Azole antifungal agent-containing liquid preparation

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 agent containing an antifungal agent and used without being washed away, such as a pharmaceutical, quasi-drug, or cosmetic, and more particularly to a liquid agent containing an azole antifungal agent and used without being washed away.

Background Art

[0002] As liquid agents used without being washed away, such as pharmaceuticals, quasi-drugs, or cosmetics, so-called leave-on type liquid agents, for example, dry shampoos, antiperspirants, deodorants, bactericides, disinfectants, etc. are known. On the other hand, as a composition containing an azole antifungal agent and a surfactant, a cleaning composition for pharmaceuticals, quasi-drugs, or cosmetics containing (A) miconazole and / or its salt, (B) a specific antioxidant, and (C) a surfactant (Patent Document 1), and an external composition containing (A) an azole antifungal agent, (B) an anti-inflammatory agent, and (C) a coconut oil fatty acid acyl amino acid-based anionic surfactant (Patent Document 2) have been proposed.

[0003] The invention related to the cleaning composition disclosed in Patent Document 1 aims to suppress the decrease in the content of miconazole over time (able to be maintained at a predetermined amount containing miconazole) regardless of coexisting components such as surfactants, and in order to achieve such an object, it is proposed to add (B) a specific antioxidant. Further, Patent Document 1 is a cleaning composition with a large amount of (C) surfactant blended, and a composition of the non-rinse type containing a small amount of surfactant is not disclosed. In addition, the invention related to the external composition disclosed in Patent Document 2 aims to suppress the increase in formulation viscosity over time and the occurrence of white residue after drying by using a combination of an azole antifungal agent and a coconut oil fatty acid acyl amino acid-based anionic surfactant, and also to suppress the decrease in the residual rate of the azole antifungal agent by using a combination of the azole antifungal agent and an anti-inflammatory agent. To achieve such an object, 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 is proposed. Therefore, Patent Documents 1 and 2 do not propose nor suggest the problem that the azole antifungal agent precipitates during storage when the content of the surfactant is small in a composition containing an azole antifungal agent and a surfactant, nor do they propose or suggest means for suppressing the precipitation of the azole antifungal agent.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] For liquids that are used as pharmaceuticals, quasi-drugs, cosmetics, etc. and are used without being washed off, low irritation is required due to their usage mode. Therefore, it is desirable that the amount of irritating substances (e.g., surfactants, alcohols, etc.) in the liquid is as small as possible. In addition, surfactants are one of the causes of stickiness after use, and from the viewpoint of suppressing stickiness, it is desirable that the amount of surfactant used is as small as possible.

[0006] Therefore, in order to provide a leave-on type liquid containing an azole antifungal agent, the present inventors used a nonionic surfactant known to be low in irritation to provide a leave-on type We studied the liquid agent that can be used for [purpose not specified]. As a result, when the content of the nonionic surfactant is low, there is a problem that azole antifungal agents such as miconazole, which have extremely low solubility during storage, will precipitate. That is, an object of the present invention is to provide a formulation of a liquid agent that contains a small amount of surfactant and an effective dose of an antifungal agent, has little stickiness, low irritation, suppresses the precipitation of the antifungal agent, and has excellent storage stability, and to provide a formulation of a liquid agent that solves at least one of these problems.

Means for Solving the Problems

[0007] As a result of intensive studies to solve the above problems, the inventors of the present invention found that by blending glycyrrhizic acid and / or its salt in a solution containing an azole antifungal agent and a nonionic surfactant, even when the content of the nonionic surfactant is small, the precipitation of the azole antifungal agent during storage can be suppressed, and it was found that the storage stability over a long period can be maintained, thus completing the present invention.

[0008] That is, the present invention is [1] A liquid agent for use without being washed away, comprising (a) an azole antifungal agent, (b) a nonionic surfactant in an amount of 0.01 to 5% by mass based on the total mass of the liquid agent, and (c) glycyrrhizic acid and / or its salt. [2] The liquid agent according to [1], comprising (b) a nonionic surfactant in an amount of 0.05 to 3% by mass based on the total mass of the liquid agent. [3] The liquid agent 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 agent according to any one of [1] to [3], which contains (a) 0.01 to 1% by mass of an azole antifungal agent based on the total mass of the liquid agent. [5] The liquid agent according to any one of [1] to [4], which contains (c) 0.001 to 1% by mass of glycyrrhizic acid and / or its salt based on the total mass of the liquid agent. [6] The liquid agent 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, croconazole, neticonazole, isoconazole, sulconazole, bifonazole, voriconazole, phosphofluconazole, lanoconazole, luliconazole, and their salts. [7] A liquid composition for use without rinsing, which contains (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) glycyrrhizic acid and / or its salt. [8] A method for producing a liquid agent for use without rinsing, comprising: (A) a step of dissolving an azole antifungal agent in a solution containing a nonionic surfactant, or a solution containing a nonionic surfactant and a polyhydric alcohol; (B) a step of dissolving glycyrrhizic acid and / or its salt in an aqueous solvent; and (C) a step of mixing the solution prepared in (A) and the solution prepared in (B). Regarding

[0009] As another aspect of the present invention, [9](c) The glycyrrhizic acid and / or its salt is glycyrrhizic acid and / or dipotassium glycyrrhizinate (GK2), the liquid preparation according to any one of [1] to [8].

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

[11] (a) The azole antifungal agent is miconazole nitrate, the liquid preparation according to any one of [1] to

[10] .

[12] Based on the total mass of the liquid preparation used without rinsing, (a) containing 0.01 to 0.5% by mass of an azole antifungal agent, the liquid preparation according to any one of [1] to

[11] ;

[13] Based on the total mass of the liquid preparation used without rinsing, (c) containing 0.01 to 0.8% by mass of glycyrrhizic acid and / or its salt, the liquid preparation according to any one of [1] to

[12] .

[14] Based on the total mass of the liquid preparation used without rinsing, (b) containing 0.2 to 1% by mass of a nonionic surfactant, the liquid preparation according to any one of [1] to

[13] .

[15] Based on the total mass of the liquid preparation used without rinsing, (a) containing 0.01 to 0.5% by mass of an azole antifungal agent, (b) containing 0.2 to 1% by mass of a nonionic surfactant, (c) containing 0.01 to 0.8% by mass of glycyrrhizic acid and / or its salt, the liquid preparation according to any one of [1] to

[14] .

[16] In the liquid preparation used without rinsing, the mixing ratio of the azole antifungal agent to the nonionic surfactant is 1:1 to 60, the liquid preparation according to any one of [1] to

[15] .

[17] In the liquid preparation used without rinsing, the mixing ratio of the azole antifungal agent to the nonionic surfactant to glycyrrhizic acid and / or its salt is 1:1 to 60:0.1 to 50, the liquid preparation according to any one of [1] to

[16] .

[18] An inhibitor for precipitation of azole antifungal agents, which contains glycyrrhizic acid and / or a salt thereof as an active ingredient,

[19] An additive for reducing the blending amount of a nonionic surfactant, which is necessary for inhibiting precipitation of azole antifungal agents and contains glycyrrhizic acid and / or a salt thereof as an active ingredient, relates to the above.

Effects of the Invention

[0010] The liquid preparation of the present invention has at least one or more effects such that precipitation of azole antifungal agents is suppressed during storage, the storage stability is good, the irritation is low, and the stickiness is low, even when the content of the nonionic surfactant is small.

Modes for Carrying Out the Invention

[0011] In this specification, "blend" is used in the same meaning as "contain" or "include". Also, "blending amount" is used in the same meaning as "content". Further, in this specification, unless otherwise specified, "MCZ" shall mean "miconazole nitrate".

[0012] The present invention will be described in more detail below. The present invention relates to a liquid preparation for use without being washed away, which contains (a) an azole antifungal agent, (b) a nonionic surfactant in an amount of 0.01 to 5% by mass based on the total mass of the liquid preparation, and (c) glycyrrhizic acid and / or a salt thereof.

[0013] Examples of the azole antifungal agent that can be used in the present invention include miconazole, clotrimazole, econazole, tioconazole, oxiconazole, fluconazole, itraconazole, ketoconazole, croconazole, neticonazole, isoconazole, sulconazole, bifonazole, voriconazole, posaconazole, lanoconazole, luliconazole and salts thereof. Examples of the salts include nitrates, hydrochlorides and the like. The above salts include nitrates, hydrochlorides and the like. The above azole antifungal agent can be used alone or in combination of two or more kinds. Examples of the azole antifungal agent include miconazole, clotrimazole, econazole, tioconazole, oxiconazole, ketoconazole, sulconazole, bifonazole, voriconazole, phosphofluconazole, lanoconazole, luliconazole or salts thereof. Among them, miconazole, ketoconazole or salts thereof, which have been used as external pharmaceuticals or quasi-drugs in Japan, are more preferable, miconazole or a salt thereof is even more preferable, and miconazole nitrate is particularly preferable. The blending amount of the azole antifungal agent is not particularly limited as long as it is an amount sufficient to exhibit its drug efficacy, and is preferably 0.01 to 1% by mass, more preferably 0.01 to 0.75% by mass, still more preferably 0.01 to 0.5% by mass, and particularly preferably 0.03 to 0.1% by mass based on the total mass of the liquid preparation.

[0014] Examples of the nonionic surfactant (b) used in the present invention include 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, polyoxyethylene glyceryl triisostearate and the like. The above nonionic surfactant can be used alone or in combination of two or more kinds.

[0015] Specific examples of polyoxyethylene hydrogenated castor oil include, for example, 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, polyoxyethylene(100) hydrogenated castor oil, and the like. More specific examples include, as polyoxyethylene hydrogenated castor oil, 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)), 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)), and the like can be used.

[0016] Specific examples of polyoxyethylene sorbitan fatty acid esters include, for example, sorbitan coconut fatty acid, polyoxyethylene sorbitan monolaurate (Tween20), polyoxyethylene sorbitan monopalmitate (Tween40), polyoxyethylene sorbitan monostearate (Tween60), and polyoxyethylene sorbitan monooleate (Tween80), and the like. More specific examples include Nonion LT-221 (manufactured by NOF Corporation, polyoxyethylene sorbitan monolaurate (20 E.O.)), Nonion PT-221 (manufactured by NOF Corporation Company-made, polyoxyethylene sorbitan monopalmitate (20 E.O.), nonionic 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), NIKKOL TO-10V (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene sorbitan monooleate (20 E.O.)), etc. can be used.

[0017] Specific examples of polyoxyethylene sorbitol fatty acid esters include, for example, polyoxyethylene sorbitol laurate, polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol tetraisostearate, and polyoxyethylene sorbitol pentaoleate. More specific examples 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), NIKKOL GO-460V (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene (60) sorbitol tetraoleate), etc. can be used.

[0018] Specific examples of polyglycerol fatty acid esters include, for example, polyglyceryl monolaurate, polyglyceryl monostearate, polyglyceryl isostearate, polyglyceryl distearate, polyglyceryl monooleate, polyglyceryl dioleate, decaglyceryl monomyristate, and the like. More specific examples 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), NIKKOL Decaglyn 2-SV (manufactured by Nikko Chemicals Co., Ltd., polyglyceryl distearate), and the like can be used.

[0019] Specific examples of polyoxyethylene glycerol fatty acid esters include, for example, polyoxyethylene glyceryl isostearate, polyoxyethylene glyceryl triisostearate, polyoxyethylene glyceryl laurate, polyoxyethylene glyceryl oleate, polyoxyethylene glyceryl coconut oil fatty acid, and the like. More specific examples include NIKKOL TMGO-15 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene glyceryl oleate), UNIGLY MK-207G (manufactured by NOF Corporation, polyoxyethylene glyceryl coconut oil fatty acid), UNIOX GM-20IS (manufactured by NOF Corporation, polyoxyethylene glyceryl isostearate), UNIOX GT-20IS (manufactured by NOF Corporation, polyoxyethylene glyceryl triisostearate), and the like can be used.

[0020] Specific examples of polyoxyethylene sterol include, for example, polyoxyethylene phyto Examples include sterols, polyoxyethylene phytosterols, and the like. More specific examples 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, which can be used.

[0021] Specific examples of polyoxyethylene alkyl ethers include, for example, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene oleyl ether. More specific examples 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), Nonion E-215 (manufactured by NOF Corporation, polyoxyethylene oleyl ether), and the like, which can be used.

[0022] Specific examples of polyoxyethylene polyoxypropylene alkyl ethers include, for example, polyoxyethylene polyoxypropylene stearyl ether, polyoxyethylene polyoxypropylene decyltetradecyl ether, and polyoxyethylene polyoxypropylene cetyl ether. More specific examples include Unisafe 34S-23 (manufactured by NOF Corporation, polyoxyethylene polyoxypropylene stearyl ether (34 E.O.) (23 P.O.)), Unisafe 10P-8 (manufactured by NOF Corporation, polyoxyethylene polyoxypropylene cetyl ether (10 E.O.) (8 P.O.)), NIKKOL PEN-4620 (manufactured by Nikko Chemicals Co., Ltd., polyoxyethylene polyoxypropylene decyltetradecyl ether), and the like, which can be used.

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

[0024] As polyoxyethylene glyceryl isostearate, EMALEX GWIS-160 (manufactured by Nippon Emulsion Co., Ltd.), Unionox GM-20IS (manufactured by NOF Corporation), etc. can be used.

[0025] As polyoxyethylene glyceryl triisostearate, NIKKOL TGI-20 (manufactured by Nikko Chemicals Co., Ltd.), Unionox GT-20IS (manufactured by NOF Corporation), etc. can be used.

[0026] The blending amount of the nonionic surfactant is desirably below a certain amount in terms of irritation and stickiness. The blending amount is 0.01 to 5% by mass, preferably 0.05 to 3% by mass, more preferably 0.1 to 1% by mass, still more preferably 0.2 to 1% by mass, still more preferably 0.3 to 0.9% by mass, and particularly preferably 0.3 to 0.8% by mass, based on the total mass of the liquid preparation. In another aspect, the blending 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, 1:1 to 60, more preferably 1:1 to 40, still more preferably 1:1 to 20, in order to sufficiently achieve the precipitation inhibition of the azole antifungal agent typified by MCZ. Preferably, it is 1:1 to 60, more preferably 1:1 to 40, still more preferably 1:1 to 20.

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

[0014] to

[0025] .

[0029] As for glycyrrhizic acid and / or its salts that can be used in the present invention, either glycyrrhizic acid or a salt of glycyrrhizic acid may be used alone, or glycyrrhizic acid and one or more salts of glycyrrhizic acid may be used in combination, or a plurality of salts of glycyrrhizic acid may be used in combination. Examples of the salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, etc. Specifically, dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc. are included. As glycyrrhizic acid and / or its salts, glycyrrhizic acid and / or an alkali metal salt of glycyrrhizic acid are preferable in that they can more effectively suppress the precipitation of azole antifungal agents, glycyrrhizic acid and / or dipotassium glycyrrhizate (GK2) are more preferable, and especially dipotassium glycyrrhizate (GK2) is preferable.

[0030] The blending amount of glycyrrhizic acid and / or its salts is not particularly limited as long as it can exhibit the effect of suppressing the precipitation of azole antifungal agents typified by MCZ. Based on the total mass of the liquid preparation, it is preferably 0.001 to 1% by mass, more preferably 0.01 to 0.8% by mass, and still more preferably 0.01 to 0.5% by mass. Furthermore, since glycyrrhizic acid and / or its salts are known to have an anti-inflammatory effect, a dosage at which an anti-inflammatory effect can be expected is preferable. As the blending amount at which an anti-inflammatory effect is expected, for example, in the case of GK2, it is 0.05% to 0.5% by mass.

[0031] Here, the "precipitation inhibition effect" in this specification refers to the effect of suppressing the precipitation of azole antifungal agents and maintaining the stability of a solution containing azole antifungal agents and nonionic surfactants over a certain period. In this specification, a substance showing such an effect is referred to as a "precipitation inhibitor". More specifically, the presence or absence of the precipitation inhibition effect can be determined, for example, by observing the presence or absence of precipitation of insoluble matter when a liquid preparation in which an azole antifungal agent is dissolved is placed in a sealed container and left at 0°C for 2 weeks. The presence or absence of precipitation of insoluble matter can usually be easily determined visually.

[0032] Also, as one aspect of the present invention, glycyrrhizic acid and / or its salts exhibit the effect of reducing the amount of surfactant necessary for suppressing the precipitation of crystals of azole antifungal agents. The blending amount of glycyrrhizic acid and / or its salts is the same as the range described above.

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

[0034] The liquid preparation of the present invention may further contain a polyhydric alcohol. The addition of the polyhydric alcohol can be expected to have effects such as suppressing the scattering of the powder of the azole antifungal agent during production and 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 above diols include butanediol, propanediol (1,3-propanediol, 1,2-propanediol), pentanediol, hexanediol, or octanediol, etc., and 1,2-propanediol (propylene glycol) is preferred. When using diols, the blending amount is not particularly limited, but based on the total mass of the liquid preparation, it is preferably 0.1 to 20% by mass, more preferably 1 to 15% by mass, and still more preferably 2 to 10% by mass. When using diols and the diol is propylene glycol, the blending amount is preferably 0.1 to 15% by mass, more preferably 1 to 10% by mass, and still more preferably 2 to 9% by mass based on the total mass of the liquid preparation.

[0035] In addition to the above-described components, the liquid preparation of the present invention can also contain, within a range not impairing the object of the present invention, active ingredients such as humectants, cooling agents, anti-inflammatory agents, ultraviolet absorbers, antioxidants, preservatives, chelating agents, pH adjusters, solubilizers, solubilizing aids, stabilizers, fragrances, dyes, etc. Specifically, salicylic acid, allantoin, tranexamic acid, piroctone olamine, isopropylmethylphenol, etc. can be mentioned. Furthermore, the liquid preparation of the present invention contains water as a solvent in addition to the above-described components. As the water, purified water can be used. The amount of water contained in the liquid preparation is usually the remainder obtained by subtracting the total amount of the above-described 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 still 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 performing treatments such as heating and stirring as necessary to dissolve the above components. The obtained liquid preparation can be adjusted to a desired pH by adding a pH adjuster as necessary. As the pH adjuster, organic acids and organic acid salts having a buffering action are generally used. Specifically, for example, citric acid, sodium citrate, anhydrous citric acid, succinic acid, phosphoric acid, etc. can be used. As a specific preparation method of the liquid preparation of the present invention, although not limited thereto, for example, an azole antifungal agent is dissolved in a solution containing a nonionic surfactant and, if desired, a polyhydric alcohol, heated if necessary, and stirred. Separately, a solution in which glycyrrhizic acid or the like is dissolved in an aqueous solvent is heated if necessary, added to the solution in which the azole antifungal agent is dissolved, and purified water is added while stirring to prepare the liquid preparation of each formulation. Here, the "aqueous solvent" in the present specification refers to a solvent containing water, and is not particularly limited. For example, water, purified water, distilled water, physiological saline, phosphate buffered saline, etc. may be mentioned, and alcohol, polyhydric alcohol, etc. may be contained as long as the effects of the present invention are not affected.

[0037] [Formulation form] The non-rinse type liquid preparation of the present invention is a liquid composition, and can take a known form as a pharmaceutical product, quasi-drug, cosmetic or miscellaneous goods. Among such known forms, for example, a liquid preparation, a lotion, a spray, a foam preparation, an aerosol, a cleansing agent, etc. can be mentioned. As the cleansing agent, for example, those in which the liquid preparation of the present invention is impregnated in a fibrous substrate, those in which the liquid preparation of the present invention is adhered, sprayed, or atomized on the surface of a fibrous substrate, those in which the liquid preparation of the present invention is adhered, sprayed, or atomized on the object to be cleaned, etc. can be mentioned. [Use] The non-rinse type liquid preparation of the present invention has uses such as dry shampoo, antiperspirant, deodorant, medicinal lotion or disinfectant in the fields of pharmaceuticals, quasi-drugs or cosmetics, or uses such as deodorant or disinfectant in the field of miscellaneous goods. In particular, the liquid preparation of the present invention is preferably applied to deodorants, disinfectants, etc. due to its antifungal effect.

Example

[0038] Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples.

[0039] In the description in the examples, each abbreviation means the following. MCZ: Miconazole nitrate GK2: Dipotassium Glycyrrhizinate PG: Propylene Glycol

[0040] Test Example 1: Effects of GK2 and Nonionic Surfactant on the Solubility of MCZ A liquid preparation was prepared so that the total amount was 100% by mass according to the formulation amounts described in Table 1. Specifically, the azole antifungal agent was dissolved in a solution containing a nonionic surfactant and optionally PG, heated to about 80 °C if necessary, and stirred using a stirrer to confirm complete dissolution. Separately, a solution of glycyrrhizic acid or the like dissolved in water was heated to about 80 °C if necessary, and after confirming complete dissolution, this was added to the solution in which the azole antifungal agent was dissolved. Further, purified water was added while stirring to prepare a liquid preparation for each formulation. The liquid preparation used for the evaluation test was transferred to a glass-sealed container, and after visually confirming that all components were completely dissolved, the sealed container was placed in an environment at 0 °C for a predetermined period to observe whether precipitation of the azole antifungal agent was observed. The presence or absence of precipitation of the azole antifungal agents MCZ or ketoconazole was determined according to the following criteria. 〇: No insoluble matter was precipitated. △: A small amount of insoluble matter was precipitated. ×: Insoluble matter was precipitated. Note that the amounts of each component in the table represent mass % based on the total mass of the liquid preparation.

[0041]

Table 1

[0042] Result: By incorporating GK2, precipitation of MCZ could be suppressed with a small amount of nonionic surfactant. That is, it was found that the MCZ-containing liquid preparation could be stably stored for a long period by incorporating a small amount of nonionic surfactant and GK2.

[0043] Test Example 2: Influence of the Blending Amounts of Glycyrrhizic Acid and GK2 According to the method of Test Example 1 and the like, a liquid preparation having the composition shown in Table 2 was prepared, and the presence or absence of precipitation of MCZ in the liquid preparation was observed for a predetermined period, and the determination was made in the same manner as in Test Example 1.

[0044] [Table 2]

[0045] Result: Even when the blending amount of GK2 was small, precipitation of MCZ could be suppressed. Glycyrrhizic acid also suppressed the precipitation of MCZ in a small amount in the same manner. Further, as a result of observing for two months, the same results as those for two weeks were obtained.

[0046] Test Example 3: Influence of the type of nonionic surfactant According to the method of Test Example 1 and the like, a liquid preparation was prepared with the blending amounts described in Tables 3-1 and 3-2, and then the presence or absence of precipitation of MCZ in the liquid preparation was observed for a predetermined period, and the determination was made in the same manner as in Test Example 1.

[0047] [Table 3] [Table 4]

[0048] Result: Regardless of the type of nonionic surfactant, for 12 nonionic surfactants, an effect of suppressing MCZ precipitation by blending GK2 was recognized (Table 3-1). Further, as a result of observing for two months the same results as those for two weeks were obtained.

[0049] Test Example 4: Effects of various anti-inflammatory components on the MCZ precipitation inhibitory effect According to the method of Test Example 1 and the like, a liquid preparation was prepared with the blending amounts described in Table 4, and then the presence or absence of precipitation of miconazole in the liquid preparation was observed for a predetermined period, and the determination was made in the same manner as in Test Example 1.

[0050] [Table 5]

[0051] Result: It was found that the effect of suppressing the precipitation of MCZ by the addition of GK2 was not affected by the presence or absence of propylene glycol (PG) (Examples 21 and 22). Also, even when only PG was added instead of GK2, the precipitation of MCZ could not be suppressed (Comparative Example 21). Even when tranexamic acid or allantoin, which are anti-inflammatory components, were added instead of GK2, the precipitation of miconazole could not be suppressed (Comparative Examples 19 and 20). As a result of further separate investigations, it was shown that the effect of suppressing the precipitation of MCZ could not be obtained only by adjusting the pH of the solution, and it was found that this is a specific action of glycyrrhizic acid and / or its salts. In other words, it was suggested that glycyrrhizic acid and / or its salts have a synergistic and specific effect of suppressing the precipitation of MCZ with nonionic surfactants.

[0052] Test Example 5: Influence of the type of azole antifungal agent According to the method of Test Example 1 et al., after preparing a solution with the compounding amounts described in Table 5, the presence or absence of precipitation of MCZ or ketoconazole in the solution was observed for a predetermined period, and the determination was made in the same manner as in Test Example 1.

[0053]

Table 6

[0054] Result: For ketoconazole as well as for MCZ, an effect of suppressing precipitation by GK2 was observed (Example 23). Also, as a result of observing for two months, the same results as those for two weeks were obtained. 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. That is, it was suggested that by adding GK2, a solution containing an azole antifungal agent can be stably stored for a long period 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).

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