 or more, from the viewpoint of improving the solubility of component (A) in the composition and its penetration into nails, and from the viewpoint of preventing damage to components when filled into a container, it is preferably 25 or less, more preferably 18 or less, even more preferably 12 or less, and even more preferably 7 or less. That is, the mass ratio [(B) / (A)] is preferably 2 to 25, more preferably 2 to 18, even more preferably 3 to 12, and even more preferably 4 to 7.

[0021] <Component (C)> The aerosol concentrate contains water as component (C), such as tap water, purified water, pure water, ion-exchanged water, and distilled water. The content of component (C) in the aerosol concentrate must be 1 to 18% by mass. When the content of component (C) is within this range, the penetration of component (A) into the nails is good. The content of component (C) in the aerosol concentrate 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 particularly preferably 8% by mass or more, from the viewpoints of improving the penetration of component (A) into nails, particularly the swelling of keratin, moisturizing the skin, and reducing irritation. Also, from the viewpoint of improving the penetration of component (A) into nails, particularly the wettability of the nail surface, the content 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 aerosol concentrate 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, still more preferably 8 to 14% by mass, and particularly preferably 8 to 12% by mass.

[0022] The mass ratio of component (C) to component (B) [(B) / (C)] is preferably 0.4 or more, more preferably 1.25 or more, even more preferably 1.5 or more, and even more preferably 2 or more, from the viewpoint of improving the solubility of component (A) in the composition and nail penetration, and from the viewpoint of the nail penetration of component (A) and preventing damage to components when filled in a container, it is preferably 40 or less, more preferably 16 or less, even more preferably 10 or less, even more preferably 7 or less, and especially preferably 5.5 or less. That is, the mass ratio [(B) / (C)] is preferably 0.4 to 40, more preferably 0.4 to 16, even more preferably 1.25 to 10, still more preferably 1.5 to 7, and especially preferably 2 to 5.5.

[0023] The aerosol concentrate may further contain ethanol as component (D). When component (D) is contained, the content of component (D) in the aerosol concentrate is preferably 50% by mass or more, more preferably 54% by mass or more, and even more preferably 58% by mass or more, from the viewpoint of further improving the penetration of component (A) into nails. The content of component (D) is not particularly limited and can be the remainder obtained by subtracting components (A), (B1), (B2), and (C) from the mass of the aerosol concentrate. For example, the content of component (D) in the aerosol concentrate can be preferably 90% by mass or less, more preferably 87% by mass or less, and even more preferably 85% by mass or less. The content of component (D) may be 0% by mass.

[0024] <Other ingredients> The pharmaceutical composition of the present invention may contain, in addition to components (A) to (C), components commonly used in topical skin preparations. Examples of such components include solvents other than component (B), 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.

[0025] [Propellant] The pharmaceutical composition of the present invention contains carbon dioxide gas as a propellant, which allows the penetration of component (A) into the nail to be significantly improved compared to when carbon dioxide gas is not contained. If the pharmaceutical composition of the present invention contains carbon dioxide gas as a propellant, it may contain it in combination with other propellants. Known other propellants can be used, including liquefied petroleum gas (ethane, propane, ethylene, isobutane, normal butane, propylene, etc.), ethers (dimethyl ether, etc.), fluorocarbons (fluorocarbons, chlorofluorocarbons, bromochlorofluorocarbons, etc.), compressed gases (nitrogen, air), and chlorofluorocarbons (monochlorodifluoroethane, tetrafluoroethane, etc.). One or more of the other propellants may be contained. The ratio of carbon dioxide gas to the other propellants can be appropriately determined within a range that does not impair the effects of the present invention.

[0026] The carbon dioxide content in the pharmaceutical composition of the present invention is preferably 0.005% by mass or more, more preferably 0.02% by mass or more, even more preferably 0.04% by mass or more, even more preferably 0.07% by mass or more, and especially preferably 0.5% by mass or more, from the viewpoint of improving the penetration of component (A) into the nail. From the viewpoint of reducing irritation, the carbon dioxide content is preferably 9% by mass or less, more preferably 7% by mass or less, and even more preferably 5% by mass or less. That is, the carbon dioxide content in the pharmaceutical composition of the present invention is preferably 0.005 to 9% by mass, more preferably 0.02 to 9% by mass, even more preferably 0.04 to 7% by mass, even more preferably 0.07 to 7% by mass, and especially preferably 0.5 to 5% by mass. The content of the aerosol concentrate in the pharmaceutical composition of the present invention is usually the remainder obtained by subtracting the propellant content from the mass of the pharmaceutical composition.

[0027] [Form of preparation] The pharmaceutical composition of the present invention is generally used as an external preparation in the form of an aerosol, such as a propellant or foam. 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, it 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.

[0028] [Application] The pharmaceutical composition of the present invention is applied to the target site in an appropriate amount, which may be taken in the hands and spread over the target site, or may be ejected directly onto the target site. In the case of a foam, it is preferable to take it in the hands and apply it without crushing the foam. In the case of direct application, it is preferable to apply it to the affected area and then spread it with the hands. Application to the target site can be carried out once or multiple times a day. The amount applied per application can be set as appropriate, but is, for example, about 20 μL per application site.

[0029] The pharmaceutical composition of the present invention can be produced, for example, by mixing components (A) to (C) and, if necessary, other components to prepare an aerosol concentrate, then mixing this with a propellant and filling a pressure-resistant container equipped with an aerosol valve and nozzle. Alternatively, the aerosol concentrate may be filled into a pressure-resistant container, and then the propellant may be sealed in the pressure-resistant container. The order in which the components are added when preparing the aerosol concentrate is not particularly limited, and they may be added in any order or simultaneously. The pressure-resistant container is not particularly limited as long as it can withstand the internal pressure of the enclosed propellant and can spray the enclosed contents, and examples thereof include containers made of metals such as aluminum and tinplate, as well as synthetic resins such as polyacetal and polycarbonate. Furthermore, the nozzle diameter and length serving as the spray outlet are not particularly limited and can be of a size and length suitable for spraying the contents depending on the capacity of the pressure-resistant container.

[0030] In relation to the above-described embodiment, the present invention further discloses the following aspects.

[0031] <1> A pharmaceutical composition comprising an aerosol concentrate and a propellant, The aerosol concentrate contains the following components (A) to (C); (A) Antifungal drugs (B) a solvent, and (C) Water: 1 to 18% by mass in the aerosol concentrate Including, Component (B) is a solvent located within the Hansen solubility sphere with a radius of 12.6, whose Hansen solubility parameters are (δD=17.5, δP=15.9, δH=6.9). Contains carbon dioxide gas as a propellant. Pharmaceutical compositions.

[0032] <2> the component (A) preferably comprises one or more selected from azole antifungals, amine antifungals, and morpholine antifungals, more preferably one or more selected from imidazole antifungals, triazole antifungals, allylamine antifungals, benzylamine antifungals, thiocarbamic acid antifungals, and morpholine antifungals, even more preferably an imidazole antifungal, even more preferably one or more selected from luliconazole, lanoconazole, ketoconazole, bifonazole, miconazole, isoconazole, clotrimazole, neticonazole, sulconazole, oxiconazole, and econazole, and even more preferably one or more selected from luliconazole, lanoconazole, ketoconazole, and bifonazole; <1> The pharmaceutical composition described.

[0033] <3> The content of component (A) in the aerosol concentrate 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 15% by mass or less, more preferably 12% by mass or less, even more preferably 9% by mass or less. <1> or <2> The pharmaceutical composition described.

[0034] <4> The content of component (A) in the aerosol concentrate is preferably 0.5 to 15% by mass, more preferably 1.5 to 12% by mass, and even more preferably 3.5 to 9% by mass. <1> ~ <3> The pharmaceutical composition according to any one of the preceding claims.

[0035] <5> The component (B) preferably contains one or more selected from benzyl alcohol, 1-phenylethanol, 2-phenylethanol, 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 is in either of the following embodiments (i) and (ii): <1> ~ <4> The pharmaceutical composition according to any one of the preceding claims. (i) One or more selected from benzyl alcohol, 1-phenylethanol, 2-phenylethanol, 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 (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.

[0036] <6> When component (B) is of the embodiment (i), the content of component (B) in the aerosol concentrate is preferably 3% by mass or more, more preferably 7% by mass or more, even more preferably 14% by mass or more, even more preferably 21% 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. <5> The pharmaceutical composition described.

[0037] <7> When the component (B) is in the form of (i), the content of the component (B) in the aerosol concentrate is preferably 3 to 30% by mass, more preferably 7 to 28% by mass, even more preferably 14 to 26% by mass, and even more preferably 21 to 26% by mass. <5> or <6> The pharmaceutical composition described.

[0038] <8> When component (B) is embodiment (ii), the total content of component (B1) and component (B2) in the aerosol concentrate is preferably 7% by mass or more, more preferably 14% by mass or more, even more preferably 21% by mass or more, and preferably 90% by mass or less, more preferably 70% by mass or less, even more preferably 50% by mass or less. <5> The pharmaceutical composition described.

[0039] <9> When the component (B) is in the form (ii), the total content of the component (B1) and the component (B2) in the aerosol concentrate is preferably 7 to 90% by mass, more preferably 14 to 70% by mass, and even more preferably 21 to 50% by mass. <5> or <8> The pharmaceutical composition described.

[0040] <10> When the component (B) is of the embodiment (ii), the mass ratio of the component (B1) to the component (B2) [(B2) / (B1)] is preferably 0.5 or more, more preferably 1 or more, even more preferably 1.5 or more, and is preferably 15 or less, more preferably 11 or less, even more preferably 8 or less. <5> , <8> and <9> The pharmaceutical composition according to any one of the preceding claims.

[0041] <11> When the component (B) is of the embodiment (ii), the mass ratio of the component (B1) to the component (B2) [(B2) / (B1)] is preferably 0.5 to 15, more preferably 1 to 11, and even more preferably 1.5 to 8. <5> , and <8> ~ <10> The pharmaceutical composition according to any one of the preceding claims.

[0042] <12> the mass ratio of component (A) to component (B) [(B) / (A)] is preferably 2 or more, more preferably 3 or more, even more preferably 4 or more, and is preferably 25 or less, more preferably 18 or less, even more preferably 12 or less, even more preferably 7 or less; <1> ~ <11> The pharmaceutical composition according to any one of the preceding claims.

[0043] <13> The mass ratio of component (A) to component (B) [(B) / (A)] is preferably 2 to 25, more preferably 2 to 18, even more preferably 3 to 12, and still more preferably 4 to 7. <1> ~ <12> The pharmaceutical composition according to any one of the preceding claims.

[0044] <14> The component (C) preferably contains one or more selected from tap water, purified water, pure water, ion-exchanged water and distilled water. <1> ~ <13> The pharmaceutical composition according to any one of the preceding claims.

[0045] <15> The content of component (C) in the aerosol concentrate 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> ~ <14> The pharmaceutical composition according to any one of the preceding claims.

[0046] <16> The content of component (C) in the aerosol concentrate is preferably 1.5 to 18 mass%, more preferably 2.5 to 18 mass%, even more preferably 3.5 to 16 mass%, even more preferably 6 to 16 mass%, even more preferably 8 to 14 mass%, and even more preferably 8 to 12 mass%. <1> ~ <15> The pharmaceutical composition according to any one of the preceding claims.

[0047] <17> the mass ratio of component (C) to component (B) [(B) / (C)] is preferably 0.4 or more, more preferably 1.25 or more, even more preferably 1.5 or more, even more preferably 2 or more, and is preferably 40 or less, more preferably 16 or less, even more preferably 10 or less, even more preferably 7 or less, even more preferably 5.5 or less; <1> ~ <16> The pharmaceutical composition according to any one of the preceding claims.

[0048] <18> the mass ratio of component (C) to component (B) [(B) / (C)] is preferably 0.4 to 40, more preferably 0.4 to 16, even more preferably 1.25 to 10, even more preferably 1.5 to 7, and even more preferably 2 to 5.5; <1> ~ <17> The pharmaceutical composition according to any one of the preceding claims.

[0049] <19> Preferably, the above-mentioned composition further contains ethanol as component (D). <1> ~ <18> The pharmaceutical composition according to any one of the preceding claims.

[0050] <20> The content of component (D) in the aerosol concentrate is preferably 50% by mass or more, more preferably 54% by mass or more, and even more preferably 58% by mass or more. <19> The pharmaceutical composition described.

[0051] <21> The content of component (D) in the aerosol concentrate is preferably 50% by mass, more preferably 54% by mass or more, even more preferably 58% by mass or more, and is preferably 90% by mass or less, more preferably 87% by mass or less, even more preferably 85% by mass or less. <19> or <20> The pharmaceutical composition described.

[0052] <22> The aerosol concentrate preferably further contains one or more selected from the group consisting of a solvent other than component (B), 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> ~ <21> The pharmaceutical composition according to any one of the preceding claims.

[0053] <23> The propellant preferably contains a propellant other than carbon dioxide gas, and more preferably contains one or more selected from liquefied petroleum gas, ether, fluorocarbon, compressed gas, and chlorofluorocarbon gas. <1> ~ <22> The pharmaceutical composition according to any one of the preceding claims.

[0054] <24> The carbon dioxide content in the pharmaceutical composition is preferably 0.005% by mass or more, more preferably 0.02% by mass or more, even more preferably 0.04% by mass or more, even more preferably 0.07% by mass or more, even more preferably 0.5% by mass or more, and preferably 9% by mass or less, more preferably 7% by mass or less, even more preferably 5% by mass or less. <1> ~ <23> The pharmaceutical composition according to any one of the preceding claims.

[0055] <25> The content of carbon dioxide in the pharmaceutical composition is preferably 0.005 to 9% by mass, more preferably 0.02 to 9% by mass, even more preferably 0.04 to 7% by mass, even more preferably 0.07 to 7% by mass, and even more preferably 0.5 to 5% by mass. <1> ~ <24> The pharmaceutical composition according to any one of the preceding claims.

[0056] <26> Preferably, the above-mentioned topical preparation is an aerosol type. <1> ~ <25> The pharmaceutical composition according to any one of the preceding claims.

[0057] <27> The dosage form is preferably a propellant or a foam. <1> ~ <26> The pharmaceutical composition according to any one of the preceding claims.

[0058] <28> 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> ~ <27> The pharmaceutical composition according to any one of the preceding claims.

[0059] <29> Preferably, the composition is applied by applying an appropriate amount to a target site. <1> ~ <28> The pharmaceutical composition according to any one of the preceding claims.

[0060] <30> Preferably, the composition is applied to the target area one to several times a day. <1> ~ <29> The pharmaceutical composition according to any one of the preceding claims.

[0061] <31> The amount applied per time is preferably about 20 μL per target site. <1> ~ <30> The pharmaceutical composition according to any one of the preceding claims.

[0062] <32> Preferably, the above is contained in a pressure-resistant container. <1> ~ <31> The pharmaceutical composition according to any one of

[0063] <33> The pressure vessel is preferably made of metal or synthetic resin, more preferably made of metal selected from aluminum and tinplate, or made of synthetic resin selected from polyacetal and polycarbonate. <32> The pharmaceutical composition described. [Example]

[0064] 1. Reagents The reagents used in this example are as follows: Benzyl alcohol: Fujifilm Wako Pure Chemical Corporation 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.

[0065] 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.

[0066] Evaluation criteria 〇: The appearance is transparent △: Appearance is slightly cloudy or cloudy ×: Some residue remains and precipitate is present

[0067] (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.

[0068] (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:

[0069] 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.)

[0070] (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.

[0071] 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

[0072] Examples 1 to 7 and Comparative Example 1 Aerosol concentrates were prepared by mixing the ingredients shown in Table 1, and these were then filled into aluminum pressure-resistant containers together with carbon dioxide gas to obtain aerosol-type pharmaceutical compositions. Each pharmaceutical composition was then evaluated. The results are also shown in Table 1.

[0073] [Table 1]

[0074] Examples 8 to 14 and Comparative Examples 2 to 3 Aerosol-type 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 shown in Table 2 together with the results of Example 1.

[0075] [Table 2]

[0076] Examples 15 to 20 Aerosol-type 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 shown in Table 3 together with the results of Example 1.

[0077] [Table 3]

[0078] Examples 21 to 32 and Comparative Examples 4 to 5 Aerosol-type 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 also shown in Table 4.

[0079] [Table 4]

[0080] Examples 33 to 39 and Comparative Examples 6 to 7 Aerosol-type 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 also shown in Table 5.

[0081] [Table 5]

[0082] Tables 1 to 5 show that by adding a specific water-soluble solvent to an antifungal drug along with carbon dioxide gas and then controlling the water content within a specific range, a pharmaceutical composition that is excellent in solubility of the antifungal drug and penetration into the nail can be obtained.

Claims

1. A pharmaceutical composition comprising an aerosol concentrate and a propellant, The aerosol concentrate comprises the following components (A) to (C): (A) antifungal drug (B) a solvent, and (C) Water: 1 to 18% by mass in the aerosol concentrate Including, Component (B) is a solvent whose Hansen solubility parameters are (δD=17.5, δP=15.9, δH=6.9) and is located within a Hansen solubility sphere with a radius of 12.6, Contains carbon dioxide gas as a propellant. Pharmaceutical compositions.

2. The pharmaceutical composition according to claim 1, comprising, as component (B), one or more selected from the group consisting of benzyl alcohol, 1-phenylethanol, 2-phenylethanol, 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 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.

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

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