JP2006347990A - Antifungal medicine composition for nail - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technique for improving the transfer of bifonazole into nails. <P>SOLUTION: This antifungal medicine composition for nails is characterized by comprising bifonazole and a sulfur atom-containing compound having a reducing ability. The sulfur atom-containing compound having the reducing ability is preferably one or more selected from l-cysteine, cysteine, d-cysteine, dl-cysteine, N-acetyl-l-cysteine, dl-homocysteine, l-cysteine methyl ester, l-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteine derivative of cysteamine and 2-mercaptoethanol, β-mercaptopropionic acid and its derivatives, benzylmercaptan, 2-mercaptoimidazole, 2-mercaptobenzothiazole and its salts, 2-mercaptobenzimidazole and its salts. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to a pharmaceutical composition suitable for a pharmaceutical composition for the treatment of fungal infections, and more particularly to a composition suitable for the treatment of antimycosis in the nail.

Onychomycosis is the main symptom of nail plate opacity, and there are few cases of prominent keratinous growth of the nail plate due to infection by ringworm fungus, Candida and other fungi. . The treatment of mycosis in the dermatological field needs to be carried out patiently for a long time, and in particular, onychomycosis is currently difficult to treat.

As treatment methods for onychomycosis, external treatment, internal use therapy, nail extraction method, X-ray irradiation method and the like have been implemented. External therapy is a method in which liquids, creams, and the like are externally applied as antifungal agents, but even if applied for a long period of time, the drug hardly permeates the nails, and thus little effect is seen. For internal therapy, griseofulvin or the like is known, but side effects such as drug eruption, hypersensitivity symptoms, renal disorder, liver disorder etc. are seen for a long period of time, and it is said that it is less effective for long-term use. . The nail removal method is a method of performing nail detachment operation to remove fungi existing in the nail together with the nail and applying a drug to the nail bed. However, not only is it accompanied by pain, but the nail of onychomycosis is fragile, so that there is a tendency for fragments of the affected nail to remain, and the healing is not complete. The X-ray irradiation method may be effective for eliminating chronic inflammation, but it is not effective for ringworm. As described above, it is difficult to treat onychomycosis, and the current treatment method itself has not been established.

There is an example of a liquid agent comprising an imidazole antifungal agent and a long-chain fatty acid described as an example of external therapy (see, for example, Patent Document 1: JP 58-32818 A). However, it is not easy to penetrate the fungal palliative part inside the nail sufficiently and continuously with the drug as the active ingredient. In addition, a method for increasing the solubility of a drug in an aqueous solution and increasing bioavailability by using urea as a solubilizer (see, for example, Patent Document 2: JP-A-63-258814), nail There is a description of a method of using a hydrophilic penetrant so that the penetrability of water is advantageous (for example, see Patent Document 3: JP-A-5-85929). As a method using a film-forming agent, a method using a pharmaceutical composition comprising a hydrophobic film-forming agent and a solvent in order to obtain a preparation excellent in adhesion to the nail keratin, permeability and storage (for example, Patent Document 4: JP-A-6-21651) and a method of using a film-forming nail enamel containing urea (for example, see Patent Document 5: JP-A-6-009342). In addition, a tropical croton genus plant in Thailand, an extract of prawn oyster, and a polyprenyl derivative contained in the extract are used in combination with bifonazole for onychomycosis topical medicine composition (for example, Patent Document 6) : See JP-A-15-160488) and bifonazole and a tissue softening cream for treating onychomycosis containing about 40 wt% urea as a tissue softening agent (for example, Patent Document 7: Japanese Patent Application Laid-Open No. 13-354591). Issue no.). Furthermore, a nail patch matrix containing an adhesive and bifonazole for maintaining or improving the condition of the nail in a healthy manner (for example, see Patent Document 8: JP-A-10-330247), clotrimazole And / or an ointment that adheres to the nail and is effective against onychomycosis characterized by bifonazole (see, for example, Patent Document 9: JP-A-9-504537). Furthermore, there is a description regarding an antifungal agent for nails containing a sulfur atom-containing compound having a reducing ability (see, for example, Patent Document 10: JP-A-8-231430). On the other hand, as an action of a substance having reducing ability on keratin such as nail, cleaning effect such as yellowing of nail and finger (for example, refer to JP-A-2002-193787), cysteine, thioglycol It is known to soften the nail with a deforming nail correction treatment containing a reducing agent selected from the group of acids and thioglycolates (see, for example, Patent Document 12: JP-A-2004-238288) ). However, the technology of combining bifonazole and a substance having a reducing ability into an antifungal pharmaceutical composition for nail can improve the drug transfer of bifonazole into the nail by combining bifonazole and a reducing agent. Not known at all.

JP 58-32818 A JP-A 63-258814 JP-A-5-85929 JP-A-6-216511 JP-A-6-009342 Japanese Patent Laid-Open No. 15-160488 Japanese Patent Laid-Open No. 13-354591 Japanese Patent Laid-Open No. 10-330247 JP-A-9-504537 JP-A-8-231430 JP 2002-193787 A JP 2004-238288 A

The present invention has been made under such circumstances, and an object of the present invention is to provide a technique for improving the transfer of bifonazole into the nail in order to treat or prevent onychomycosis.

In view of such a situation, the inventor has sought for a technique for improving the transfer of bifonazole into the nail, and as a result of intensive studies, the present inventors have found that for nail containing bifonazole and a sulfur atom-containing compound having a reducing ability. The inventors have found that an antifungal pharmaceutical composition has such properties, and have completed the present invention. That is, the present invention is as follows.

(1) An antifungal pharmaceutical composition for nails characterized by containing bifonazole and a sulfur atom-containing compound having a reducing ability; (2) a sulfur atom-containing compound having a reducing ability is 1-cysteine, cysteine, d- Cysteine, d1-cysteine, N-acetyl-1-cysteine, d1-homocysteine, 1-cysteine methyl ester, 1-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteine derivatives of cysteamine and 2-mercaptoethanol, β- Mercaptopropionic acid and its derivatives, benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and its salt, 2-mercaptobenzimidazole and its salt, 2-mercaptomethylbenzimidazole, 6-mercapto , 6-methylmercaptopurine, 5-mercaptouracil, and mercaptans of thiomalic acid and its derivatives and ammonium thioglycolate, 2-ethylhexyl thioglycolate, butyl thioglycolate, methoxybutyl thioglycolate and trimethylolpropane tris ( (1) the antifungal pharmaceutical composition for nail according to (1), wherein the sulfur atom-containing compound having a reducing ability is 1-cysteine, cysteine, d-cysteine, d1-cysteine, d1-homocysteine, 1-cysteine methyl ester, 1-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteine derivatives of cysteamine and 2-mercaptoethanol, β-mercaptop Pionic acid and derivatives thereof, benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof, 2-mercaptobenzimidazole and salts thereof, 2-mercaptomethylbenzimidazole, 6-mercaptopurine, 6-methylmercaptopurine, Selected from 5-mercaptouracil and mercaptans of thiomalic acid and its derivatives and ammonium thioglycolate, 2-ethylhexyl thioglycolate, butyl thioglycolate, methoxybutyl thioglycolate and trimethylolpropane tris (thioglycolate) 1 type or 2 types or more of antifungal pharmaceutical compositions for nails according to (1) (4) a sulfur atom-containing compound having reducing ability is 1-cysteine, cysteine, d-cysteine d1-cysteine, N-acetyl-1-cysteine, d1-homocysteine, 1-cysteine methyl ester, 1-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteine derivatives of cysteamine and ammonium thioglycolate, thioglycolic acid 2 -Antifungal pharmaceutical composition for nail according to (1), which is one or more selected from ethylhexyl, butyl thioglycolate, methoxybutyl thioglycolate and trimethylolpropane tris (thioglycolate) (5) Sulfur atom-containing compounds having reducing ability are 2-mercaptoethanol, β-mercaptopropionic acid and derivatives thereof, benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof; Mercaptobenzimidazole and its salts, 2-mercaptomethylbenzimidazole, 6-mercaptopurine, 6-methylmercaptopurine, 5-mercaptouracil and thiomalic acid and its derivatives mercaptans and ammonium thioglycolate, 2-ethylhexyl thioglycolate Or an antifungal pharmaceutical composition for nail according to (1), wherein the composition is one or more selected from butyl thioglycolate, methoxybutyl thioglycolate and trimethylolpropane tris (thioglycolate) (6) ) When 1 part by mass of bifonazole coexists with 5 parts by mass of a sulfur compound having a reducing ability contained in the preparation and stored for 7 days at 40 ° C., the decomposition of the bifonazole is characterized by 5% or less (1 ) To (5) Composition

According to the present invention, it is possible to provide a technique for improving the transfer of bifonazole into the nail.

The antifungal pharmaceutical composition for nail of the present invention comprises bifonazole and a sulfur atom-containing compound having a reducing ability as essential components. Examples of the sulfur atom-containing compound having a reducing ability include hydrocarbons having a reducible thiol group, hydrogen atoms or carbon atoms of the hydrocarbon substituted with oxygen atoms or nitrogen atoms, or their tomatoes. It can be applied without any particular limitation. The hydrocarbon, hydrocarbon oxygen or nitrogen-substituted product can be applied to either aliphatic or aromatic, and its molecular weight is suitably 100 to 600. Preferable specific examples of such a sulfur atom-containing compound having a reducing ability include, for example, 1-cysteine, cysteine, d-cysteine, d1-cysteine, N-acetyl-1-cysteine, d1-homocysteine, 1 Cysteine methyl ester, 1-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteine derivatives of cysteamine, 2-mercaptoethanol, β-mercaptopropionic acid and its derivatives (β-mercaptopropionic acid 2-ethylhexyl, β-mercaptopropion) Acid 3-methoxybutyl, trimethylolpropane tris (β-thiopropionate, etc.), benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof (sodium salt, zinc salt, etc.) , 2-mercaptobenzimidazole and salts thereof (zinc salt etc.), 2-mercaptomethylbenzimidazole, 6-mercaptopurine, 6-methylmercaptopurine, 5-mercaptouracil, thiomalic acid and derivatives thereof (sodium salt etc.) Preferred examples include, but not limited to, those containing the same type of synergistic drugs. N-acetyl-1-cysteine or cysteamine is particularly preferred. All of these components are known compounds, and there are commercially available products. When using them, commercially available products can be purchased and used. Examples of commercially available products include acetylcysteine (Wako Pure Chemical Industries, Ltd.) and cysteamine (Wako Pure Chemical Industries, Ltd.).

Although there is no restriction | limiting in particular about the compounding quantity of the sulfur atom containing compound which has a reducing ability, It is preferable to determine according to a formulation form. For example, in the case of a dosage form such as a liquid that does not form a film, the effective amount for bifonazole localization to the nail is 0.1% to 20%, preferably 0.5%, based on the total weight of the formulation. Or 10%. In a preparation that forms a film, the content can be reduced as compared with a liquid agent, for example, 0.01 to 15% by mass, and more preferably 0.05 to 5% by mass.

Although there is no restriction | limiting about the compounding quantity of a bifonazole, What is necessary is just to use the quantity which is effective antifungal, and this can be changed with a formulation. For example, in a dosage form that does not form a film such as a liquid, the content is preferably 0.5% by mass to 10% by mass, and more preferably 1% by mass to 5% by mass with respect to the total mass. In the formulation which forms a film, it is 0.1-5 mass%, for example, More preferably, it is 0.3-3 mass%. Such a compounding quantity can be set according to the suitability of a formulation.

The dosage form of the composition of the present invention is not limited as long as it is an external preparation, and any suspension, emulsion, liquid, cream, ointment, plaster, patch, patch, tape, etc. can be applied. In addition, various kinds of additives such as stabilizers, surfactants, plasticizers, solubilizers, bases, suspending agents, antioxidants, wetting agents, softeners, emollients, absorptions as pharmaceutical ingredients Arbitrary components such as accelerators, pressure-sensitive adhesives, thickeners, pH adjusters, preservatives, solvents, and solubilizers can be added as necessary. Specific examples of such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, hardened coconut Oil, hydrogenated oil, mole, hardened castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, oils, waxes; liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, Hydrocarbons such as petrolatum, microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol, isos Higher alcohols such as allyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, apple Diisostearyl acid, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, Synthetic ester oils such as trimethylolpropane triisostearate and pentane erythritol tetra-2-ethylhexanoate; dimethylpolysiloxane, methylpheny Linear polysiloxanes such as polysiloxane and diphenylpolysiloxane; cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; amino-modified polysiloxane, polyether-modified polysiloxane, and alkyl-modified polysiloxane Oils such as silicone oil such as modified polysiloxane such as fluorine-modified polysiloxane; anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, alkylsulfuric acid triethanolamine ether; Cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2- Imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaines, amide betaines, sulfobetaines, etc.), and amphoteric surfactants such as acylmethyl taurine; sorbitan fatty acid esters ( Sorbitan monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (such as glyceryl monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ether, POE sorbitan fatty acid ester (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fat Acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonyl) Phenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.) , Nonionic surfactants such as sucrose fatty acid ester and alkyl glucoside; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, pro Polyhydric alcohols such as lenglycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol; pyrrolidonecarboxylic acid Moisturizing ingredients such as sodium, lactic acid, sodium lactate; surface may be treated, such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate, etc. Powders; surface may be treated, bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide inorganic pigments; surface may be treated, Pearl agents such as titanium mica, fish phosphorus foil, bismuth oxychloride; red 202 which may be raked No., Red 228, Red 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Organic dyes such as Blue No. 1, Green No. 201, Purple No. 201 and Red No. 204; Organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; Paraaminobenzoic acid UV absorber Anthranilic acid UV absorber; salicylic acid UV absorber; cinnamic acid UV absorber; benzophenone UV absorber; sugar UV absorber; 2- (2′-hydroxy-5′-t-octylphenyl); ) UV absorbers such as benzotriazole, 4-methoxy-4′-t-butyldibenzoylmethane; ethanol, isopropanol, etc. Lower alcohols; vitamin B or its derivatives, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or a derivative thereof, vitamin B such as vitamin B12, vitamin B15 or a derivative thereof; α-tocopherol, Preferred examples include vitamins such as β-tocopherol, γ-tocopherol, vitamin E acetate, vitamin D, vitamin D, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone, and the like; and antibacterial agents such as phenoxyethanol. The antifungal pharmaceutical composition for nail of the present invention can be produced by treating the essential component and the optional component according to a conventional method. The antifungal pharmaceutical composition for nail of the present invention thus obtained has excellent transfer of bifonazole as a drug into the nail when applied to the nail or higher, and therefore oral administration must be continued for a long period of time. Treatment of onychomycosis can be achieved by topical administration.

Anhydrous ethanol and 50% (v / v) ethanol were added and dissolved so that N-acetyl-1-cysteine was 5% (w / v), bifonazole and terbinafine were 10 mg / mL (hereinafter referred to as “bifonazole with reducing agent”). Solution ”,“ terbinafine solution with reducing agent ”). In addition, as a control group, anhydrous ethanol and 50% (v / v) ethanol were added and dissolved so that bifonazole and terbinafine would be 10 mg / mL without N-acetyl-1-cysteine (hereinafter referred to as “bifonazole without reducing agent”). Solution "," reducing agent-free terbinafine solution "). These solutions were left for 5 days in a 40 ° C. incubator.
On the other hand, a nail is set in a Franz-type cell. 500 μL of bifonazole solution with reducing agent, terbinafine solution with reducing agent, bifonazole solution without reducing agent, and terbinafine solution without reducing agent after standing at 40 ° C. for 5 days to this Franz-type cell on the nail plate side of Franz-type cell. And left in a 40 ° C. incubator for 7 days.
After standing for 7 days, the administration solution was removed, and the remaining drug was wiped off with a cotton swab soaked in water from the nail plate side. The contact part between the drug and the nail was punched with a biopsy punch of φ4mm. The nail piece was placed in a vial for liquid chromatography, ethanol was added to the vial, sonication was performed for 30 minutes, and bifonazole and terbinafine were extracted from the nail. The extract was measured by liquid chromatography. As a result, in the terbinafine solution-administered group (group 1) without reducing agent, about 0.43 mg / cm ^{3 of} terbinafine (hereinafter the same as “drug amount per 1 cm ³ nail piece”) penetrated into the nail, but reduced Terbinafine was not detected at all in the terbinafine solution-administered group (Group 2). On the other hand, in the group administered bifonazole solution without reducing agent (Group 3), about 0.32 mg / cm ^{3 of} bifonazole penetrated, whereas in the group administered with bifonazole solution containing reducing agent (Group 4), about 5.50 mg / cm ³ The difference in permeability was about 17 times. From this, it can be seen that the antifungal pharmaceutical composition for nail of the present invention is excellent in the action of transferring bifonazole as a drug to the nail. (Figure 1)

Anhydrous ethanol was added to 5% (w / v) of N-acetyl-1-cysteine or 5% (w / v) of cysteamine so that bifonazole was 10 mg / mL and dissolved. These solutions were left in a 40 ° C. incubator for 7 days. The concentration of bifonazole on the first day after standing and the concentration of bifonazole on the seventh day after standing were measured by liquid chromatography to determine the decomposition rate of bifonazole. As a result, bifonazole showed a degradation rate of 5% or less with N-acetyl-1-cysteine and cysteamine, and almost no degradation of bifonazole was observed. Thus, the antifungal pharmaceutical composition for nail of the present invention not only promotes the transfer of bifonazole to the nail, but also improves the stability of bifonazole near body temperature and further increases the effective drug utilization. I understand that.

  According to the formulation shown below, the antifungal pharmaceutical composition for nail of the present invention was produced. That is, the prescription ingredients were stirred at room temperature and solubilized by sonication to obtain the antifungal pharmaceutical composition for nail of the present invention. In the following formulation, bifonazole is hardly decomposed, and it can be presumed that N-acetyl-1-cysteine and cysteamine reduce the S—S bond in the nail and transfer it to the nail.

[Prescription 1]
Bifonazole 1% by mass
N-acetyl-1-cysteine 5% by mass
Ethanol 94 mass%
[Prescription 2]
Bifonazole 1% by mass
Cysteamine 5% by mass
Ethanol 94 mass%

The present invention can be applied to antifungal pharmaceutical compositions for nails.

It is a figure which shows the amount of bifonazole in the nail | claw of Example 1, and the amount of terbinafine.

Claims (6)

Antifungal pharmaceutical composition for nail, comprising bifonazole and sulfur atom-containing compound having reducing ability The sulfur atom-containing compound having reducing ability is 1-cysteine, cysteine, d-cysteine, d1-cysteine, N-acetyl-1-cysteine, d1-homocysteine, 1-cysteine methyl ester, 1-cysteine ethyl ester, N -Carbamoylcysteine, glutathione and cysteamine cysteine derivatives and 2-mercaptoethanol, β-mercaptopropionic acid and its derivatives, benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof, 2-mercaptobenzimidazole and salts thereof , 2-mercaptomethylbenzimidazole, 6-mercaptopurine, 6-methylmercaptopurine, 5-mercaptouracil, and thiomalic acid and its derivatives 2. One or more selected from ammonium thioglycolate, 2-ethylhexyl thioglycolate, butyl thioglycolate, methoxybutyl thioglycolate and trimethylolpropane tris (thioglycolate) Antifungal pharmaceutical composition for nail as described Sulfur atom-containing compounds having reducing ability include 1-cysteine, cysteine, d-cysteine, d1-cysteine, d1-homocysteine, 1-cysteine methyl ester, 1-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteamine. Cysteine derivatives and 2-mercaptoethanol, β-mercaptopropionic acid and derivatives thereof, benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof, 2-mercaptobenzimidazole and salts thereof, 2-mercaptomethylbenzimidazole, 6-mercaptopurine, 6-methylmercaptopurine, 5-mercaptouracil, and thiomalic acid and its derivatives mercaptans and ammonium thioglycolate It is 1 type or 2 types or more selected from 2-ethylhexyl thioglycolate, butyl thioglycolate, methoxybutyl thioglycolate, and trimethylol propane tris (thioglycolate). Antifungal pharmaceutical composition The sulfur atom-containing compound having reducing ability is 1-cysteine, cysteine, d-cysteine, d1-cysteine, N-acetyl-1-cysteine, d1-homocysteine, 1-cysteine methyl ester, 1-cysteine ethyl ester, N A cysteine derivative of carbamoylcysteine, glutathione and cysteamine and one or more selected from ammonium thioglycolate, 2-ethylhexyl thioglycolate, butyl thioglycolate, methoxybutyl thioglycolate and trimethylolpropane tris (thioglycolate) The antifungal pharmaceutical composition for nails according to claim 1, wherein is at least two kinds A sulfur atom-containing compound having a reducing ability is 2-mercaptoethanol, β-mercaptopropionic acid and derivatives thereof, benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof, 2-mercaptobenzimidazole and salts thereof, 2-mercaptomethylbenzimidazole, 6-mercaptopurine, 6-methylmercaptopurine, 5-mercaptouracil and mercaptans of thiomalic acid and its derivatives and ammonium thioglycolate, 2-ethylhexyl thioglycolate, butyl thioglycolate, thio The antifungal pharmaceutical composition for nail according to claim 1, wherein the composition is one or more selected from methoxybutyl glycolate and trimethylolpropane tris (thioglycolate). The decomposition of the bifonazole is 5% or less when 5 parts by mass of a sulfur compound having a reducing ability contained in the preparation coexists with 1 part by mass of bifonazole and stored at 40 ° C for 7 days. Or an antifungal pharmaceutical composition according to claim 5.

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