JP7046612B2 - External composition - Google Patents

Description

The present invention relates to an external composition. More specifically, it relates to an external composition containing an antifungal agent.

Antifungal agents that inhibit the growth of fungi are widely used to treat, prevent, and ameliorate various diseases and symptoms caused by fungal infections. Generally, an external composition containing an antifungal agent is used, and in particular, a preparation suitable for topical application to each is used.

It is necessary for pharmaceutical products to maintain the stability of the active ingredient for a specified period of time, and it is also important to maintain the stability as a pharmaceutical product. After the compounded ingredient is formulated, it becomes unstable over time under various environmental conditions (for example, under high temperature, low temperature, exposure, high humidity environment, etc.), and when the content is significantly reduced, the ingredient becomes There is concern that the desired effect will not be achieved. In particular, in a pharmaceutical composition in which the dose of a compounding ingredient should be strictly controlled, a higher degree of pharmaceutical stability is required (Patent Document 1). Further, in order for this active ingredient to exert a certain desired effect, it is important to improve the stability of the pharmaceutical product and to reduce the change in properties in the manufacturing process and the market distribution process as much as possible.

Japanese Unexamined Patent Publication No. 2015-10059

However, the effective means for keeping the external composition containing the antifungal agent stable is not fully known.

The present invention has been made in view of the above, and an object of the present invention is to provide a stable external composition containing an antifungal agent.

In view of the above problems, the present inventors have conducted diligent studies and found that the coexistence of a certain concentration of salicylic acid or a salt thereof and an antifungal agent imparts stability to the external composition. The invention was completed.

That is, the present invention provides the external composition listed below.
Item 1.
An external composition containing (A) an antifungal agent and (B) salicylic acid and / or a salt thereof in an amount of 1 to 20% by mass based on the total amount of the composition.
Item 2.
Item 2. The external composition according to Item 1, wherein the (A) antifungal agent is an amine-based antifungal agent.
Item 3.
Item 3. The external composition according to Item 1 or Item 2, wherein the (A) antifungal agent is at least one selected from the group consisting of terbinafine and a salt thereof.
Item 4.
Item 2. The external composition according to any one of Items 1 to 3, wherein the content of the (A) antifungal agent is 0.01 to 25% by mass with respect to the total amount of the composition.
Item 5.
The external composition according to any one of Items 1 to 4, further comprising (C) urea.
Item 6.
Item 5. The external composition according to Item 5, wherein the content of (C) urea is 1 to 30% by mass with respect to the total amount of the composition.
Item 7.
Item 6. The external composition according to any one of Items 1 to 6 for use in the heel.
Item 8.
Item 6. The external composition according to any one of Items 1 to 7, further comprising at least one selected from the group consisting of an antihistamine, a local anesthetic, an anti-inflammatory agent, and a bactericidal agent.
Item 9.
Item 8. The external composition according to any one of Items 1 to 8, wherein the external composition is contained in a container in which a part or all of the portion in contact with the external composition is made of a polyolefin resin.

The present invention also provides the methods listed below.
Item 10.
A method for suppressing precipitation by coexisting (A) an antifungal agent and (B) salicylic acid and / or a salt thereof in an external composition.
Item 11.
(A) antifungal agent and (B) salicylic acid and / or a salt thereof coexist in the composition for external use.
A method of suppressing adsorption of the antifungal agent to a container by accommodating a part or all of a portion in contact with the external composition in a container molded of a polyolefin resin.
Item 12.
(A) antifungal agent and (B) salicylic acid and / or a salt thereof coexist in the composition for external use.
A method for suppressing a decrease in hardness due to storage of the external composition.

According to the present invention, it is possible to provide an external composition having excellent stability.

FIG. 1 is a diagram showing the results of verifying the degree of cloudiness of a composition containing terbinafine hydrochloride (Comparative Example 1) and a composition containing terbinafine hydrochloride and salicylic acid (Examples 1-1 to 1-4). Is.

The present invention relates to an external composition containing (A) an antifungal agent and (B) salicylic acid and / or a salt thereof.

[(A) Antifungal agent (antifungal component)]
Antifungal agents are substances that have the function of inhibiting or suppressing the growth of fungi or killing fungi, and are used to treat, prevent, and improve various diseases and symptoms caused by fungal infections. ..

Examples of the type of antifungal agent of the present invention include amine-based antifungal agents such as allylamine-based antifungal agents, benzylamine-based antifungal agents, and thiocarbamine-based antifungal agents, imidazole-based antifungal agents, and triazole-based antifungal agents. Examples thereof include azole antifungal agents such as fungal agents and morpholin antifungal agents.

As the amine-based antifungal agent of the present invention, any pharmaceutically or physiologically acceptable amine-based antifungal agent, which is a well-known compound as an antifungal agent having an amine in common, can be used. Examples of the amine-based antifungal agent include allylamine-based antifungal agents such as terbinafine or naftifine, benzylamine-based antifungal agents such as butenafine, and thiocarbamine-based antibiotics such as tolnaftate and liranaftate. Among them, representatively, an allylamine-based antifungal agent is preferably used, and among them, terbinafine or a salt of terbinafine such as terbinafine hydrochloride is particularly preferable.

The azole antifungal agent of the present invention is a compound known as an antifungal agent having an azole skeleton (a complex 5-membered ring compound containing one or more nitrogen atoms) in common, and is pharmaceutically or physiologically acceptable. Any possible azole antifungal agent can be used. Examples of the azole antifungal agent include an imidazole-based antifungal agent having an imidazole ring (a complex 5-membered ring containing two nitrogen atoms) and a triazole ring (a complex 5-membered ring containing three nitrogen atoms). Examples thereof include triazole-based antifungal agents. More specifically, imidazole antifungal agents such as miconazole, lanoconazole, luriconazole, isoconazole, ketoconazole, clotrimazole, neticonazole, sulconazole, bifonazole, oxyconazole, econazole and salts thereof; fluconazole, itraconazole, phosfluconazole, Examples thereof include triazole antifungal agents such as bifonazole, eficonazole, butconazole, fenticonazole, sertaconazole and salts thereof, and can be suitably used for the present invention.

As the morpholinic antifungal agent of the present invention, any morpholinic antifungal agent that is a well-known compound as an antifungal agent having morpholin in common and is pharmaceutically or physiologically acceptable is used. Can be done. Typical examples of the morpholinic antifungal agent include amorolfine or a salt thereof. All of these components (A) may be used alone or in any combination of two or more.

(A) The total content of the antifungal agent is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, still more preferably 0.3% by mass, based on the total amount of the external composition. As mentioned above, it is particularly preferably 0.5% by mass or more. (A) The total content of the antifungal agent is preferably 25% by mass or less, more preferably 10% by mass or less, still more preferably 8% by mass or less, and particularly preferably 5 with respect to the total amount of the external composition. It is mass% or less, more preferably 3% by mass or less, and particularly preferably 2% or less. The total content of the (A) antifungal agent is preferably 0.01% by mass to 25% by mass, more preferably 0.1% by mass to 10% by mass, still more preferably, based on the total amount of the external composition. It is 0.3% by mass to 5% by mass, particularly preferably 0.5% by mass to 2% by mass. Of these, 1% by mass is most preferable.

[(B) Salicylic acid and its salts]
As salicylic acid and a salt thereof, known substances can be used and are not particularly limited. The salt of salicylic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and examples thereof include salts with alkali metal salts, alkaline earth metal salts, organic bases and the like. Illustrated. Examples of salicylate include sodium salicylate, calcium salicylate, magnesium salicylate and potassium salicylate, ammonium salicylate, lithium salicylate, zinc salicylate and the like. As the (B) salicylic acid and its salt, salicylic acid, sodium salicylate, calcium salicylate, magnesium salicylate and potassium salicylate are preferable, and salicylic acid is more preferable, from the viewpoint of remarkably exerting the effect of the present invention. Salicylic acid and its salt may be used synthetically, or a commercially available product may be used.

All of these components (B) may be used alone or in any combination of two or more.

(B) The total content of salicylic acid or a salt thereof is preferably 1% by mass or more, more preferably 1.3% by mass or more, still more preferably 1.5% by mass or more, based on the total amount of the external composition. It is even more preferably 2% by mass or more. (B) The total content of salicylic acid or a salt thereof is preferably 20% by mass or less, more preferably 18% by mass or less, still more preferably 15% by mass or less, and particularly preferably 15% by mass or less, based on the total amount of the external composition. It is 10% by mass or less. The total content of (B) salicylic acid or a salt thereof is preferably 1% by mass to 20% by mass, more preferably 1.3% by mass to 15% by mass, and further preferably 1 with respect to the total amount of the external composition. It is .5% by mass to 10% by mass, and even more preferably 2 to 10% by mass.

In the external composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the blending ratio of the component (B) to the component (A) is, for example, with respect to 1 part by mass of the total content of the component (A). , (B) The total content of the component can be 0.05 to 2000 parts by mass, preferably 0.1 to 500 parts by mass, preferably 0.1 to 200 parts by mass, and 0.5 to 100 parts by mass. It is more preferably 1 to 50 parts by mass, and even more preferably 2 to 10 parts by mass.

In particular, but not limited to, in a preferred embodiment of the present invention, the composition for external use contains (A) 0.01 to 25% by mass of the antifungal agent and (B) 1 to 20% by mass of salicylic acid or a salt thereof. preferable.

In the present invention, in addition to (A) an antifungal agent and (B) salicylic acid and / or a salt thereof, any known known product can be used as a pharmaceutical product, quasi-drug, cosmetic product, etc. as long as its function is not impaired. Can be included in the composition for external use. As any component, (C) urea can be particularly preferably contained.

[(C) Urea]
The raw material of urea that can be arbitrarily contained in the present invention is not particularly limited. It can be synthesized by a known production method, or a commercially available product can be used.

The content of (C) urea is usually 0.1% by mass or more, preferably 1% by mass or more, more preferably 3% by mass or more, still more preferably 5% by mass, based on the total amount of the external composition. % Or more. The total content of (C) urea is preferably 30% by mass or less, more preferably 28% by mass or less, still more preferably 25% by mass or less, and particularly preferably 20% by mass, based on the total amount of the external composition. It is less than or equal to, more preferably 15% by mass or less, and most preferably 10% by mass or less. The total content of (C) urea is preferably 1% by mass to 30% by mass, more preferably 3% by mass to 25% by mass, and further preferably 5% by mass to 20% by mass with respect to the total amount of the external composition. %.

In the external composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the blending ratio of the component (C) to the component (A) is, for example, with respect to 1 part by mass of the total content of the component (A). , (C) The total content of the component can be 0.1 to 3000 parts by mass, 0.3 to 300 parts by mass, 0.5 to 100 parts by mass, and 1 to 20 parts by mass. be.

The external composition of the present invention may further contain any component other than (A) an antifungal agent and (B) salicylic acid and / or a salt thereof. Such optional components may be used in combination of one or more thereof as appropriate.

Typical examples of such an optional component include antihistamines.

The antihistamine contained as an optional component in the external composition of the present invention is not limited, but is limited to diphenhydramine, chlorpheniramine, isotipendyl, ketotifen, bepotastin, dimenhydrinate, cyproheptazine, diphenylpyraline, promethazine, iproheptin, emedastin, clemastine, Examples thereof include azelastin, levocabastine, hydroxyzine, mequitazine, loratadine, fexofenadine, cetirizine, oxatomido, terfenadine, epinastine, astemizole, evastin, diphenylimidazole, or salts of these compounds. The salt of the above compound is not particularly limited as long as it is pharmacologically or physiologically acceptable, and for example, the organic acid salt as exemplified for the component (A) and the component (B) above. Various salts such as inorganic acid salts and metal salts can be mentioned.

Preferred examples of the antihistamine are diphenylpyraline, diphenhydramine, chlorpheniramine, diphenylimidazole, or salts thereof, more preferred examples are diphenhydramine, chlorpheniramine, or salts thereof, and even more preferred examples are hydrochloric acid. Diphenhydramine, diphenhydramine salicylate, diphenhydramine, chlorpheniramine, chlorpheniramine maleate. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

The content of the antihistamine is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, still more preferably 0.1% by mass or more, and 0.5% by mass, based on the total amount of the external composition. The above is particularly preferable. The content of the antihistamine is preferably 10% by mass or less, more preferably 5% by mass or less, still more preferably 2% by mass or less, based on the total amount of the external composition. Within the above range, the above-mentioned effects of the present invention can be sufficiently obtained with the usual amount of quasi-drugs, pharmaceuticals and the like.

In the present invention, the ratio of the content of the antihistamine to the component (A) is not particularly limited, but the total amount of the component (A) is 1 part by mass and the total amount of the antihistamine is preferably 0.001 part by mass or more. It is more preferably 0.01 parts by mass or more, still more preferably 0.1 parts by mass or more. The ratio of the content of the antihistamine to the component (A) is as follows.
The total amount of the component (A) is 1 part by mass and the total amount of the antihistamine is 20 parts by mass or less, more preferably 10 parts by mass or less, still more preferably 5 parts by mass or less, and particularly preferably 2 parts by mass. It is less than a part.

The external composition of the present invention may also contain a local anesthetic. Examples of local anesthetics include procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, oxypolyethoxydodecane, and pharmaceutically acceptable salts thereof, or ethyl aminobenzoate. Although not limited, dibucaine hydrochloride or lidocaine is particularly preferred. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

The content of the local anesthetic is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, still more preferably 0.5% by mass or more, based on the total amount of the external composition. The content of the local anesthetic is preferably 20% by mass or less, more preferably 10% by mass or less, still more preferably 6% by mass or less, based on the total amount of the external composition. Within the above range, the above-mentioned effects of the present invention can be sufficiently obtained with the usual amount of quasi-drugs, pharmaceuticals and the like.

In the present invention, the ratio of the content of the local anesthetic to the component (A) is not particularly limited, but the total amount of the component (A) is 1 part by mass and the total amount of the local anesthetic is 0. It is 0.01 part by mass or more, more preferably 0.05 part by mass or more, and further preferably 0.5 part by mass or more. As for the ratio of the content of the local anesthetic to the component (A), the total amount of the component (A) is 1 part by mass and the total amount of the local anesthetic is preferably 30 parts by mass or less, more preferably 15 parts by mass. It is 10 parts by mass or less, more preferably 10 parts by mass or less, and particularly preferably 6 parts by mass or less.

The external composition of the present invention may also contain an anti-inflammatory agent. Anti-inflammatory agents include steroidal anti-inflammatory agents such as prednisolone valerate acetate, dexamethasone acetate, hydrocortisone acetate, or pharmaceutically acceptable salts thereof, allantin, glycyrrhizinic acid, glycyrrhetinic acid, aldioxa, ufenamate, bufexamac, ibuprofen. Non-steroids such as piconol, indomethacin, diclofenac, pyroxycam, epsilon-aminocaproic acid, velverine, lysoteam, sodium azulene sulfonate, dimethylisopropylazulenate, bromeline, therapeptase, semi-alkali proteinase, or pharmaceutically acceptable salts thereof. A system of anti-inflammatory agents is exemplified. Among these agents, non-steroidal anti-inflammatory drugs are preferable, glycyrrhetinic acid, glycyrrhizinic acid, and allantoin are more preferable, and glycyrrhetinic acid is particularly preferable. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

The content of the anti-inflammatory agent is preferably 0.001% by mass or more, more preferably 0.01% by mass or more, still more preferably 0.1% by mass or more, based on the total amount of the external composition. The content of the anti-inflammatory agent is preferably 20% by mass or less, more preferably 10% by mass or less, based on the total amount of the external composition. Within the above range, the above-mentioned effects of the present invention can be sufficiently obtained with the usual amount of quasi-drugs, pharmaceuticals and the like.

In the present invention, the ratio of the content of the anti-inflammatory agent to the component (A) is not particularly limited, but the total amount of the component (A) is 1 part by mass and the total amount of the anti-inflammatory agent is preferably 0.01. By mass or more, more preferably 0.1 parts by mass or more. As for the ratio of the content of the anti-inflammatory agent to the component (A), the total amount of the component (A) is 1 part by mass and the total amount of the anti-inflammatory agent is preferably 50 parts by mass or less, more preferably 20 parts by mass. It is less than a part.

The external composition of the present invention may also contain a bactericide. As disinfectants, isopropylmethylphenol, decalinium chloride, decalinium acetate, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, ethanol, chlorobutanol. , Sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, acrinol, hinokithiol, resorcin, benzoic acid Examples are velverine, or biguanide compounds. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

The content of the bactericide is usually 0.0001% by mass, preferably 0.001% by mass or more, more preferably 0.01% by mass or more, and 0.1% by mass or more, based on the total amount of the external composition. Is even more preferable. The content of the bactericide is preferably 20% by mass or less, more preferably 10% by mass or less, still more preferably 5% by mass or less, based on the total amount of the external composition. Within the above range, the above-mentioned effects of the present invention can be sufficiently obtained with the usual amount of quasi-drugs, pharmaceuticals and the like.

In the present invention, the ratio of the content of the disinfectant to the component (A) is not particularly limited, but the total amount of the component (A) is 1 part by mass and the total amount of the disinfectant is usually 0.0001 part by mass or more. It is preferably 0.001 part by mass or more, more preferably 0.01 part by mass or more, and further preferably 0. It is 1 part by mass or more. The ratio of the content of the disinfectant to the component (A) is such that the total amount of the component (A) is 1 part by mass and the total amount of the disinfectant is preferably 50 parts by mass or less, more preferably 20 parts by mass or less. It is more preferably 10 parts by mass or less, and even more preferably 5 parts by mass or less.

The external composition of the present invention may further contain any local stimulant or the like. Such local stimulants include menthol (l-menthol, dl-menthol, etc.), camphor (d-camphor, dl-camphor, etc.), terpenoids such as borneol, essential oils containing terpenoids (hakka oil), crotamitone, and the like. Ilcamol, menthol, timol, or pharmaceutically acceptable salts thereof are exemplified. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

Examples of the "salt" as used herein include salts with alkali metal salts, alkaline earth metal salts, organic bases and the like, and sodium, potassium, calcium, magnesium, ammonium, or diethanolamine, triethanolamine, ethylenediamine. And so on. Also, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, etc. Salts with organic acids such as malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, silicic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid; or aspartic acid, glutamic acid. Examples include salts with acidic amino acids such as. The "salt" may contain a solvate or a hydrate of the salt. In particular, the form of the salt of the component (A) is not particularly limited, but is preferably a salt of an inorganic acid, and more preferably a hydrochloride, a nitrate, or the like.

[container]
The container for filling the external composition of the present invention is not particularly limited. Any container may be used as a container for external medicines, quasi-drugs, and cosmetics. As such a container material, for example, a part or all, preferably all of the contact surface with the external composition is a polyolefin resin, an acrylic acid resin, a polyester, a polycarbonate, a fluororesin, a polyvinyl chloride, a polyamide, an ABS resin, and the like. Examples thereof include a container made of at least one material selected from the group consisting of AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, aluminum, and glass.

Polyethylene (PE) (high density polyethylene (HDPE), low density polyethylene (LDPE), ultra low density polyethylene, in that the effect of the present invention can be exerted more remarkably and the adsorption of the composition over time can be prevented. Linear low-density polyethylene (LLDPE), ultra-high molecular weight polyethylene, etc.), Polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), and ethylene-propylene copolymer, polymethyl Polyethylene resins such as penten, polybutene-1,1,2-polybutadiene are preferred, and polyethylene or polypropylene is more preferred.

The shape of the container is preferably a tube, a roll ball applicator, a squeezed container, a wide-mouthed bottle with a lid, or the like, and particularly preferably a wide-mouthed bottle.

[Dosage form]
The composition for external use of the present invention is provided in any form that can be widely used as a pharmaceutical product, a quasi-drug, or the like. Preferably, it is provided as a preparation that can be used as an external preparation for skin. The external composition of the present invention is not particularly limited as long as it is in a known form, but is, for example, an aqueous external composition such as a cream, a liquid, a suspension, an emulsion, a gel, a lotion, an aerosol, or a mist. It is preferably provided in the form of, and more preferably a cream, a liquid, a suspension, an emulsion, a lotion, or a mist. In particular, it is preferably a cream. Here, the aqueous external composition refers to a dosage form in which the ratio of water content to the total amount of the composition is 10% by mass or more, preferably 20% by mass or more, and more preferably 30% by mass or more.

In addition to this, it can also be formulated by a known method in the form of a sheet agent or the like in which a sheet such as an ointment, a powder agent or a non-woven fabric is impregnated with the external composition of the present invention.

When the composition for external use is formulated in the form of an emulsion, a cream, a lotion or the like, the composition may include, but is not limited to, an oily base and an aqueous base. In this case, the W / O type may be used, or the O / W type may be used, but the O / W type is preferable from the viewpoint of exerting the effect of the present invention more remarkably.

The pharmaceutical product can be manufactured by mixing each component in accordance with or in accordance with the 16th revised Japanese Pharmacopoeia General Regulations.

[Production method]
The external composition of the present invention can be produced by a known method. If desired, a sterilization step can be included.

[Base or carrier]
The external composition of the present invention can be formulated by mixing with a known base or carrier that can be used as a pharmaceutical product, a quasi-drug, a cosmetic product, etc., as long as the effect of the present invention is not impaired. In addition, the external composition of the present invention includes, for example, surfactants, oils, alcohols, higher fatty acids, thickeners, preservatives, antioxidants, antioxidants, preservatives, chelating agents, pH adjusters. , Stabilizers, solubilizing agents, suspending agents, tonicity agents, buffering agents, soothing agents, dispersants, fragrances, colorants, pigments and other additives can be added. These additives may be used alone or in combination of two or more.

Bases or carriers include liquid paraffins, squalanes, gelled silicones (such as plastibase), ozokelite, α-olefin oligomers, light liquid paraffin-like hydrocarbons; methylpolysiloxanes, crosslinked methylpolysiloxanes, highly polymerized methyls. Polysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, cross-linked alkyl polyether-modified silicone, silicone-alkyl chain Silicone oils such as modified polyether modified silicones, silicone-alkyl chain co-modified polyglycerin modified silicones, polyether modified branched silicones, polyglycerin modified branched silicones, acrylic silicones, phenyl modified silicones, silicone resins; dioxane; isopropyl myristate, Esters such as octyldodecyl myristite, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythlitte tetra2-ethylhexanoate; lower alcohols such as isopropanol; diethylene glycol monomethyl ether, diethylene glycol monoethyl ether Glycol ethers; polyhydric alcohols such as polyethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, isoprene glycol; aqueous bases such as purified water can be mentioned.

The base or carrier may be used alone or in combination of two or more.

Examples of the surfactant include nonionic surfactants. Nonionic surfactants include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, penta-2-ethylhexyl acid diglycerol sorbitan, and tetra-2-ethylhexyl acid diglycerol sorbitan. Sorbitane fatty acid esters such as; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene Hardened castor oil derivatives such as cured castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80; polyoxyethylene monolaurylate (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (20) Polyoxyethylene sorbitan fatty acid esters such as polysorbate 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), polyoxyethylene isostearate (20) sorbitan; polyoxyethylene monopalm oil fatty acid glyceryl; glycerin alkyl Ethers; alkyl glucosides; polyoxyalkylene alkyl ethers such as polyoxyethylene cetyl ethers; amines such as stearylamine and oleylamine; polyoxyethylene / methylpolysiloxane copolymers, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, Silicone-based surfactants such as PEG-9 polydimethylsiloxyethyl dimethicone; polyoxyethylene lauryl alcohol ether and the like are exemplified.

Other surfactants include laurate, palmitate, cocoyl glutamate, coconut oil methylalanine salt, acylmethyltaurine salt, anionic surfactants such as polyoxyethylene lauryl sulfate, and lauryldiamino. Examples thereof include amphoteric surfactants such as ethyl glycine salt and betaine salt of coconut oil fatty acid.

Examples of the oil include natural animal and vegetable oils and fats, hydrocarbon oils, ester oils, silicone oils, higher alcohols, higher fatty acids, animal and plant and synthetic essential oils.

Examples of natural animal and vegetable oils and fats include avocado oil, flaxseed oil, almond oil, olive oil, cacao oil, beef fat, millet oil, wheat germ oil, sesame oil, rice germ oil, rice bran oil, safflower oil, soybean oil, and evening primrose oil. , Camellia oil, corn oil, rapeseed oil, horse fat, persic oil, palm oil, palm kernel oil, sunflower oil, sunflower oil, pork fat, grape oil, jojoba oil, macadamia nut oil, mink oil, cottonseed oil, mokurou, honeybee, Examples thereof include Sarashimitsuro, palm oil, hardened palm oil, peanut oil, lanolin, egg yolk oil, rose hip oil and the like.

As the hydrocarbon oil, paraffin-based hydrocarbons and olefin-based hydrocarbons are used, and examples thereof include squalane, squalene, selecin, paraffin, pristan, microcrystalline wax, liquid paraffin, and petrolatum.

As the ester oil, synthetic esters and esters of higher alcohols and higher fatty acids are used. For example, diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, isostearyl isostearate, etc. Trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, neopentylglycol di-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, Oleyl oleate, octyldodecyl oleate, decyl oleate, neopentyl glycol dicaprate, 2-ethylhexyl succinate, isosetyl stearate, butyl stearate, diisopropyl sebacate, cetyl lactate, tetradecyl lactate, isopropyl myristate, octyl myristate Dodecyl, cetyl myristate, myristyl myristate, octyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearate, phytosteryl oleate, diisoartrate Examples thereof include stearyl, paramethoxysilicate derice, tetraloginate pentaerislit and the like.

Examples of the silicone oil include dimethylpolysiloxane, highly polymerized methylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, octamethylcyclotetrasiloxane, octamethylcyclopentasiloxane, decamethylcyclohexasiloxane, and stearoxysilicone. Examples thereof include higher alkoxy-modified silicones, alkyl-modified silicones, and higher fatty acid ester-modified silicones.

Examples of the alcohol include lower alcohols such as isopropanol; higher alcohols such as octyldodecanol, isostearyl alcohol, oleyl alcohol, stearyl alcohol, cetanol and behenyl alcohol.

As the higher fatty acid, a saturated or unsaturated linear or branched fatty acid having 12 to 22 carbon atoms can be used, and for example, isostearic acid, oxystearic acid, oleic acid, stearic acid, palmitic acid, behenic acid, and the like. Examples thereof include myristic acid, lauric acid, lanoric acid, linoleic acid, and linolenic acid.

Examples of the thickener include guar gum, locust bean gum, carrageenan, xanthan gum, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydrophobicized hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymer. , Alkyl methacrylate copolymer, polyethylene glycol, bentonite, (hydroxyethyl acrylate / acryloyldimethyltaurine Na) copolymer, (acryloyldimethyltaurine ammonium / vinylpyrrolidone) copolymer and the like.

Preferable examples of preservatives include, for example, benzoic acid, acetic acid, phenol, iodine tincture, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and the like.

Preferable examples of antioxidants include, for example, sulfites, ascorbic acid and the like.

Examples of the antioxidant include dibutylhydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride and the like.

Preservatives include benzoic acid, sodium benzoate, dehydroacetate, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, benzyl paraoxybenzoate, paraoxy Examples thereof include methyl benzoate and phenoxyethanol.

Examples of the chelating agent include EDTA / 2-sodium salt and EDTA / calcium / 2-sodium salt. From the viewpoint of significantly exerting the effect of the present invention, it is preferable that the external composition of the present invention further contains EDTA · 2 sodium salt.

As pH adjusters, inorganic acids (hydrogen, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.) ), Organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.) and the like.

Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Suspension agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glycerin monostearate; eg polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cell. -BR> Fragrance [Su, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and other hydrophilic polymers can be mentioned.

Examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like.

Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates and citrates.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinylpyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, organic acid and the like.

Examples of the colorant include inorganic pigments and natural pigments.

The external composition of the present invention may further contain other active ingredients as long as the effects of the present invention are not impaired. Specific examples of such components include moisturizing components, pearl gloss-imparting agents, conditioning agents, scrubbing agents, blood circulation promoting components, astringent components, cleaning components, peptides or derivatives thereof, amino acids or derivatives thereof, and cell activating components. And so on.

Moisturizing ingredients include polyhydric alcohols such as glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol, diglycerin; saccharides such as trehalose, xylitol, oligosaccharides; sodium hyaluronate, heparin analogs, chondroitin sulfate. High molecular weight compounds such as sodium, collagen, elastin, keratin, chitin, chitosan; amino acids such as glycine, aspartic acid, arginine; natural moisturizing factors such as sodium lactate, urea, sodium pyrrolidone carboxylate; ceramide, cholesterol, phosphorus Lipids such as lipids; examples include plant extracts such as chamomile extract, hamamelis extract, cha extract, and perilla extract.

Examples of the pearl gloss imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

Conditioning agents include, for example, cationized cellulose, cationized starch, cationized phenuglique gum, cationized guar gum, cationized tara gum, cationized locust bean gum, cationized xanthan gum, diallyl quaternary ammonium salt / acrylamide copolymer, polyquaternium. , Vinyl imidazolium trichloride / vinylpyrrolidone copolymer, hydroxyethyl cellulose / dimethyldialylammonium chloride copolymer, vinylpyrrolidone / quaternized dimethylaminoethylmethacrylate copolymer, polyvinylpyrrolidone / alkylaminoacrylate copolymer, polyvinylpyrrolidone / Alkylaminoacrylate / Vinyl caprolactum copolymer, Vinylpyrrolidone / Methalamide propyltrimethylammonium chloride copolymer, Alkylacrylamide / Aacrylate / Alkylaminoalkylacrylamide / Polyethylene glycol methacrylate copolymer, Adipic acid / Dimethylaminohydroxypropylethylenetriamine Examples thereof include copolymers.

Examples of the scrubbing agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride granules, olive kernel powder, seawater dried product granules, candelilla wax, walnut shell powder, cherry kernel powder, coral powder, charcoal powder, and the like. Examples include Hashibami husk powder, polyethylene powder, silicic acid anhydride and the like.

Examples of the blood circulation promoter include acetylcholine, caffeine, capsaicin, cantalis tincture, gamma oryzanol, shokyo tincture, zingeron, cepharanthin, sembry extract, tannin acid, tocopherol, trazoline, tocopherol nicotinic acid, nicotinic acid benzyl ester and the like. Can be mentioned.

Examples of the astringent component include zinc sulfate, hydroxyaluminum, aluminum chloride, zinc sulfovalent and tannic acid.

Cleaning components include alkali metal salts such as potassium laurate, potassium myristate, potassium palmitate or potassium stearate, soaps such as alkanolamide salts or amino acid salts, and amino acid-based interfaces such as sodium cocoylglutamate and sodium cocoylmethyltaurine. Activator, ether sulfate ester salt such as sodium laureth sulfate, ether carboxylate such as lauryl ether sodium acetate, sulfosuccinate ester salt such as alkis sulfosuccinate sodium, coconut oil fatty acid monoethanolamide, coconut oil fatty acid diethanolamide, etc. Monoalkyl phosphate ester salts such as fatty acid alkanolamide, sodium lauryl phosphate, sodium polyoxyethylene lauryl ether phosphate, coconut oil fatty acid amide propyldimethylaminoacetic acid betaine, lauryldimethylaminoacetic acid betaine, 2-alkyl-N-carboxy Betain-type amphoteric surfactants such as methyl-N-hydroxyethylimidazolinium betaine, laurylhydroxysulfobetaine and lauroylamide ethylhydroxyethylcarboxymethylbetaine hydroxypropylphosphate sodium, amino acid-type amphoteric surfactants such as sodium laurylaminopropionate Agents and the like can be mentioned.

Examples of the peptide or its derivative include keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, and elastin-degrading peptide. , Conchiolin-degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, hydrolyzed soybean protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, casein-degrading peptide , Aylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.) and the like.

Amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine, methionine. , Leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnosine, carnosine, creatine and the like.

The cell activating components include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid, vitamins such as retinol, thiamine, riboflavin, pyridoxin hydrochloride, pantothenic acid, α-hydroxy acids such as glycolic acid and lactic acid, and tannin. Examples thereof include frabonoid, saponin, and photosensitizer No. 301.

[PH]
The pH of the external composition of the present invention is appropriately set according to the type of the component (A), the type and content of other compounding components, the pharmaceutical form, the method of use, etc., and is within a physiologically or pharmaceutically acceptable range. If there is, the pH is not limited, but can be, for example, pH 2 to 9, preferably about 3 to 8, and more preferably about 5 to 7.

[Use]
The external composition of the present invention is preferably used for treating athlete's foot or worm, candidiasis, etc., without limitation. The external composition of the present invention can be used not only on the arms, hands and feet in general, but also on the body surface in general, and in particular, water bugs in the hands or toes, between the hands or toes, or in the elbows and heels. Or it is used to treat worms. Particularly preferably, it is used for heels and can be applied to athlete's foot.

Athlete's foot is a skin condition caused by Trichophyton. Symptoms and characteristics include itching, small bumps, peeling, dead skin cells, powder blowing, and rough heels. It may also appear as a symptom such as a scab. Symptoms such as onychomycosis on the feet or hands may also appear. Ringworm is especially prone to form on the thicker parts of the keratin, where keratin, a component of the keratin of the skin, is present, and may be particularly symptomatic on the heels.

Ringworm is a skin condition caused by ringworm. There is a small red ring on the skin that gradually spreads. Itchy and similar to athlete's foot, but worms tend to form on thin skin.

Candidiasis is caused by candida, and symptoms such as rough skin on the surface of the hands, peeling of the skin between the fingers, and discoloration of the base of the nails to white appear. In addition, symptoms such as diaper rash may appear. Symptoms may appear in the mouth, lips, body surface, digestive tract, vagina, etc.

The external composition of the present invention can be used for treating symptoms caused by Trichophyton, tinea versicolor, candidiasis, interfinger erosion, intertrigo and the like, without limitation.

The external composition of the present invention is preferably provided as a therapeutic agent for athlete's foot as a cream for heels, without limitation.

The method of using the external composition of the present invention varies depending on the condition of the skin, age, gender, etc., but for example, the following method may be used. That is, if an appropriate amount (for example, about 0.5 to 2 g) is applied to the skin (for example, heel) several times a day (for example, about 1 to 5 times, preferably 1 to 3 times, more preferably once). good. Also, the composition may be applied to the skin (eg, heel) such that the daily use of the antifungal agent (eg, terbinafine or a salt thereof) is, for example, about 5-20 mg. The application method is performed according to the dosage form, preferably coating. The application period is preferably, for example, about 30 days or more.

[Stabilization method]
In the present invention, the precipitation of the antifungal agent can be suppressed by the coexistence of (A) the antifungal agent and (B) salicylic acid and / or a salt thereof, and the components in the preparation are kept in a uniform state. Also provided are methods for achieving the desired effect. In the present invention, in order to suppress the precipitation of such an antifungal agent, the same conditions as the concentration, pH, formulation, container material and the like of each component in the above-mentioned external composition of the present invention are adopted.

[Method of suppressing hardness decrease]
In the present invention, by coexisting (A) an antifungal agent and (B) salicylic acid and / or a salt thereof with the external composition, it is possible to suppress the decrease in hardness of the external composition after storage, and it is possible to suppress the decrease in hardness of the external composition after storage. A method for good retention of the ingredients in is provided. In the present invention, in order to suppress such a decrease in hardness, the same conditions as the concentration, pH, formulation, container material and the like of each component in the above-mentioned external composition of the present invention are adopted. The suppression of hardness reduction is particularly useful when the external composition of the present invention is a cream.

[Suppression of adsorption to containers]
The present invention provides a method for suppressing adsorption of the antifungal agent to a container by coexisting (A) an antifungal agent and (B) salicylic acid or a salt thereof in the external composition. In the present invention, in order to suppress such adsorption to a container, the same conditions as those of the concentration, pH, formulation, container material and the like of each component in the above-mentioned external composition of the present invention are adopted. Here, the suppression of adsorption means that the adsorption rate to the antifungal agent in the container is such that the composition is adsorbed to the container after the external composition is brought into contact with the container and stored at 60 ° C. for 1 day. It refers to the case where the amount of the antifungal agent is 20% or less, preferably 10% or less. The external composition of the present invention is particularly excellent in suppressing the adsorption of the antifungal agent on the polyolefin resin container. Here, the polyolefin container includes polyethylene (PE) (including high-density polyethylene (HDPE), low-density polyethylene (LDPE), ultra-low-density polyethylene, linear low-density polyethylene (LLDPE), ultra-high molecular weight polyethylene, etc.). , Polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), and ethylene-propylene copolymers, polymethylpentene, or polybutene-1,1,2-polybutadiene, in particular polyethylene. Or polypropylene is more preferred. Further, HDPE is particularly preferable as PE.

Next, the present invention will be specifically described with reference to Examples and Test Examples, but the present invention is not limited to the following Examples and Test Examples.

[Example]
External compositions having the compositions of Examples shown in Tables 1 to 3 and Table 5 were prepared according to a conventional method.

[Comparison example]
Similarly, the external composition of Comparative Examples shown in Tables 1 to 3 and Table 5 was prepared according to a conventional method. The water content is about 25 to 39% by mass in Tables 1 to 3 and Table 5.

[Test Example 1. Evaluation test for turbidity]
15 mL each of the compositions of Examples and Comparative Examples was filled in a container made of high density polyethylene (HDPE) and stored at 60 ° C. under shading for about 15 hours. The composition was then transferred to a glass screw cap bottle (capacity 20 mL). The properties of the composition after storage were visually observed, and the degree of turbidity of each composition was evaluated according to the following criteria. Then, 0.2 mL each is dispensed into a 96-well plate (flat bottom, made of polystyrene) with a glass measuring pipette, and the absorbance at 660 nm is measured with a microplate reader device (VersaMax manufactured by Molecular Devices), which is an index of turbidity. And said.
The results are shown in Table 1.
Further, FIG. 1 shows a photograph of the result at this time.

<Evaluation criteria for turbidity>
◎: It is clear without any turbidity ○: It is a little turbid but the background can be easily confirmed △: It is turbid but somehow the background can be confirmed ×: It is turbid and the background cannot be confirmed at all

It was confirmed that when terbinafine hydrochloride was contained, cloudiness occurred, whereas when salicylic acid was further coexisted, cloudiness was suppressed.
Further, both the composition of Comparative Example 1 filled in a glass screw cap bottle (capacity 20 mL) and operated in the same manner and the one stored in the above HDPE container were both glass screw cap bottles (capacity). When transferred to 20 mL) and visually compared, it was confirmed that the white turbidity tended to occur more remarkably when stored in an HDPE container.

[Test Example 2. Container adsorption test 1]
The compositions shown in Table 2 were filled in a container made of high-density polyethylene (HDPE) (capacity: 15 mL) and a glass screw cap bottle (capacity: 20 mL) by 15 mL each, and stored at 60 ° C. for 1 day under shading. The terbinafine hydrochloride content in each sample before and after storage was measured using HPLC, and the adsorption rate (%) with respect to the HDPE container was calculated.

(Equation 1) Adsorption rate (%) = Residual rate (%) of 100-terbinafine hydrochloride

It was confirmed that when terbinafine hydrochloride was contained, terbinafine was adsorbed to the container, whereas when salicylic acid was further coexisted, the adsorption was suppressed.
On the other hand, in the formulation filled in the glass screw cap bottle, the residual rate was 100%. Therefore, it can be seen that the addition of salicylic acid suppresses the adsorption of terbinafine hydrochloride in the HDPE container.

[Test Example 3. Container adsorption test 2]
The compositions of Example 3 and Comparative Example 3 shown in Table 3 below were filled in 15 mL of a high-density polyethylene (HDPE) container (capacity: 15 mL) and stored at 60 ° C. for 1 day under shading. The butenafine hydrochloride content in each sample before and after storage was measured using HPLC, and the residual ratio of butenafine hydrochloride in the salicylic acid-containing sample (Example 3) to the salicylic acid-free sample (Comparative Example 3) was calculated by the formula. Calculated based on 2.

(Equation 2)
Residual rate ratio = {(Residual rate of salicylic acid-containing sample) / (Residual rate of salicylic acid-free sample)}

As a result of the calculation, the residual rate ratio was 1.8. Therefore, it was confirmed that the sample containing salicylic acid had a higher residual amount of butenafine hydrochloride than the sample containing no salicylic acid. That is, it can be seen that the addition of salicylic acid suppresses the adsorption of butenafine hydrochloride in the HDPE container.

[Test Example 4 Pellet adsorption test]
8 g of the composition of Example 3 shown in Table 3 is placed in a glass bottle (capacity: 30 mL), and 8 g of spherical pellets made of HDPE or polypropylene (PP) (diameter: about 3 mm) are mixed and filled, and the composition is shielded from light. Stored at 60 ° C. for 1 day. The composition of Comparative Example 3 shown in Table 3 was also subjected to the same experiment. Butenafine hydrochloride content in each composition before and after storage was measured using HPLC. The residual ratio of butenafine hydrochloride of the salicylic acid-blended composition (Example 3) to the salicylic acid-free composition (Comparative Example 3) was calculated for each resin pellet based on the formula 2.

The results obtained are shown in Table 4. In each case, the residual rate ratio exceeded 1, and it was confirmed that the residual amount of butenafine hydrochloride was higher in the composition containing salicylic acid than in the composition not containing salicylic acid. Therefore, it can be seen that the addition of salicylic acid suppresses the adsorption of butenafine hydrochloride on HDPE pellets and PP pellets.

[Test Example 5. Suppression of hardness decrease]
In creams, it is important to maintain the hardness stability of the preparation. Therefore, the hardness stability when the present invention was applied to a cream was evaluated.
Specifically, each component shown in Table 5 was mixed in a predetermined amount (% by mass), and then dissolved with heating and stirring to obtain a uniform cream preparation. In Examples 4-1 and 4-2, and Comparative Example 4 are "other additives" such as lactic acid, sodium hydroxide, fragrance, glycine, sodium edetate hydrate, propylene glycol, liquid paraffin, and dimethylpoly. Each formulation contains a common amount of siloxane, isopropyl palmitate, cetomacrogol, cetanol, stearic acid, sorbitan stearate, palmitic acid, cetyl lactate, paraffin, sardine wax, and carboxyvinyl polymer. Subsequently, the cream was cooled to about 25 ° C. to prepare samples of Examples and Comparative Examples. When the sample is put into a plastic 55 g jar by scraping and measured with a rheometer (Sun RHEO METER manufactured by Sun Kagaku Co., Ltd.) under the conditions of a table moving speed of 2 cm / min and a φ20 (compressive elasticity) adapter, when the bottom of the adapter enters 1 cm. The maximum value up to was taken as the measured value. The unit is g. Then, the sample was transferred to a constant temperature bath at 60 ° C. and kept warm for one week. After one week, the sample that had been kept warm at 60 ° C. was taken out, kept at a constant temperature at 25 ° C., and the measurement was performed again. After the measurement, the hardness reduction rate was calculated according to the following formula 3.
(Equation 3)
Hardness reduction rate (%) = [{(Hardness of start product)-(Hardness of aging product)} / (Hardness of start product)] × 100
The results are shown in Table 5.

It was confirmed that in the case of Comparative Example 4, the decrease in hardness was significantly suppressed, whereas in the case of the compositions of Example 4-1 and Example 4-2 containing salicylic acid, the decrease in hardness was suppressed. Was done. In addition, it was confirmed that the decrease in hardness was further suppressed when glycyrrhetinic acid was allowed to coexist.
Therefore, it can be seen that the stability of the cream containing terbinafine hydrochloride is improved by the addition of salicylic acid and the coexistence of salicylic acid and glycyrrhetinic acid.

Hereinafter, an example of a pharmaceutical prescription of the present invention will be shown. The composition for external use was prepared by a conventional method according to the formulations shown in Tables 6 to 10. These formulations are effectively used on the heel. All formulations can also be contained and used in PP containers.

Claims (7)

(A) At least one antifungal agent selected from the group consisting of terbinafine, butenafine, and salts thereof, and (B) containing 1 to 20% by mass of salicylic acid and / or a salt thereof based on the total amount of the composition. External composition. The external composition according to claim 1 , further comprising (C) urea. The external composition according to claim 1 or 2 , for use in the heel. The external composition according to any one of claims 1 to 3 , further comprising at least one selected from the group consisting of an antihistamine, a local anesthetic, an anti-inflammatory agent, and a bactericidal agent. The external composition according to any one of claims 1 to 4 , wherein a part or all of the portion in contact with the external composition is contained in a container made of a polyolefin resin. Antifungal by coexisting (A) at least one antifungal agent selected from the group consisting of terbinafine, butenafine, and salts thereof , and (B) salicylic acid and / or a salt thereof in the external composition. A method of suppressing the precipitation of an agent. At least one antifungal agent selected from the group consisting of (A) terbinafine, butenafine, and salts thereof , and (B) salicylic acid and / or a salt thereof coexist in the external composition.
A method of suppressing adsorption of the antifungal agent to a container by accommodating a part or all of a portion in contact with the external composition in a container molded of a polyolefin resin.

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