Azole antifungal agent-containing solution

Abstract

To provide a solution that is used as a pharmaceutical, a quasi drug or a cosmetic product or the like, contains an azole antifungal agent, and is used without washing away.SOLUTION: A solution contains (a) an azole antifungal agent, (b) a nonionic surfactant of 0.01 to 5 mass% based on the total mass of the solution, and (c) a glycyrrhizinic acid and / or a salt thereof, and the solution is used without washing away.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a liquid preparation containing an antifungal agent and used without rinsing, which is used as a medicine, a quasi-drug, a cosmetic, or the like, and more specifically, to a liquid preparation containing an azole antifungal agent and used without rinsing. [Background technology]

[0002] 2. Description of the Related Art Known examples of liquid preparations that are used as medicines, quasi-drugs, cosmetics, and the like and that are used without being washed off, i.e., so-called leave-on type liquid preparations, include dry shampoos, antiperspirants, deodorants, disinfectants, and disinfectants. On the other hand, proposed compositions containing an azole antifungal agent and a surfactant include a cleaning composition for pharmaceuticals, quasi-drugs, or cosmetics containing (A) miconazole and / or a salt thereof, (B) a specific antioxidant, and (C) a surfactant (Patent Document 1), and a topical composition containing (A) an azole antifungal agent, (B) an anti-inflammatory agent, and (C) a coconut oil fatty acid acylamino acid-based anionic surfactant (Patent Document 2).

[0003] The invention relating to a cleaning composition disclosed in Patent Document 1 aims to suppress the decrease in the content of miconazole over time (enabling miconazole to be maintained at a prescribed amount) without being affected by coexisting ingredients such as surfactants, and proposes the addition of a specific antioxidant (B) to achieve this aim. Furthermore, Patent Document 1 discloses a cleaning composition containing a large amount of surfactant (C), and does not disclose a leave-on type composition containing a small amount of surfactant. Furthermore, the invention relating to a topical composition disclosed in Patent Document 2 aims to suppress an increase in the viscosity of the formulation over time and the occurrence of white residue after drying caused by the combined use of an azole antifungal agent and a coconut oil fatty acid acyl amino acid based anionic surfactant, and also aims to suppress a decrease in the residual rate of the azole antifungal agent caused by the combined use of an azole antifungal agent and an anti-inflammatory agent. In order to achieve these aims, the invention proposes a combination of (A) an azole antifungal agent, (B) an anti-inflammatory agent, and (C) a coconut oil fatty acid acyl amino acid based anionic surfactant. Therefore, Patent Documents 1 and 2 do not propose or suggest the problem that, in a composition containing an azole antifungal agent and a surfactant, when the content of the surfactant is small, the azole antifungal agent precipitates during storage, nor do they propose or suggest a means for inhibiting the precipitation of the azole antifungal agent. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2015-168615 A [Patent Document 2] JP 2016-3199 A Summary of the Invention [Problem to be solved by the invention]

[0005] Liquid preparations that are used as medicines, quasi-drugs, cosmetics, etc. and that are not to be rinsed off are required to be low in irritation due to the manner of use, and therefore it is desirable that the amount of irritating substances (e.g., surfactants, alcohol, etc.) in the liquid preparation be as small as possible. Furthermore, surfactants are one of the causes of stickiness after use, and from the viewpoint of suppressing stickiness, it is desirable to use as little surfactant as possible.

[0006] Therefore, in order to provide a leave-on type liquid preparation containing an azole-based antifungal agent, the present inventors have developed a leave-on type liquid preparation using a nonionic surfactant that is known to be low in irritation. As a result, we found that when the content of nonionic surfactants was low, azole antifungal agents such as miconazole, which have extremely low solubility, precipitated during storage. That is, the present invention aims to provide a liquid formulation which contains a small amount of a surfactant and an effective dose of an antifungal agent, is less sticky, has low irritation, inhibits precipitation of the antifungal agent, and has excellent storage stability, and provides a liquid formulation which solves at least one of these problems. [Means for solving the problem]

[0007] As a result of intensive research to solve the above-mentioned problems, the inventors have discovered that by adding glycyrrhizinic acid and / or a salt thereof to a solution containing an azole antifungal agent and a nonionic surfactant, it is possible to inhibit precipitation of the azole antifungal agent during storage even when the content of the nonionic surfactant is small, and that storage stability can be maintained over a long period of time, thereby completing the present invention.

[0008] That is, the present invention provides: [1] A leave-on liquid preparation comprising: (a) an azole antifungal agent; (b) 0.01 to 5% by mass of a nonionic surfactant based on the total mass of the liquid preparation; and (c) glycyrrhizinic acid and / or a salt thereof; [2] The liquid preparation according to [1], which contains (b) 0.05 to 3 mass % of a nonionic surfactant based on the total mass of the liquid preparation. [3] The liquid preparation according to [1] or [2], wherein the (b) nonionic surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sterol, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene glyceryl isostearate, and polyoxyethylene glyceryl triisostearate. [4] The liquid preparation according to any one of [1] to [3], comprising (a) 0.01 to 1% by mass of an azole antifungal agent based on the total mass of the liquid preparation. [5] The liquid preparation according to any one of [1] to [4], comprising (c) 0.001 to 1% by mass of glycyrrhizinic acid and / or a salt thereof, based on the total mass of the liquid preparation. [6] The liquid preparation according to any one of [1] to [5], wherein the (a) azole antifungal agent is at least one selected from the group consisting of miconazole, clotrimazole, econazole, tioconazole, oxiconazole, fluconazole, itraconazole, ketoconazole, cloconazole, neticonazole, isoconazole, sulconazole, bifonazole, voriconazole, fosfluconazole, lanoconazole, luliconazole, and salts thereof. [7] A leave-on liquid composition comprising: (a) an azole antifungal agent; (b) 0.01 to 5% by mass of a nonionic surfactant based on the total mass of the liquid composition; and (c) glycyrrhizinic acid and / or a salt thereof. [8] (A) dissolving an azole antifungal agent in a solution containing a nonionic surfactant or a solution containing a nonionic surfactant and a polyhydric alcohol; (B) dissolving glycyrrhizinic acid and / or a salt thereof in an aqueous solvent; and (C) A step of mixing the solution prepared in (A) with the solution prepared in (B). A method for producing a liquid formulation for use without rinsing, comprising: Regarding.

[0009] Another aspect of the present invention is [9] (c) The liquid preparation according to any one of [1] to [8], wherein the glycyrrhizinic acid and / or a salt thereof is glycyrrhizinic acid and / or dipotassium glycyrrhizinate (GK2).

[10] (a) The liquid preparation according to any one of [1] to [9], wherein the azole antifungal agent is at least one selected from the group consisting of miconazole, ketoconazole, and salts thereof.

[11] (a) The liquid preparation according to any one of [1] to

[10] , wherein the azole antifungal agent is miconazole nitrate.

[12] The liquid preparation according to any one of [1] to

[11] , which contains, based on the total mass of the liquid preparation to be used without rinsing, (a) 0.01 to 0.5% by mass of an azole antifungal agent;

[13] The liquid preparation according to any one of [1] to

[12] , which contains, based on the total mass of the liquid preparation to be used without rinsing, (c) 0.01 to 0.8% by mass of glycyrrhizinic acid and / or a salt thereof;

[14] The liquid preparation according to any one of [1] to

[13] , which contains (b) 0.2 to 1 mass% of a nonionic surfactant based on the total mass of the liquid preparation to be used without rinsing.

[15] The liquid preparation according to any one of [1] to

[14] , which contains, based on the total mass of the liquid preparation to be used without rinsing, (a) 0.01 to 0.5 mass% of an azole antifungal agent, (b) 0.2 to 1 mass% of a nonionic surfactant, and (c) 0.01 to 0.8 mass% of glycyrrhizinic acid and / or a salt thereof.

[16] The liquid preparation according to any one of [1] to

[15] , which is used without rinsing, and has an azole antifungal agent:nonionic surfactant ratio of 1:1 to 60.

[17] The liquid preparation according to any one of [1] to

[16] , which is used without rinsing, and has a blending ratio of the azole antifungal agent: the nonionic surfactant: the glycyrrhizinic acid and / or a salt thereof of 1:1 to 60:0.1 to 50.

[18] A precipitation inhibitor for an azole antifungal agent, comprising glycyrrhizinic acid and / or a salt thereof as an active ingredient.

[19] An additive for reducing the amount of a nonionic surfactant required to inhibit the precipitation of an azole antifungal agent, the additive comprising glycyrrhizinic acid and / or a salt thereof as an active ingredient. Regarding. Effect of the Invention

[0010] The liquid preparation of the present invention has at least one of the following effects: inhibition of precipitation of the azole antifungal agent during storage, good storage stability, low irritation, and low stickiness, even when the content of the nonionic surfactant is small. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In this specification, "blended" is used as the same as "included" or "containing". Furthermore, "blended amount" is used as the same as "content". Furthermore, in this specification, "MCZ" means "miconazole nitrate" unless otherwise specified.

[0012] The present invention will now be described in further detail. The present invention relates to a leave-on liquid preparation comprising (a) an azole antifungal agent, (b) 0.01 to 5% by mass of a nonionic surfactant based on the total mass of the liquid preparation, and (c) glycyrrhizinic acid and / or a salt thereof.

[0013] Examples of azole antifungal agents that can be used in the present invention include miconazole, clotrimazole, econazole, tioconazole, oxiconazole, fluconazole, itraconazole, ketoconazole, cloconazole, neticonazole, isoconazole, sulconazole, bifonazole, voriconazole, fosfluconazole, lanoconazole, and lubricant. Conazole and salts thereof, such as nitrates and hydrochlorides, are included. The above-mentioned azole antifungal agents can be used alone or in combination of two or more. As the azole antifungal agent, miconazole, clotrimazole, econazole, tioconazole, oxiconazole, ketoconazole, sulconazole, bifonazole, voriconazole, fosfluconazole, lanoconazole, luliconazole, or a salt thereof is preferred, and miconazole, ketoconazole, or a salt thereof, which have a proven track record of use as topical medicines or quasi-drugs in Japan, is more preferred, miconazole or a salt thereof is even more preferred, and miconazole nitrate is particularly preferred. The amount of the azole antifungal agent to be incorporated is not particularly limited as long as it is an amount sufficient to exert its medicinal effect, and is preferably 0.01 to 1 mass%, more preferably 0.01 to 0.75 mass%, even more preferably 0.01 to 0.5 mass%, and particularly preferably 0.03 to 0.1 mass%, based on the total mass of the liquid.

[0014] Examples of the nonionic surfactant (b) used in the present invention include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbit fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene sterol, polyoxyethylene alkyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene glyceryl isostearate, and polyoxyethylene glyceryl triisostearate. The nonionic surfactants may be used alone or in combination of two or more.

[0015] Specific examples of polyoxyethylene hydrogenated castor oils include polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castor oil. Further specific examples of polyoxyethylene hydrogenated castor oils include NIKKOL HCO-20 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene hydrogenated castor oil (PEG-20 hydrogenated castor oil)), NIKKOL HCO-30 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene hydrogenated castor oil (PEG-30 hydrogenated castor oil)), NIKKOL HCO-40 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene hydrogenated castor oil (PEG-40 hydrogenated castor oil)), NIKKOL HCO-50 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene hydrogenated castor oil (PEG-50 hydrogenated castor oil)), NIKKOL HCO-60 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene hydrogenated castor oil (PEG-60 hydrogenated castor oil)), and NIKKOL HCO-80 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene hydrogenated castor oil (PEG-80 Hydrogenated castor oil), NIKKOL HCO-100 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene hydrogenated castor oil (PEG-100 hydrogenated castor oil), etc. can be used.

[0016] Specific examples of polyoxyethylene sorbitan fatty acid esters include coconut oil fatty acid sorbitan, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan monostearate (Tween 60), and polyoxyethylene sorbitan monooleate (Tween 80). More specific examples include Nonion LT-221 (manufactured by NOF Corp., polyoxyethylene sorbitan monolaurate (20E.O.)), Nonion PT-221 (manufactured by NOF Corp., Manufactured by the company, Polyoxyethylene sorbitan monopalmitate (20E.O.), nonionic Examples of usable products include OT-80 (manufactured by NOF Corporation, polyoxyethylene sorbitan monooleate (20 E.O.)), NIKKOL TL-10 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene coconut oil fatty acid sorbitan (20 E.O.)), NIKKOL TP-10EX (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene sorbitan monopalmitate (20 E.O.)), NIKKOL TS-10V (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene sorbitan monostearate), and NIKKOL TO-10V (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene sorbitan monooleate (20 E.O.)).

[0017] Specific examples of polyoxyethylene sorbitol fatty acid esters include polyoxyethylene sorbitol laurate, polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol tetraisostearate, and polyoxyethylene sorbitol pentaoleate. Further specific examples that can be used include UNIOX ST-30IS (manufactured by NOF Corporation, polyoxyethylene sorbitol tetraisostearate), UNIOX SP-40E (manufactured by NOF Corporation, polyoxyethylene sorbitol pentaoleate), NIKKOL GL-1 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene sorbitol monolaurate), NIKKOL GS-460V (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene (60) sorbitol tetrastearate), and NIKKOL GO-460V (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene (60) sorbitol tetraoleate).

[0018] Specific examples of polyglycerol fatty acid esters include polyglyceryl monolaurate, polyglyceryl monostearate, polyglyceryl isostearate, polyglyceryl distearate, polyglyceryl monooleate, polyglyceryl dioleate, and decaglyceryl monomyristate. Further specific examples that can be used include NIKKOL Decaglyn 1-MVEX (manufactured by Nikko Chemicals Co., Ltd., decaglyceryl monomyristate), NIKKOL Decaglyn 1-L (manufactured by Nikko Chemicals Co., Ltd., polyglyceryl monolaurate), NIKKOL Decaglyn 1-OVEX (manufactured by Nikko Chemicals Co., Ltd., polyglyceryl monooleate), NIKKOL Decaglyn 1-SV (manufactured by Nikko Chemicals Co., Ltd., polyglyceryl monostearate), NIKKOL Decaglyn 1-ISV (manufactured by Nikko Chemicals Co., Ltd., polyglyceryl isostearate), and NIKKOL Decaglyn 2-SV (manufactured by Nikko Chemicals Co., Ltd., polyglyceryl distearate).

[0019] Specific examples of polyoxyethylene glycerin fatty acid esters include polyoxyethylene glyceryl isostearate, polyoxyethylene glyceryl triisostearate, polyoxyethylene glyceryl laurate, polyoxyethylene glyceryl oleate, and polyoxyethylene glyceryl coconut oil fatty acid. Further specific examples that can be used include NIKKOL TMGO-15 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene glyceryl oleate), Unigly MK-207G (manufactured by NOF Corporation, polyoxyethylene coconut oil fatty acid glyceryl), Uniox GM-20IS (manufactured by NOF Corporation, polyoxyethylene glyceryl isostearate), and Uniox GT-20IS (manufactured by NOF Corporation, polyoxyethylene glyceryl triisostearate).

[0020] Specific examples of polyoxyethylene sterols include polyoxyethylene phytosulfate. sterols, polyoxyethylene phytostanols, etc. More specific examples that can be used include NIKKOL BPS-5 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene phytosterol), NIKKOL BPSH-25 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene phytostanol), and the like.

[0021] Specific examples of polyoxyethylene alkyl ethers include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene oleyl ether. More specific examples that can be used include NIKKOL BL-9EX (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene lauryl ether), NIKKOL BC-20 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene cetyl ether), and Nonion E-215 (manufactured by NOF Corporation, polyoxyethylene oleyl ether).

[0022] Specific examples of polyoxyethylene polyoxypropylene alkyl ethers include polyoxyethylene polyoxypropylene stearyl ether, polyoxyethylene polyoxypropylene decyl tetradecyl ether, and polyoxyethylene polyoxypropylene cetyl ether. Further specific examples that can be used include Unisafe 34S-23 (manufactured by NOF Corp., polyoxyethylene polyoxypropylene stearyl ether (34E.O.) (23P.O)), Unisafe 10P-8 (manufactured by NOF Corp., polyoxyethylene polyoxypropylene cetyl ether (10E.O.) (8P.O.)), and NIKKOL PEN-4620 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene polyoxypropylene decyl tetradecyl ether).

[0023] Specific examples of polyethylene glycol fatty acid esters include polyethylene glycol monolaurate, polyethylene glycol monostearate, and polyethylene glycol monooleate. Further specific examples that can be used include Nonion L-1 (manufactured by NOF Corporation, polyethylene glycol monolaurate), NIKKOL MYS-25V (manufactured by Nikko Chemicals Co., Ltd., polyethylene glycol monostearate), and EMALEX OE-6 (manufactured by Nippon Emulsion Co., Ltd., polyethylene glycol monooleate).

[0024] Examples of polyoxyethylene glyceryl isostearate that can be used include EMALEX GWIS-160 (manufactured by Nippon Emulsion Co., Ltd.) and UNIOX GM-20IS (manufactured by NOF Corporation).

[0025] Examples of polyoxyethylene glyceryl triisostearate that can be used include NIKKOL TGI-20 (manufactured by Nikko Chemicals Co., Ltd.) and UNIOX GT-20IS (manufactured by NOF Corporation).

[0026] The amount of nonionic surfactant to be blended is desirably a certain amount or less in terms of irritation and stickiness, and the blending amount is 0.01 to 5 mass%, preferably 0.05 to 3 mass%, more preferably 0.1 to 1 mass%, even more preferably 0.2 to 1 mass%, even more preferably 0.3 to 0.9 mass%, and particularly preferably 0.3 to 0.8 mass%, based on the total mass of the liquid. In another embodiment, the amount of the nonionic surfactant is preferably 0.1 to 0.6% by mass, more preferably 0.2 to 0.5% by mass, based on the total mass of the liquid preparation.

[0027] In the liquid preparation of the present invention, the blending ratio of the azole antifungal agent to the nonionic surfactant is preferably, in terms of mass ratio, from the viewpoint of sufficiently achieving inhibition of precipitation of the azole antifungal agent represented by MCZ. Preferably, the ratio is 1:1 to 60, more preferably 1:1 to 40, and even more preferably 1:1 to 20.

[0028] Preferred specific examples of the nonionic surfactant that can be used in the present invention are those described in paragraphs

[0014] to

[0025] above.

[0029] The glycyrrhizinic acid and / or salts thereof that can be used in the present invention may be either glycyrrhizinic acid or a salt of glycyrrhizinic acid used alone, or glycyrrhizinic acid may be used in combination with one or more salts of glycyrrhizinic acid, or multiple salts of glycyrrhizinic acid may be used in combination. Examples of the salt include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts. Specific examples include dipotassium glycyrrhizinate and monoammonium glycyrrhizinate. As glycyrrhizinic acid and / or its salts, glycyrrhizinic acid and / or alkali metal salts of glycyrrhizinic acid are preferred, from the viewpoint of more effectively suppressing the precipitation of azole antifungal agents, and glycyrrhizinic acid and / or dipotassium glycyrrhizinate (GK2) are more preferred, with dipotassium glycyrrhizinate (GK2) being particularly preferred.

[0030] The amount of glycyrrhizic acid and / or its salt is not particularly limited as long as it is an amount that can exhibit the effect of suppressing the precipitation of azole antifungal agents represented by MCZ, and is preferably 0.001 to 1 mass%, more preferably 0.01 to 0.8 mass%, and even more preferably 0.01 to 0.5 mass% based on the total mass of the liquid. Furthermore, since glycyrrhizic acid and / or its salt are known to have anti-inflammatory effects, a dosage that can be expected to have anti-inflammatory effects is preferable. The amount of GK2 that can be expected to have anti-inflammatory effects is, for example, 0.05 mass% to 0.5 mass%.

[0031] Here, the "precipitation suppression effect" in this specification refers to the effect of suppressing the precipitation of an azole antifungal agent and maintaining the stability of a solution containing an azole antifungal agent and a nonionic surfactant for a certain period of time. In this specification, a substance that exhibits such an effect is called a "precipitation suppressant". More specifically, the presence or absence of the precipitation suppression effect can be determined by, for example, placing a liquid agent in which an azole antifungal agent is dissolved in a sealed container and leaving it at 0°C for 2 weeks, and observing the presence or absence of precipitation of insoluble matter. The presence or absence of precipitation of insoluble matter can usually be easily determined by visual inspection.

[0032] In one embodiment of the present invention, glycyrrhizinic acid and / or its salt exhibits the effect of reducing the amount of surfactant required to suppress the precipitation of crystals of the azole antifungal agent. The amount of glycyrrhizinic acid and / or its salt to be blended is the same as the range described above.

[0033] In the liquid preparation of the present invention, the content ratio of the azole antifungal agent to glycyrrhizinic acid and / or its salt is not particularly limited as long as it is a ratio that can exhibit the effect of inhibiting precipitation of the azole antifungal agent, and is preferably 1:0.01-100, more preferably 1:0.1-50, and even more preferably 1:0.1-10, in mass ratio.

[0034] The liquid preparation of the present invention may further contain a polyhydric alcohol. The addition of the polyhydric alcohol is expected to have the effect of suppressing scattering of the powder of the azole antifungal agent during production, preventing adhesion to the container, and facilitating formulation. The polyhydric alcohol is not particularly limited as long as it does not interfere with the effects of the present invention, and examples thereof include diols. Examples of the diols include butanediol, propanediol (1,3-propanediol, 1,2-propanediol), pentanediol, hexanediol, and octanediol, and 1,2-propanediol (propylene glycol) is preferred. When diols are used, the blending amount is not particularly limited, but is preferably 0.1 to 20 mass %, more preferably 1 to 15 mass %, and even more preferably 2 to 10 mass %, based on the total mass of the liquid preparation. When a diol is used, the amount of the diol that is propylene glycol is preferably 0.1 to 15% by mass, more preferably 1 to 10% by mass, and even more preferably 2 to 9% by mass, based on the total mass of the liquid preparation.

[0035] In addition to the above-mentioned components, the liquid preparation of the present invention may contain active ingredients such as moisturizers, cooling agents, and anti-inflammatory agents, as well as ultraviolet absorbers, antioxidants, preservatives, chelating agents, pH adjusters, solubilizers, dissolution aids, stabilizers, fragrances, and colorants, within the scope of the object of the present invention. Specific examples include salicylic acid, allantoin, tranexamic acid, piroctone olamine, and isopropyl methylphenol. Furthermore, the liquid preparation of the present invention contains water as a solvent in addition to the above-mentioned components. The water used may be purified water. The amount of water contained in the liquid is usually the remainder obtained by subtracting the total amount of each of the above-mentioned components from 100% by mass. The amount of water contained in the liquid preparation of the present invention is usually 50 to 99.9% by mass, preferably 60 to 99% by mass, more preferably 70 to 99% by mass, and even more preferably 80 to 99% by mass, based on the total mass of the liquid preparation.

[0036] The liquid preparation of the present invention can be prepared, for example, by mixing the above components in water such as purified water, and dissolving the above components by heating, stirring, or other treatment as necessary. The resulting solution can be adjusted to a desired pH by adding a pH adjuster as necessary. The pH adjuster is generally an organic acid or an organic acid salt having a buffering effect, such as citric acid, sodium citrate, anhydrous citric acid, succinic acid, phosphoric acid, etc. The specific preparation method of the liquid agent of the present invention is not limited thereto, but for example, dissolve azole antifungal agent in a solution containing nonionic surfactant and optionally polyhydric alcohol, heat and stir as necessary.Apart from this, heat glycyrrhizic acid or the like dissolved in an aqueous solvent as necessary, add this to the solution in which azole antifungal agent is dissolved, and add purified water while stirring to prepare the liquid agent of each formulation.Here, "aqueous solvent" in this specification refers to a solvent containing water, and is not particularly limited thereto, but examples thereof include water, purified water, distilled water, physiological saline, phosphate buffered saline, etc., and may contain alcohol, polyhydric alcohol, etc., as long as it does not affect the effect of the present invention.

[0037] [Formulation] The leave-on liquid of the present invention is a liquid composition, and can take a known form as a pharmaceutical, quasi-drug, cosmetic, or miscellaneous goods. Among such known forms, for example, liquid, lotion, spray, foam, aerosol, wiping agent, etc. can be mentioned. Examples of wiping agents include those in which the liquid of the present invention is impregnated into a fibrous substrate, those in which the liquid of the present invention is attached, scattered, sprayed, etc. to the surface of a fibrous substrate, and those in which the liquid of the present invention is attached, scattered, sprayed, etc. to the object to be wiped. [Application] The leave-on liquid preparation of the present invention can be used, for example, in the fields of medicines, quasi-drugs, and cosmetics as a dry shampoo, antiperspirant, deodorant, medicated lotion, or germicide, or in the field of sundries as a deodorant or germicide. In particular, the liquid preparation of the present invention is preferably used as a deodorant, germicide, or the like because of its antifungal effect. EXAMPLES

[0038] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

[0039] In the descriptions in the examples, the abbreviations have the following meanings. MCZ: Miconazole nitrate GK2: Dipotassium glycyrrhizinate PG: Propylene glycol

[0040] Test Example 1: Effect of GK2 and nonionic surfactants on the solubility of MCZ A liquid formulation was prepared so that the total mass was 100% with the blend amounts shown in Table 1. Specifically, the azole antifungal agent was dissolved in a solution containing a nonionic surfactant and, if necessary, PG, and heated to about 80°C as necessary, and stirred with a stirrer to confirm complete dissolution. Separately, a solution containing glycyrrhizic acid and the like dissolved in water was heated to about 80°C as necessary, and after confirming complete dissolution, this was added to the solution containing the azole antifungal agent. Purified water was further added while stirring to prepare a liquid formulation of each formulation. The liquid formulation to be used in the evaluation test was transferred to a sealed glass container, and after visually confirming that all components were completely dissolved, the sealed container was left in an environment of 0°C for a specified period of time to observe whether precipitation of the azole antifungal agent was observed. The presence or absence of precipitation of the azole antifungal agent MCZ or ketoconazole was judged according to the following criteria. ◯: No insoluble matter was precipitated. △: A small amount of insoluble matter was precipitated. ×: Insoluble matter was precipitated. The amount of each component in the table is expressed as mass % based on the total mass of the liquid preparation.

[0041] [Table 1]

[0042] Results: By adding GK2, the precipitation of MCZ could be suppressed with a small amount of nonionic surfactant. In other words, it was found that the MCZ-containing liquid formulation can be stored stably for a long period of time by adding small amounts of nonionic surfactant and GK2.

[0043] Test Example 2: Effect of the amount of glycyrrhizinic acid and GK2 According to the method of Test Example 1, etc., a liquid preparation having the composition shown in Table 2 was prepared, and the presence or absence of MCZ precipitation in the liquid preparation was observed for a predetermined period of time and judged in the same manner as in Test Example 1.

[0044] [Table 2]

[0045] Results: Even with a small amount of GK2, MCZ precipitation was suppressed. Similarly, even with a small amount of glycyrrhizinic acid, MCZ precipitation was suppressed. Furthermore, after observing for two months, the same results were obtained as after two weeks.

[0046] Test Example 3: Effect of the type of nonionic surfactant According to the method of Test Example 1, etc., a liquid formulation was prepared in the blending amounts shown in Tables 3-1 and 3-2, and then the presence or absence of MCZ precipitation in the liquid formulation was observed for a specified period of time and judged in the same manner as in Test Example 1.

[0047] [Table 3] [Table 4]

[0048] Results: Regardless of the type of nonionic surfactant, the MCZ precipitation suppression effect was observed for 12 types of nonionic surfactants when GK2 was added (Table 3-1). The results were similar to those obtained after two weeks.

[0049] Test Example 4: Effects of various anti-inflammatory ingredients on the precipitation inhibition effect of MCZ In accordance with the method of Test Example 1, etc., a liquid formulation was prepared in the amount shown in Table 4, and then the presence or absence of precipitation of miconazole in the liquid was observed for a specified period of time and judged in the same manner as in Test Example 1.

[0050] [Table 5]

[0051] Results: It was found that the effect of GK2 in suppressing MCZ precipitation was not affected by the presence or absence of propylene glycol (PG) (Examples 21 and 22). In addition, even when PG was used instead of GK2, MCZ precipitation could not be suppressed (Comparative Example 21). Even when anti-inflammatory ingredients such as tranexamic acid and allantoin were added in place of GK2, the deposition of miconazole could not be suppressed (Comparative Examples 19 and 20). Further, as a result of separate investigation, it was shown that the MCZ precipitation suppression effect cannot be obtained by only adjusting the pH of the liquid, and it was found that this is an action specific to glycyrrhizinic acid and / or its salts. In other words, it was suggested that glycyrrhizinic acid and / or its salts have a specific MCZ precipitation suppression effect that is synergistic with the nonionic surfactant.

[0052] Test Example 5: Effect of the type of azole antifungal agent According to the method of Test Example 1, etc., a liquid formulation was prepared in the blend amount shown in Table 5, and then the presence or absence of precipitation of MCZ or ketoconazole in the liquid formulation was observed for a specified period of time and judged in the same manner as in Test Example 1.

[0053] [Table 6]

[0054] Results: The precipitation suppression effect of GK2 was observed for ketoconazole as well as MCZ (Example 23). In addition, the results of the observation for two months were similar to those of two weeks. Therefore, it was suggested that the precipitation of azole antifungal agents can be suppressed by adding GK2 regardless of the type of azole antifungal agent. In other words, it was suggested that the liquid preparation containing azole antifungal agents can be stably stored for a long period of time by adding GK2, even under conditions where the amount of nonionic surfactant is small.

Claims

1. A liquid preparation for use without rinsing, (a) at least one azole antifungal agent selected from the group consisting of miconazole, ketoconazole, and salts thereof, (b) 0.01 to less than 5% by mass of a nonionic surfactant based on the total mass of the liquid preparation, and (c) glycyrrhizinic acid and / or a salt thereof, Contains only nonionic surfactants as surfactants, the content ratio of the azole antifungal agent to glycyrrhizinic acid and / or a salt thereof (azole antifungal agent:glycyrrhizinic acid and / or a salt thereof) is 1:0.01 to 100 by mass; Liquid formulation (however, the liquid formulation does not contain a keratinase activity inhibitor containing one or more active ingredients selected from the group consisting of hop extract, Acacia extract, Quillaja quillago bark extract, Loquat leaf extract, Elm extract, Sasa kumazasa extract and tannic acid).

2. 2. The solution of claim 1, comprising (b) 0.05 to 3% by weight of a nonionic surfactant, based on the total weight of the solution.

3. The liquid preparation according to claim 1 or 2, wherein the (b) nonionic surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sterol, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene glyceryl isostearate, and polyoxyethylene glyceryl triisostearate.

4. The liquid preparation according to any one of claims 1 to 3, comprising, based on the total mass of the liquid preparation, (a) 0.01 to 1 mass% of an azole antifungal agent, and (c) 0.001 to 1 mass% of glycyrrhizinic acid and / or a salt thereof.

5. A liquid composition for use without rinsing, comprising: (a) at least one azole antifungal agent selected from the group consisting of miconazole, ketoconazole, and salts thereof, (b) 0.01 to less than 5% by mass of a nonionic surfactant based on the total mass of the liquid composition, and (c) glycyrrhizinic acid and / or a salt thereof, Contains only nonionic surfactants as surfactants, the content ratio of the azole antifungal agent to glycyrrhizinic acid and / or a salt thereof (azole antifungal agent:glycyrrhizinic acid and / or a salt thereof) is 1:0.01 to 100 by mass; A liquid composition (however, the liquid composition does not contain a keratinase activity inhibitor containing one or more active ingredients selected from the group consisting of hop extract, Acacia japonica extract, Quillaja quillaris bark extract, Loquat leaf extract, Eleuthera japonica extract, Kumazasa extract and tannic acid).

6. A method for producing a liquid preparation for use without rinsing, comprising the steps of: (a) at least one azole antifungal agent selected from the group consisting of miconazole, ketoconazole, and salts thereof, (b) 0.01 to less than 5% by mass of a nonionic surfactant based on the total mass of the liquid preparation, and (c) glycyrrhizinic acid and / or a salt thereof, Contains only nonionic surfactants as surfactants, the content ratio of the azole antifungal agent to glycyrrhizinic acid and / or a salt thereof (azole antifungal agent:glycyrrhizinic acid and / or a salt thereof) is 1:0.01 to 100 by mass; A method for producing a liquid formulation, (A) dissolving an azole antifungal agent in a solution containing a nonionic surfactant or a solution containing a nonionic surfactant and a polyhydric alcohol; (B) dissolving glycyrrhizinic acid and / or a salt thereof in an aqueous solvent; and (C) A step of mixing the solution prepared in (A) with the solution prepared in (B). A method for producing a liquid preparation comprising the steps of: (provided that the liquid preparation does not contain a keratinase activity inhibitor containing one or more active ingredients selected from the group consisting of hop extract, Acacia japonica extract, Quillaja quillaris bark extract, Loquat leaf extract, Eleuthera japonica extract, Kumazasa extract and tannic acid).