WO2004073715A1 - Antifungal agents - Google Patents

Antifungal agents Download PDF

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Publication number
WO2004073715A1
WO2004073715A1 PCT/JP2004/001892 JP2004001892W WO2004073715A1 WO 2004073715 A1 WO2004073715 A1 WO 2004073715A1 JP 2004001892 W JP2004001892 W JP 2004001892W WO 2004073715 A1 WO2004073715 A1 WO 2004073715A1
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Prior art keywords
hydrochloride
amorolfine hydrochloride
foot
amorolfine
composition
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PCT/JP2004/001892
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French (fr)
Japanese (ja)
Inventor
Hideki Kohita
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Taisho Pharmaceutical Co., Ltd.
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Priority to JP2005502765A priority Critical patent/JP4730094B2/en
Publication of WO2004073715A1 publication Critical patent/WO2004073715A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to an antifungal composition having enhanced efficacy of amorolfine hydrochloride.
  • Athlete's foot is generally said to be difficult to heal, due to the long-term application of the drug. Many of the patients stop the drug application on their own judgment because the symptoms of athlete's foot subside when the activity of the bacteria is reduced in the winter, and the therapeutic effect of the drug cannot be fully exerted.
  • Amorolfine hydrochloride is one of the most commonly used antifungal agents in Japan. Amorolfine hydrochloride is classified as a morpholine antifungal and has a new structure different from conventional imidazoles, thiocarbamates, benzylamines, and arylamines. The mechanism of action is to inhibit the biosynthesis of ergosterol in the fungal cell wall, and the site of action exhibits strong antifungal activity by selectively inhibiting the two steps of ⁇ U reductase reaction and isomerase reaction.
  • Amorolfine hydrochloride has a broad antibacterial spectrum against pathogenic fungi such as Trichophyton, Candida, Microspores, Epidermophytes, Aspergillus and Penicillium, and its MIC against dermatophytes is particularly high. Very low.
  • amorolfine hydrochloride also requires continuous administration for a long period of time to completely cure athlete's foot, and often fails to provide a sufficient therapeutic effect. Therefore, antifungal agents having more excellent effects have been demanded.
  • the present inventors have conducted various studies on antifungal agents having an effect on Trichophyton, and as a result, exhibiting an excellent antifungal effect by combining amorolfine and certain components simultaneously as an antifungal agent This led to the completion of the present invention.
  • the present invention provides:
  • An antifungal agent containing amololfin hydrochloride and at least one selected from the following (1) to (4).
  • a method for treating athlete's foot, cotton beetle or cold bug comprising applying to the affected area a drug containing at least one selected from amorolfine hydrochloride and the following (1) to (4).
  • amorolfine hydrochloride and at least one component selected from the following (1) to (4) for the production of an antifungal agent.
  • the compounding amount of amololfin hydrochloride is 0.1 to 1% by mass, preferably 0.2 to 0.8% by mass of the whole preparation (in the case of an azol agent, in a stock solution).
  • the compounding amount of the components to be added at the same time varies depending on the components.
  • 1 part by mass of amololfin hydrochloride 1 the compounding amount of miconazole nitrate is 0.2 to 5 parts by mass
  • 2 the compounding amount of ciclopirox olamine is , 0.2 to 5 parts by mass, preferably 0.5 to 2 parts by mass
  • 3 tolnaphthate is 0.4 to 10 parts by mass, preferably 1 to 4 parts by mass, 4 salicylic acid
  • the compounding amount is 0.2 to 5 parts by mass, preferably 0.5 to 2 parts by mass.
  • the compounding amount of chlorhexidine hydrochloride is 0.1 to 5 parts by mass, preferably 0.5 to 2 parts by mass.
  • the amount of benzethonium chloride is 0.01 to 5 parts by mass, preferably 0.05 to 2 parts by mass, and the amount of decalinium chloride is 0.01 to 5 parts by mass, preferably 0.00 parts by mass. 5 to 2 parts by mass, 8 Hinokitiol: 0.0: 0.5 to 0.5 parts by mass, preferably 0.05 to 0.2 parts by mass, zinc
  • the amount of Richion is from 0.1 to 5.0 parts by weight, preferably from 1.0 to 5.0 parts by weight.
  • composition of the present invention may be mixed with ordinary additives, if necessary, and used in a conventional manner to give a solution, a mouthwash, an emulsion, a tincture, an ointment, a cream, a water-based gel, an oil External preparations such as gels, aerosols, and powders can be used.
  • Examples of the components that can be added in the present invention include water-soluble components such as propylene glycol, 1,3-butylene glycol, glycerin, ethanol, and macrogol.
  • the oily components that can be blended in the present invention include diisopropyl adipate, stearyl alcohol, cetanol, squalane, medium-chain triglyceride, and the like.
  • Examples of the polymer that can be blended in the present invention include lipoxyvinyl polymer, methyl cellulose, and ethyl cellulose.
  • pH adjusters that can be added in the present invention citric acid, sodium hydroxide, diisopropa Nordamine and the like.
  • antioxidant examples include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), sodium tocopherol, erythorbic acid, sodium pyrosulfite and the like.
  • surfactants examples include polyoxetylene hardened castor oil, sorbitan monostearate, solpimonomonopalate; Kishetylene, holoxyp ⁇ pyrene block copolymer, polysorbates, lauryl sulfate natucum, sucrose fatty acid ester, lecithin, and the like. EDTA-2 Na and the like.
  • composition of the present invention has an excellent antifungal effect on Trichophyton, it has an excellent therapeutic effect on athlete's foot, bedbug, or common bug.
  • Aqueous phase components (1,3—butylene glycol, urea,. EDTA-2N purified water) And the oil phase components (amorolfine hydrochloride, miconazole nitrate, lidocaine, sorbitan monostearate, polyoxyethylene sorbitan monostearate, medium-chain fatty acid triglyceride, glycerin monostearate) and then mixed Then, 100 g of a cream was produced in a usual manner.
  • the oil phase components (amorolfine hydrochloride, lidocaine, 1-menthol, polyoxyethylene sorbitan monostearate, white petrolatum, stearyl alcohol, liquid paraffin) are heated and dissolved, and purified water is used. After adding the oil phase to the swollen lipoxyvinyl polymer and emulsifying, 1,3-butylene glycol and decalinium chloride, benzalkonium chloride, dipotassium glycyrrhizinate, dipotassium glycyrrhizinate, diisopropanolamine and EDTA-2 dissolved in purified water Na was added to produce a gel cream.
  • a stock solution was prepared by dissolving other stock solution components in a base of ethanol and purified water. After filling the container, a valve was attached, and the propellant was filled to produce an aerosol.
  • the FIC index (Fractional Inhibitory Concentration index) was measured using a combination of amorolfine hydrochloride and each sample, and the synergistic effect and synergistic effect were measured.
  • the antibacterial activity was determined visually when the growth control clearly turned red.
  • the minimum concentration of the blue well similar to the negative control was defined as the MIC value (minimum inhibitory concentration, ⁇ gZml).
  • the FIC index Fractional Inhibitory Concentration index
  • FIC index + 'MIC of amo mouth rufin hydrochloride alone MIC judgment of other drugs alone, antagonism of greater than 2 is additive, 2-1 is additive, and 1 or less is synergistic Determined the effect.
  • amorolfine hydrochloride since the action of amorolfine hydrochloride can be further enhanced, it has become possible to provide an antifungal agent which is extremely effective against dermatophytes.

Abstract

An antifungal agent containing amorolfine hydrochloride together with at least one member selected from the following components (1) to (9): (1) miconazole nitrate, (2) ciclopriox olamine, (3) tolnaftate, (4) salicylic acid, (5) chlorhexidine hydrochloride, (6) benzethonium chloride, (7) decalinium chloride, (8) hinokitiol and (9) zinc pyrithione. Compared with the case of used alone, individual components exert synergistic effects on the fungus causative of athlete’s foot. Thus, the above agent is useful as a drug for athlete’s foot on which satisfactory therapeutic effects can be hardly exerted hitherto because of interruption in continuous drug application before complete cure.

Description

明 鲁  Akira 鲁
抗真菌剤 技術分野  Antifungal technology
本発明は、 塩酸ァモロルフィ ンの効力が増強された抗真菌組成物に関 する。 背景技術  The present invention relates to an antifungal composition having enhanced efficacy of amorolfine hydrochloride. Background art
水虫は一般的に治りにくいといわれているが、 それは長期間薬剤を塗 布し続けなければならないことに起因する。 患者の多くは冬場に菌の活 動が緩和になると水虫の症状が治まることから、 自己判断で薬剤塗布を 中断してしまい、 薬剤の治療効果が十分発揮できないからである。  Athlete's foot is generally said to be difficult to heal, due to the long-term application of the drug. Many of the patients stop the drug application on their own judgment because the symptoms of athlete's foot subside when the activity of the bacteria is reduced in the winter, and the therapeutic effect of the drug cannot be fully exerted.
したがって短期間で優れた効果を現す抗真菌剤を提'供できれば水虫の 治療に有効であるが、 従来十分満足できるものは無かった。  Therefore, providing an antifungal agent that exhibits excellent effects in a short period of time would be effective in treating athlete's foot, but none of them has been satisfactory until now.
塩酸ァモロルフィ ンは、 我が国でも現在凡用されている抗真菌剤の一 つである。 塩酸ァモロルフイ ンは、 モルホリ ン系抗真菌剤に分類され、 従来のイミダゾール系、 チォカルバメート系、 ベンジルァミン系、 ァリ ルァミン系とは異なる新しい構造を有する。 作用機序は真菌細胞壁エル ゴステロールの生合成の阻害にあり、 その作用点は△ U レダクターゼ反. 応および イソメラーゼ反応の 2段階を選択的に阻害すること により強い抗真菌活性を示す。  Amorolfine hydrochloride is one of the most commonly used antifungal agents in Japan. Amorolfine hydrochloride is classified as a morpholine antifungal and has a new structure different from conventional imidazoles, thiocarbamates, benzylamines, and arylamines. The mechanism of action is to inhibit the biosynthesis of ergosterol in the fungal cell wall, and the site of action exhibits strong antifungal activity by selectively inhibiting the two steps of △ U reductase reaction and isomerase reaction.
塩酸ァモロルフイ ンは白癬菌属、 カンジダ属をはじめ、 小胞子菌属、 表皮菌属、 ァスペルギルス属、 ぺニシリウム属などの病原性真菌に対し 幅広い抗菌スペク トルをもち、 特に皮膚糸状菌に対する M I C値は非常 に低い。  Amorolfine hydrochloride has a broad antibacterial spectrum against pathogenic fungi such as Trichophyton, Candida, Microspores, Epidermophytes, Aspergillus and Penicillium, and its MIC against dermatophytes is particularly high. Very low.
しかし、 塩酸ァモロルフィ ンも水虫を完治させるためには長期間の継 続した投与が必要であり、十分な治療効果が得られない.ことが多かつた。 そのため、 より優れた効果を有する抗真菌剤が求められていた。  However, amorolfine hydrochloride also requires continuous administration for a long period of time to completely cure athlete's foot, and often fails to provide a sufficient therapeutic effect. Therefore, antifungal agents having more excellent effects have been demanded.
従来、 ァモロルフイ ンについては、 その持効性の向上を目的とした技 術 （日本国特開 2 00 1 - 3 3 5487 ) などが知られているが、 その相乗効果を 発現させる成分については報告されていない。 発明の開示 Conventionally, with regard to amorolfine, a technology aimed at improving its durability was developed. (Japanese Patent Application Laid-Open No. 2000-1335487) and the like, but there is no report on a component exhibiting the synergistic effect. Disclosure of the invention
本発明者らは、 白癬菌属に効力を有する抗真菌剤について種々検討し た結果、 抗真菌剤としてァモロルフイ ンとある種の成分を同時に配合す ることにより、 優れた抗真菌効果を発揮することを見出し本発明を完成 した。  The present inventors have conducted various studies on antifungal agents having an effect on Trichophyton, and as a result, exhibiting an excellent antifungal effect by combining amorolfine and certain components simultaneously as an antifungal agent This led to the completion of the present invention.
すなわち、 本発明は、 - That is, the present invention provides:
1 . 塩酸ァモロルフイ ンおよび以下の①〜⑨から選ばれた少なく とも 1 種を含む抗真菌剤。 1. An antifungal agent containing amololfin hydrochloride and at least one selected from the following (1) to (4).
①硝酸ミコナゾ一ル、 ②シクロピロクスオラミン、 ③トルナフテート、 ④サリチル酸、 ⑤塩酸クロルへキシジン、 ⑥塩化べンゼトニゥム、 ⑦塩 化デカリニゥム、 ⑧ヒノキチオール、 ⑨ジンクピリチオン  ①Miconazole nitrate, ②Ciclopirox olamine, ③Tornaphthate, ④Salicylic acid, ⑤Chlorohexidine hydrochloride, ⑥Benzetonium chloride, ⑦Decalinium chloride, ⑧Hinokitiol, ⑨Zinc pyrithione
2 . 塩酸ァモロルフイ ンの配合量が製剤全体の 0 . 1 〜 1質量％である 1記載の抗真菌剤。  2. The antifungal agent according to 1, wherein the amount of amololfin hydrochloride is 0.1 to 1% by mass of the whole preparation.
3 . 塩酸ァモロルフイ ンおよび以下の①〜⑨から選ばれた少なく とも 1 種を含む薬剤を患部に塗布することを特徴とする、 水虫、 いんきんたむ し又はぜにたむしの治療方法。  3. A method for treating athlete's foot, cotton beetle or cold bug, comprising applying to the affected area a drug containing at least one selected from amorolfine hydrochloride and the following (1) to (4).
①硝酸ミコナゾール、 ②シクロピロクスオラミン、 ③トルナフテ一 ト、 ④サリチル酸、 ⑤塩酸クロルへキシジン、 ⑥塩化べンゼトニゥム、 ⑦塩 化デカリニゥム、 ⑧ヒノキチオール、 ⑨ジンクピリチオン  (1) Miconazole nitrate, (2) Ciclopirox olamine, (3) Tolnaphthate, (4) Salicylic acid, (4) Chlorhexidine hydrochloride, (4) Benzetonium chloride, (4) Decalinium chloride, (6) Hinokitiol, (6) zinc pyrithione
4 . 塩酸ァモロルフイ ンおよび以下の①〜⑨から選ばれた少なく とも 1 種の成分の、 抗真菌剤製造のための使用。 4. Use of amorolfine hydrochloride and at least one component selected from the following (1) to (4) for the production of an antifungal agent.
①硝酸ミコナゾ一ル、 ②シクロピロクスオラミン、 ③トルナフテート、 ④サリチル酸、 ⑤塩酸クロルへキシジン、 ⑥塩化べンゼトニゥム、 ⑦塩 化デカリニゥム、 ⑧ヒノキチオール、 ⑨ジンクピリチオン  ①Miconazole nitrate, ②Ciclopirox olamine, ③Tornaphthate, ④Salicylic acid, ⑤Chlorohexidine hydrochloride, ⑥Benzetonium chloride, ⑦Decalinium chloride, ⑧Hinokitiol, ⑨Zinc pyrithione
である。 本発明において、 塩酸ァモロルフイ ンの配合量は、 製剤全体 （エアゾ ール剤の場合は原液中） の 0. 1〜 1質量％であり、 好ましくは 0. 2 〜 0. 8質量％である。 It is. In the present invention, the compounding amount of amololfin hydrochloride is 0.1 to 1% by mass, preferably 0.2 to 0.8% by mass of the whole preparation (in the case of an azol agent, in a stock solution).
同時配合する成分の配合量はその成分により異なり、 塩酸ァモロルフ イ ン 1質量部に対して、 ①硝酸ミコナゾ一ルの配合量は 0. 2〜 5質量 部、 ②シクロピロクスオラミンの配合量は、 0. 2〜 5質量部、 好まし くは 0. 5質量部〜 2質量部、 ③トルナフテートの配合量は、 0. 4〜 1 0質量部、 好ましくは 1〜 4質量部、 ④サリチル酸の配合量は、 0. 2〜 5質量部、 好ましくは 0. 5〜 2質量部、 ⑤塩酸クロルへキシジン の配合量は、 0. 1〜 5質量部、 好ましくは 0. 5〜 2質量部、 ⑥塩化 ベンゼトニゥムの配合量は 0. 0 1〜 5質量部、 好ましくは 0. 0 5〜 2質量部、 ⑦塩化デカリニゥムの配合量は、 0. 0 1〜 5質量部、 好ま しくは 0. 0 5質量部〜 2質量部、 ⑧ヒノキチオールの配合量は 0. 0 ：!〜 0. 5質量部、 好ましくは 0. 0 5質量部〜 0. 2質量部、 ⑨ジン クピリチオンの配合量は、 0. 1〜 5. 0質量部、 好ましくは 1. 0〜 5. 0質量部である。  The compounding amount of the components to be added at the same time varies depending on the components. For 1 part by mass of amololfin hydrochloride, ① the compounding amount of miconazole nitrate is 0.2 to 5 parts by mass, and ② the compounding amount of ciclopirox olamine is , 0.2 to 5 parts by mass, preferably 0.5 to 2 parts by mass, ③ tolnaphthate is 0.4 to 10 parts by mass, preferably 1 to 4 parts by mass, ④ salicylic acid The compounding amount is 0.2 to 5 parts by mass, preferably 0.5 to 2 parts by mass.The compounding amount of chlorhexidine hydrochloride is 0.1 to 5 parts by mass, preferably 0.5 to 2 parts by mass. The amount of benzethonium chloride is 0.01 to 5 parts by mass, preferably 0.05 to 2 parts by mass, and the amount of decalinium chloride is 0.01 to 5 parts by mass, preferably 0.00 parts by mass. 5 to 2 parts by mass, ⑧ Hinokitiol: 0.0: 0.5 to 0.5 parts by mass, preferably 0.05 to 0.2 parts by mass, zinc The amount of Richion is from 0.1 to 5.0 parts by weight, preferably from 1.0 to 5.0 parts by weight.
本発明の組成物は、 必要に応じて通常の添加剤などを混合して常法に より、 液剤、 口一シヨ ン剤、 乳剤、 チンキ剤、 軟膏剤、 クリーム剤、 水 性ゲル剤、 油性ゲル剤、 エアゾール剤、 パウダー剤などの外用製剤とす ることができる。  The composition of the present invention may be mixed with ordinary additives, if necessary, and used in a conventional manner to give a solution, a mouthwash, an emulsion, a tincture, an ointment, a cream, a water-based gel, an oil External preparations such as gels, aerosols, and powders can be used.
本発明において配合できる成分としては、 水溶性成分として、 プロピ レンダリコール、 1 , 3 —ブチレングリ コ一ル、 グリセリン、 エタノー ル、 マクロゴール類などがあげられる。 本発明において配合できる油性 成分として、 アジピン酸ジイソプロピル、 ステアリルアルコール、 セタ ノール、 スクヮラン、 中鎖トリグリセライ ドなどがあげられる。 本発明 において配合できる高分子として、 力ルポキシビ二ルポリマー、 メチル セルロース、 ェチルセルロースなどがあげられる。 本発明において配合 できる p H調整剤として、 クェン酸、 水酸化ナトリウム、 ジイソプロパ ノールァミ ンなどがあげられる。 本発明において配合できる抗酸化剤と して、 ジブチルヒ ドロキシトルエン （ B H T )、 プチルヒ ドロキシァニソ ール （B H A )、 ひ一 トコフエロール、 エリ ソルビン酸、 ピロ亜硫酸ナト リウムなどがあげられる。本発明において配合できる界面活性剤と して、 ポリォキシェチレン硬化ヒマシ油 、 ソルビ夕ンモノステアレー 卜 、 ソル ピ夕ンモノパル ；テ一卜、 グリセリ ンモノステアレ一ト、 ソルビ夕ンモ ノ ラウレ一 ト、 ポリォキシェチレン 、 ホリォキシプ □ピレンブロックコポ リマ一、 ポリ ソルべー ト類、 ラウリル硫酸ナ卜 U クム 、 ショ糖脂肪酸ェ ステル、 レシチンなどがあげられ 本発明において配合できる安定化 剤として、 E D T A— 2 N aなどがあげられる。 Examples of the components that can be added in the present invention include water-soluble components such as propylene glycol, 1,3-butylene glycol, glycerin, ethanol, and macrogol. The oily components that can be blended in the present invention include diisopropyl adipate, stearyl alcohol, cetanol, squalane, medium-chain triglyceride, and the like. Examples of the polymer that can be blended in the present invention include lipoxyvinyl polymer, methyl cellulose, and ethyl cellulose. As pH adjusters that can be added in the present invention, citric acid, sodium hydroxide, diisopropa Nordamine and the like. Examples of the antioxidant that can be added in the present invention include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), sodium tocopherol, erythorbic acid, sodium pyrosulfite and the like. Examples of the surfactants that can be blended in the present invention include polyoxetylene hardened castor oil, sorbitan monostearate, solpimonomonopalate; Kishetylene, holoxyp □ pyrene block copolymer, polysorbates, lauryl sulfate natucum, sucrose fatty acid ester, lecithin, and the like. EDTA-2 Na and the like.
本発明の組成物は白癬菌に対して優れた抗真菌効果を有するので、 水 虫、 いんきんたむし又はぜにたむしに対して優れた治療効果を有する。 発明を実施するための最良の形態  Since the composition of the present invention has an excellent antifungal effect on Trichophyton, it has an excellent therapeutic effect on athlete's foot, bedbug, or common bug. BEST MODE FOR CARRYING OUT THE INVENTION
以下実施例および試験例により 、 本発明を詳細に説明する  Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples.
実施例 1 Example 1
(ク リーム）  (Cream)
塩酸ァモロルフィ ン 0 . 5 5 7 5 g Amorolfine hydrochloride 0.5 5 7 5 g
硝酸ミ コナゾール 1 . 0 g 1.0 g of miconazole nitrate
リ ドカイン 2 . 0 g Lidocaine 2.0 g
rリオキシヱチレンソルビタンモノステアレ-ト 4 . 0 g r Reoxydylene sorbitan monostearate 4.0 g
ソルビタンモノステアレー ト 2 . 0 g Sorbitan monostearate 2.0 g
1 , 3 —ブチレングリ コール 1 5 . 0 g  1, 3 —butylene glycol 15.0 g
中鎖脂肪酸 ト リ グリセリ ド 1 5 . 0 g Medium-chain fatty acid triglyceride 15.0 g
グリセリ ンモノステアレー ト 2 5 . 0 g Glycerin monostearate 25.0 g
E D T A— 2 N a 0 . 1 g  E D T A— 2 N a 0.1 g
精製水 全 1 0 0 g Purified water 100 g
水相成分 （ 1 , 3 —ブチレングリ コ、ール, . E D T A - 2 N 精製水） および油層成分（塩酸ァモロルフイ ン、 硝酸ミコナゾ一ル、 リ ドカイ ン、 ソルビタンモノステアレー ト、 ポリオキシエチレンソルビタンモノステ ァレー ト、 中鎖脂肪酸ト リ グリセリ ド、 グリセリ ンモノステアレー ト） をそれぞれ加温後混合し、 通常の方法でク リーム 1 0 0 gを製造した。 実施例 2 Aqueous phase components (1,3—butylene glycol, urea,. EDTA-2N purified water) And the oil phase components (amorolfine hydrochloride, miconazole nitrate, lidocaine, sorbitan monostearate, polyoxyethylene sorbitan monostearate, medium-chain fatty acid triglyceride, glycerin monostearate) and then mixed Then, 100 g of a cream was produced in a usual manner. Example 2
(ゲルク リーム）  (Gel cream)
塩酸ァモロルフィ ン 0 . 5 5 Amorolfine hydrochloride 0.5 5
ヒノキチオール 0 . 1 g Hinokitiol 0.1 g
リ ドカイ ン 2 . 0 g Lidocaine 2.0 g
ホ。リオキシエチレンリルビタンモノステアレ-ト 1 . 0 g E. Lioxyethylene rubitan monostearate 1.0 g
プロピレングリ コール 1 0 . 0 g Propylene glycol 10.0 g
中鎖脂肪酸ト リ グリセリ ド 5 . 0 g Medium-chain fatty acid triglyceride 5.0 g
ステアリルアルコール 1 . 0 g Stearyl alcohol 1.0 g
力ルポキシビ二ルポリマー 0 . 5 g 0.5 g of Ripoxyvinyl polymer
ジイソプロパノールァミ ン Μ Diisopropanolamine Μ
E D T A - 2 N a 0 . 1 g  E D T A-2 N a 0.1 g
If $¾ 7χ 全 1 0 0 g If $ ¾ 7 χ 1 0 0 g
油相成分 （塩酸ァモロルフイ ン、 ヒノキチオール、 リ ドカイ ン、 ポリ ォキシエチレンソルビタンモノステアレー ト、 中鎖脂肪酸ト リ グリセリ ド、 ステアリルアルコール） を加温溶解し、 プロピレングリ コールを加 え、 さ らに、 精製水により膨潤させた力ルポキシビ二ルポリマーに油相 を加え乳化後、 精製水に溶解した中和剤および E D T A— 2 N a を添加 し、 ゲルク リームを製造した。 実施例 3  Heat and dissolve the oil phase components (amololfin hydrochloride, hinokitiol, lidocaine, polyoxyethylene sorbitan monostearate, medium-chain fatty acid triglyceride, stearyl alcohol), add propylene glycol, and add. Then, the oil phase was added to the lipoxyvinyl polymer swollen with purified water, emulsified, and a neutralizing agent and EDTA-2Na dissolved in the purified water were added to produce a gel cream. Example 3
(ゲルク リーム）  (Gel cream)
塩酸ァモロルフィ ン 0 . 5 5 7 5 g 塩化デカリニゥム 0. 1 g Amorolfine hydrochloride 0.5 5 7 5 g Decalinium chloride 0.1 g
リ ドカイ ン 2. 0 g Lidocaine 2.0 g
グリチルリチン酸二カリ ウム 0. 5 g 0.5 g of dipotassium glycyrrhizinate
塩化ベンザルコニゥム 0. 0 5 g Benzalkonium chloride 0.0 5 g
1 —メ ン トール 1. 0 g  1—menthol 1.0 g
ホ。リオキシ Iチレンソルビタンモノステアレ-ト 3. 0 g E. Reoxy I-butylene sorbitan monostearate 3.0 g
1 , 3 —ブチレングリ コ一ル 5. 0 g  1, 3 — Butylene glycol 5.0 g
ステアリルアルコール 5. 0 g Stearyl alcohol 5.0 g
白色ヮセリ ン 5. 0 g White cellulose 5.0 g
中鎖脂肪酸ト リ グリセリ ド 5. 0 g Medium chain fatty acid triglyceride 5.0 g
カルボキシビ二ルポリマー 1 . 0 g Carboxyvinyl polymer 1.0 g
E D T A- 2 N a 0. 1 g  E D T A- 2 N a 0.1 g
ジイソプロパノ一ルァミ ン 適量 Diisopropanolamine qs
精製水 全 1 0 0 g Purified water 100 g
油相成分 （塩酸ァモロルフイ ン、 リ ドカイ ン、 1 —メン トール、 ポリ ォキシエチレンソルビタンモノステアレー ト、 白色ワセリ ン、 ステアリ ルアルコール、 流動パラフィ ン） を加温溶解し、 精製水によ り膨潤させ た力ルポキシビ二ルポリマーに油相を加え乳化後、 1， 3 —ブチレング リ コールおよび精製水に溶解した塩化デカリニゥム、 塩化ベンザルコニ ゥム、 グリチルリチン酸二カリウム、 ジイソプロパノールァミ ンおよび E D T A— 2 N aを添加し、 ゲルク リームを製造した。 実施例 4  The oil phase components (amorolfine hydrochloride, lidocaine, 1-menthol, polyoxyethylene sorbitan monostearate, white petrolatum, stearyl alcohol, liquid paraffin) are heated and dissolved, and purified water is used. After adding the oil phase to the swollen lipoxyvinyl polymer and emulsifying, 1,3-butylene glycol and decalinium chloride, benzalkonium chloride, dipotassium glycyrrhizinate, dipotassium glycyrrhizinate, diisopropanolamine and EDTA-2 dissolved in purified water Na was added to produce a gel cream. Example 4
(口一ショ ン）  (Mouthpiece)
塩酸ァモロルフィ ン 0. 5 5 7 5 g Amorolfine hydrochloride 0.5 5 7 5 g
塩化べンゼ卜ニゥム 0. 1 g Benzene chloride 0.1 g
リ ドカイン 2. 0 g Lidocaine 2.0 g
グリチルリチン酸ジカリ ウム 0. 5 g ポリエチレングリコール 4 0 0 1 0 . 0 g エタノール 5 0 . 0 g 精製水 全 1 0 0 m 1 上記処方で、 常法によりローシヨ ン剤を製造した。 実施例 5 0.5 g of dicalidium glycyrrhizinate Polyethylene glycol 40.00.0 g Ethanol 50.0 g Purified water Total 100 m1 A lotion formulation was produced according to the above-mentioned formulation by an ordinary method. Example 5
(ローショ ン）  (Lotion)
塩酸ァモロルフィ ン 0 . 5 5 7 ！ 塩化べンゼトニゥム 0 . 1 g リ ドカイン 2 . 0 g ダリチルリチン酸二力リウム 0 . 5 g 塩化ベンザルコニゥム 0 . 0 5 gAmorolfine hydrochloride 0.5 5 7! Benzetonium chloride 0.1 g Lidocaine 2.0 g Dilithium lithium daricyllithate 0.5 g Benzalkonium chloride 0.05 g
1 一メントール 1 . 0 g ポリエチレングリコール 4 0 0 1 0 . 0 g 力ルポキシビ二ルポリマ一 0 . 2 g ポリ ビニルピ口リ ドン 1 . 0 g エタノール 4 5 . 0 g ジイソプロパノ一ルァミン 適 —曰- 精製水 全 1 0 0 m 1 上記処方で、 常法により ローシヨ ン剤を製造した。 実施例 6 1 Menthol 1.0 g Polyethylene glycol 400 10.0 g Ripoxyvinyl polymer 0.2 g Polyvinylpiperidone 1.0 g Ethanol 45.0 g Diisopropanolamine Suitable for-purified water A total of 100 m 1 was prepared with the above formulation and a lotion formulation in a conventional manner. Example 6
(エアゾール剤）  (Aerosol)
原液 ： Stock solution:
塩酸ァモロルフィ ン 2 7 . 8 9 5 i トルナフテート 5 0 g Amorolfine hydrochloride 27.8 9 5 i Tolnaftate 50 g
グリチルリチン酸ジカリウム 2 5 g Dipotassium glycyrrhizinate 25 g
エタノール 2 5 0 0 g 精製水 全 5 0 0 0 m 1 Ethanol 250 g Purified water Total 5 0 0 0 m 1
噴射剤 ： Propellant:
D ME 5 0 0 0 m l  D ME 500 0 0 ml
エタノール、精製水の基剤に他の原液成分を溶解しで原液を製造した。 容器に充填後、 バルブを装着し、 噴射剤を充填してエアゾール剤を製造 した。  A stock solution was prepared by dissolving other stock solution components in a base of ethanol and purified water. After filling the container, a valve was attached, and the propellant was filled to produce an aerosol.
試験例 1 Test example 1
塩酸ァモロルフイ ンと各検体の組み合わせにより F I Cインデックス (Fractional Inhibitory Concentration index) を測定し、 相力口 · 相乗 効果を測定した。  The FIC index (Fractional Inhibitory Concentration index) was measured using a combination of amorolfine hydrochloride and each sample, and the synergistic effect and synergistic effect were measured.
検体として、 硝酸ミコナゾ一ル、 シクロピロクスオラミン、 トルナフ テート、 サリチル酸、 塩酸クロルへキシジン、 塩化べンゼトニゥム、 塩 化デカリニゥム、 ヒノキチオールおよびジンクピリチオンを用いた。 感受性試験は日本医真菌学会 （標準化委員会） 提案微量液体希釈法に て行った。 感受性測定用培地として、 0.165M MOPS-RPMI 1640 を用いた。 薬剤を含む培地に約 1 05分生子/] nl に調製した菌液を接種、 2 8 °C、 にて最長 7 日間培養した。 抗菌力の判定は発育コン トロールが明らかに 赤変した時点で目視にて行った。 陰性コントロールと同様の青色を示す ゥエルの最小濃度を M I C値 （最小発育阻止濃度、 ^ gZml) とした。 チ エツ力一ボー ド法により F I Cイ ンデックス （Fractional Inhibitory Concentration index) を算出した。 As samples, miconazole nitrate, ciclopirox olamine, tolnaphthate, salicylic acid, chlorhexidine hydrochloride, benzethonium chloride, decalinium chloride, hinokitiol and zinc pyrithione were used. The susceptibility test was performed using the microfluidic dilution method proposed by the Japanese Society for Medical Mycology (Standardization Committee). As a culture medium for sensitivity measurement, 0.165M MOPS-RPMI 1640 was used. Inoculated about 1 0 5 conidia /] bacterial solution prepared in nl in a medium containing the drug, 2 8 ° C, and cultured up to 7 days at. The antibacterial activity was determined visually when the growth control clearly turned red. The minimum concentration of the blue well similar to the negative control was defined as the MIC value (minimum inhibitory concentration, ^ gZml). The FIC index (Fractional Inhibitory Concentration index) was calculated by the Chietz force board method.
算出式 ； Calculation formula;
併用時の塩酸ァモロルフイン M I C 併用時の他剤 M I C Amorolfine hydrochloride in combination with M I C Other agent in combination with M I C
F I Cインデックス = + ' 塩酸ァモ口ルフィン単独時の M I C 他剤単独時の M I C 判定は、 2より大きいものを拮抗作用、 2〜 1のものを相加作用、 1 以下のものを相乗効果として併用効果の判定をした。 FIC index = + 'MIC of amo mouth rufin hydrochloride alone MIC judgment of other drugs alone, antagonism of greater than 2 is additive, 2-1 is additive, and 1 or less is synergistic Determined the effect.
得られた F I Cインデックスの結果を表 1 に示した。 表 1 塩酸ァモロルフィ ンの併用時における併用効果 The results of the obtained FIC index are shown in Table 1. Table 1 Effect of combination use of amorolfine hydrochloride
Figure imgf000010_0001
表から明らかなように、 全ての薬剤で水虫の代表的な菌種に対して相 乗効果を有することがわかった。 産業上の利用可能性
Figure imgf000010_0001
As is clear from the table, all the drugs were found to have a synergistic effect on the representative bacterial species of athlete's foot. Industrial applicability
本発明により、 塩酸ァモロルフィ ンの作用をより高めることができた ので、 皮膚糸状菌に対して極めて効力の強い抗真菌剤を提供することが 可能になつた。  According to the present invention, since the action of amorolfine hydrochloride can be further enhanced, it has become possible to provide an antifungal agent which is extremely effective against dermatophytes.

Claims

請求の範囲 The scope of the claims
1 . 塩酸ァモロルフイ ンおよび硝酸ミコナゾールを含む抗真菌剤。 1. Antifungal agents including amorolfine hydrochloride and miconazole nitrate.
2 .塩酸ァモロルフイ ンおよびシクロピロクスオラミンを含む抗真菌剤。 2. Antifungal agents including amorolfine hydrochloride and ciclopirox olamine.
3 . 塩酸ァモロルフイ ンおよびトルナフテートを含む抗真菌剤。 3. Antifungal agents including amorolfine hydrochloride and tolnaftate.
4 . 塩酸ァモロルフイ ンおよびサリチル酸を含む抗真菌剤。 4. Antifungal agents including amorolfine hydrochloride and salicylic acid.
5 . 塩酸ァモロルフイ ンおよび塩酸クロルへキシジンを含む抗真菌剤。 5. Antifungal agents including amorolfine hydrochloride and chlorhexidine hydrochloride.
6 . 塩酸ァモロルフィ ンおよび塩化べンゼトニゥムを含む抗真菌剤。 6. Antifungal agents including amorolfine hydrochloride and benzethonium chloride.
7 . 塩酸ァモロルフィ ンおよび塩化デカリニゥムを含む抗真菌剤。 7. Antifungal agents including amorolfine hydrochloride and decalinium chloride.
8 . 塩酸ァモロルフイ ンおよびヒノキチォ一ルを含む抗真菌剤。 8. Antifungal agents including amorolfine hydrochloride and hinokitiol.
9 . 塩酸ァモロルフイ ンおよびジンクピリチオンを含む抗真菌剤。 9. Antifungal agents including amorolfine hydrochloride and zinc pyrithione.
1 0 . 塩酸ァモロルフイ ンの配合量が製剤全体の 0 . 1 〜 1質量％でぁ る 1 〜 9のいずれかに記載の抗真菌剤。 10. The antifungal agent according to any one of 1 to 9, wherein the amount of amololfin hydrochloride is 0.1 to 1% by mass of the whole preparation.
1 1 . 塩酸ァモロルフイ ンおよび硝酸ミコナゾ一ルを含む薬剤を患部に 塗布することを特徴とする、 水虫、 いんきんたむし又はぜにたむしの治 療方法。 1 1. A method for treating athlete's foot, insect repellent or cold insect, which comprises applying a drug containing amorolfine hydrochloride and miconazole nitrate to the affected area.
1 2 . 塩酸ァモロルフイ ンおよびシクロピロクスオラミンを含む薬剤を 患部に塗布することを特徴とする、 水虫、 いんきんたむし又はぜにたむ しの治療方法。 12. Drugs containing amorolfine hydrochloride and ciclopirox olamine A method for treating athlete's foot, cotton beetle or cold bug, which is applied to an affected area.
1 3 . 塩酸ァモロルフィ ンおよびトルナフテートを含む薬剤を患部に塗 布することを特徴とする、 水虫、 いんきんたむし又はぜにたむしの治療 方法。 13 3. A method for treating athlete's foot, cotton beetle, or cold bug, which comprises applying a drug containing amorolfine hydrochloride and tolnaftate to the affected area.
1 4 . 塩酸ァモロルフイ ンおよびサリチル酸を含む薬 を患部に塗布す ることを特徴とする、水虫、いんきんたむし又はぜにたむしの治療方法。 14. A method for treating athlete's foot, cotton beetle, or cold bug, comprising applying a drug containing amorolfine hydrochloride and salicylic acid to the affected area.
1 5 . 塩酸ァモロルフイ ンおよび塩酸クロルへキシジンを含む薬剤を患 部に塗布することを特徴とする、 水虫、 いんきんたむし又はぜにたむし の治療方法。 15. A method for treating athlete's foot, cotton beetle, or cold bug, comprising applying a drug containing amorolfine hydrochloride and chlorhexidine hydrochloride to the affected area.
1 6 . 塩酸ァモロルフィ ンおよび塩化べンゼトニゥムを含む薬剤を患部 に塗布することを特徴とする、 水虫、 いんきんたむし又はぜにたむしの 治療方法。 16. A method for treating athlete's foot, cotton beetle, or cold bug, comprising applying a drug containing amorolfine hydrochloride and benzethonium chloride to the affected area.
1 7 . 塩酸ァモロルフィ ンおよび塩化デカリ二ゥムを含む薬剤を患部に 塗布することを特徴とする、 水虫、 いんきんたむし又はぜにたむしの治 療方法。 17. A method for treating athlete's foot, cotton beetle, or cold bug, comprising applying a drug containing amorolfine hydrochloride and decalinium chloride to the affected area.
1 8 . 塩酸ァモロルフイ ンおよびヒノキチオールを含む薬剤を患部に塗 布することを特徵とする、 水虫、 いんきんたむし又はぜにたむしの治療 方法。 18. A method for treating athlete's foot, cotton beetle, or cold bug, which comprises applying a drug containing amorolfine hydrochloride and hinokitiol to the affected area.
1 9 . 塩酸ァモロルフイ ンおよびジンクピリチオンを含む薬剤を患部に 塗布することを特徴とする、 水虫、 いんきんたむし又はぜにたむしの治 療方法。 1 9. Application of a drug containing amorolfine hydrochloride and zinc pyrithione to the affected area, for the treatment of athlete's foot, cotton beetle, or common bug Treatment method.
2 0 . 塩酸ァモロルフイ ンおよび硝酸ミコナゾールからなる組成物の、 抗真菌剤製造のための使用。 20. Use of a composition comprising amorolfine hydrochloride and miconazole nitrate for the production of an antifungal agent.
2 1 . 塩酸ァモロルフイ ンおよびシクロピロクスオラミンからなる組成 物の、 抗真菌剤製造のための使用。 21. Use of a composition comprising amorolfine hydrochloride and ciclopirox olamine for the production of an antifungal agent.
2 2 . 塩酸ァモロルフイ ンおよびトルナフテートからなる組成物の、 抗 真菌剤製造のための使用。 2 2. Use of a composition comprising amorolfine hydrochloride and tolnaftate for the production of an antifungal agent.
2 3 . 塩酸ァモロルフイ ンおよびサリチル酸からなる組成物の、 抗真菌 剤製造のための使用。 23. Use of a composition comprising amorolfine hydrochloride and salicylic acid for the production of an antifungal agent.
2 4 . 塩酸ァモロルフィ ンおよび塩酸クロルへキシジンからなる組成物 の、 抗真菌剤製造のための使用。 24. Use of a composition comprising amorolfine hydrochloride and chlorhexidine hydrochloride for the production of an antifungal agent.
2 5 .塩酸ァモロルフィ ンおよび塩化べンゼトニゥムからなる組成物の、 抗真菌剤製造のための使用。 25. Use of a composition comprising amorolfine hydrochloride and benzethonium chloride for producing an antifungal agent.
2 6 . 塩酸ァモロルフィ ンおよび塩化デカリニゥムからなる組成物の、 抗真菌剤製造のための使用。 26. Use of a composition comprising amorolfine hydrochloride and decalinium chloride for the production of an antifungal agent.
2 7 . 塩酸ァモロルフイ ンおよびヒノキチオールからなる組成物の、 抗 真菌剤製造のための使用。 27. Use of a composition comprising amorolfine hydrochloride and hinokitiol for the production of an antifungal agent.
2 8 . 塩酸ァモロルフイ ンおよびジンクピリチオンからなる組成物の、 抗真菌剤製造のための使用。 28. Use of a composition comprising amorolfine hydrochloride and zinc pyrithione for the production of an antifungal agent.
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