JPWO2005002561A1 - Antifungal composition for external use - Google Patents
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- JPWO2005002561A1 JPWO2005002561A1 JP2005511357A JP2005511357A JPWO2005002561A1 JP WO2005002561 A1 JPWO2005002561 A1 JP WO2005002561A1 JP 2005511357 A JP2005511357 A JP 2005511357A JP 2005511357 A JP2005511357 A JP 2005511357A JP WO2005002561 A1 JPWO2005002561 A1 JP WO2005002561A1
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- 239000012871 anti-fungal composition Substances 0.000 title claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229960000699 terbinafine hydrochloride Drugs 0.000 claims abstract description 43
- 238000002360 preparation method Methods 0.000 claims abstract description 35
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 229920005862 polyol Polymers 0.000 claims abstract description 14
- 150000003077 polyols Chemical class 0.000 claims abstract description 14
- 230000007935 neutral effect Effects 0.000 claims abstract description 8
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 claims abstract 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 16
- 238000009472 formulation Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 8
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 235000013772 propylene glycol Nutrition 0.000 claims description 3
- 102000011782 Keratins Human genes 0.000 abstract description 12
- 108010076876 Keratins Proteins 0.000 abstract description 12
- 229940121375 antifungal agent Drugs 0.000 abstract description 8
- 238000013508 migration Methods 0.000 abstract description 5
- 230000005012 migration Effects 0.000 abstract description 5
- 230000000843 anti-fungal effect Effects 0.000 abstract description 2
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000006210 lotion Substances 0.000 description 19
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 14
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000008213 purified water Substances 0.000 description 12
- 238000007796 conventional method Methods 0.000 description 9
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 8
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 8
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 7
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 7
- 239000003429 antifungal agent Substances 0.000 description 7
- 210000000434 stratum corneum Anatomy 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 6
- 229960004194 lidocaine Drugs 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 2
- 241001480043 Arthrodermataceae Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960001747 cinchocaine Drugs 0.000 description 1
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- -1 tinctures Substances 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
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- 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
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- 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
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Abstract
塩酸テルビナフィンの角質移行性を高めるためには分子型（非解離型）として溶解配合する方が有利である。しかし、中性〜アルカリ性の製剤中では塩酸テルビナフィンの溶解性が極めて低いため、分子型として溶解配合することは困難であった。 本発明である塩酸テルビナフィン、ポリオールおよび低級アルコールを配合し、製剤のｐＨが中性〜アルカリ性の領域である澄明な外用抗真菌剤組成物は、優れた角質移行性を有する塩酸テルビナフィン含有外用抗真菌剤である。In order to enhance the keratin migration of terbinafine hydrochloride, it is advantageous to dissolve and blend it as a molecular type (non-dissociated type). However, since the solubility of terbinafine hydrochloride is very low in neutral to alkaline preparations, it has been difficult to dissolve and blend it as a molecular type. A clear external antifungal composition comprising terbinafine hydrochloride, a polyol and a lower alcohol according to the present invention, wherein the pH of the preparation is in a neutral to alkaline region, is a terbinafine hydrochloride-containing external antifungal having excellent keratin migration It is an agent.
Description
本発明は、抗真菌剤組成物に関する。さらに、詳しくは塩酸テルビナフィンの角質移行量を向上させた外用抗真菌剤組成物に関する。 The present invention relates to an antifungal composition. More specifically, the present invention relates to an antifungal composition for external use in which the amount of terbinafine hydrochloride transferred to the keratin is improved.
真菌は皮膚角質層で増殖するため、抗真菌剤が効力を発生するには抗真菌活性、抗菌スペクトルだけでなく、真菌の生息部位である角質層における薬物濃度が重要である。 Since fungi grow in the stratum corneum of the skin, not only the antifungal activity and antibacterial spectrum but also the drug concentration in the stratum corneum, where fungi inhabit, are important for antifungal agents to become effective.
抗真菌剤としては、塗布後速やかに角質内薬物濃度が高まり、そのレベルが長時間維持されるものが理想的である。 As an antifungal agent, an agent having an increased drug concentration in the stratum corneum immediately after application and maintaining the level for a long time is ideal.
一般的に、薬物は解離したイオン型より分子型（非解離型）の方が経皮吸収性に優れ、角質移行量も多いことが知られている。 In general, it is known that a molecular type (non-dissociation type) drug has better transdermal absorbability and a larger amount of keratin transfer than a dissociated ionic type.
塩酸テルビナフィンは、優れた薬理効果から外用抗真菌剤として使用されている成分である。 Terbinafine hydrochloride is a component used as an external antifungal agent because of its excellent pharmacological effect.
塩酸テルビナフィンも一般的な薬物同様、角質移行性を高めるためには分子型として溶解配合する方が有利である。 Terbinafine hydrochloride, like a general drug, is more advantageous to be dissolved and blended as a molecular type in order to enhance the keratin migration.
塩酸テルビナフィンを分子型として溶解配合するためには、外用抗真菌剤組成物のｐＨは塩酸テルビナフィンの解離定数（ｐＫａ）７．１３を超える、中性〜アルカリ性領域に設定することが望ましい。 In order to dissolve and blend terbinafine hydrochloride as a molecular type, it is desirable that the pH of the antifungal composition for external use is set in a neutral to alkaline region where the dissociation constant (pKa) of terbinafine hydrochloride exceeds 7.13.
しかしながら、塩酸テルビナフィンは中性〜アルカリ性製剤中での溶解性が極めて低いため、分子型として溶解配合することは困難であった。 However, since terbinafine hydrochloride has extremely low solubility in neutral to alkaline preparations, it has been difficult to dissolve and blend it as a molecular type.
従来、粉末エアゾール中で抗真菌剤を溶解状態で存在させる技術は開示されている（特許文献１）。 Conventionally, a technique for allowing an antifungal agent to exist in a dissolved state in a powder aerosol has been disclosed (Patent Document 1).
本発明は、優れた角質移行性を有する塩酸テルビナフィン含有外用抗真菌剤を提供することを目的とする。 An object of the present invention is to provide a terbinafine hydrochloride-containing external antifungal agent having excellent keratin transferability.
本発明者らは、中性〜アルカリ性の液性で、塩酸テルビナフィンが溶解された液剤を提供するため種々検討した結果、低級アルコールとポリオールを同時に配合し、その液性を特定の範囲に限定することにより、塩酸テルビナフィンを分子型として溶解させ、優れた角質移行性を示すことを見出し、本発明を完成した。 As a result of various investigations to provide a liquid agent having neutral to alkaline liquidity and terbinafine hydrochloride dissolved therein, the present inventors simultaneously blended a lower alcohol and a polyol and limited the liquidity to a specific range. As a result, it was found that terbinafine hydrochloride was dissolved in a molecular form and exhibited excellent keratin migration, and the present invention was completed.
すなわち、本発明は、
（１）塩酸テルビナフィン、ポリオールおよび低級アルコールを配合し、製剤の液性が中性〜アルカリ性の領域である外用抗真菌剤組成物。
（２）ポリオールがポリエチレングリコール、プロピレングリコール、１，３−ブチレングリコールおよびグリセリンからなる群から選ばれる１種または２種以上である（１）に記載の外用抗真菌剤組成物。
（３）ポリオールの配合量が製剤全体の１０〜３０Ｗ／Ｖ％である（１）に記載の外用抗真菌剤組成物。
（４）低級アルコールがエタノールである（１）に記載の外用抗真菌剤組成物。
（５）エタノールの配合量が４７〜５６Ｗ／Ｖ％である（４）に記載の外用抗真菌剤組成物。
（６）塩酸テルビナフィンの配合量が製剤全体の０．２〜２Ｗ／Ｖ％である（１）に記載の外用抗真菌剤組成物。
（７）製剤のｐＨが７．５〜９．０である（１）に記載の外用抗真菌剤組成物。
である。That is, the present invention
(1) An antifungal composition for external use in which terbinafine hydrochloride, a polyol and a lower alcohol are blended, and the liquidity of the preparation is in a neutral to alkaline region.
(2) The antifungal composition for external use according to (1), wherein the polyol is one or more selected from the group consisting of polyethylene glycol, propylene glycol, 1,3-butylene glycol and glycerin.
(3) The antifungal agent composition for external use as described in (1) whose compounding quantity of a polyol is 10-30 W / V% of the whole formulation.
(4) The antifungal composition for external use according to (1), wherein the lower alcohol is ethanol.
(5) The antifungal composition for external use according to (4), wherein the blending amount of ethanol is 47 to 56 W / V%.
(6) The antifungal composition for external use according to (1), wherein the amount of terbinafine hydrochloride is 0.2 to 2 W / V% of the whole preparation.
(7) The antifungal composition for external use according to (1), wherein the formulation has a pH of 7.5 to 9.0.
It is.
本発明において、塩酸テルビナフィンの配合量は、製剤全体（エアゾールの場合は原液中）の０．２〜２Ｗ／Ｖ％が好ましく、さらに好ましくは０．５〜１．５Ｗ／Ｖ％である。０．２Ｗ／Ｖ％未満であると効力が不十分になり、２Ｗ／Ｖ％を超えて配合すると溶解度の点から製品として提供することが難しいからである。 In the present invention, the blending amount of terbinafine hydrochloride is preferably 0.2 to 2 W / V%, more preferably 0.5 to 1.5 W / V% of the whole preparation (in the case of aerosol, in the stock solution). This is because if it is less than 0.2 W / V%, the efficacy becomes insufficient, and if it exceeds 2 W / V%, it is difficult to provide it as a product in terms of solubility.
本発明で、低級アルコールとは炭素原子数２〜４の直鎖状、分岐鎖状のアルコールで、外用剤として安全に塗布できるもののことである。好ましい低級アルコールとしては、エタノールおよびイソプロパノールがあげられ、エタノールが特に好ましい。 In the present invention, the lower alcohol is a linear or branched alcohol having 2 to 4 carbon atoms and can be safely applied as an external preparation. Preferred lower alcohols include ethanol and isopropanol, with ethanol being particularly preferred.
低級アルコールの配合量は、塩酸テルビナフィンの溶解度の点では多いほど好ましいが、低級アルコールを多量に配合しすぎると、皮膚塗布時に刺激を生じる可能性がある。したがって、低級アルコールの配合量は４０〜６０Ｗ／Ｖ％が好ましく、４７Ｗ／Ｖ％（６０体積％）〜５６Ｗ／Ｖ％（７０体積％）がさらに好ましい。 The blending amount of the lower alcohol is preferably as much as possible in terms of the solubility of terbinafine hydrochloride, but if too much lower alcohol is blended, there is a possibility of causing irritation during skin application. Therefore, the blending amount of the lower alcohol is preferably 40 to 60 W / V%, more preferably 47 W / V% (60 vol%) to 56 W / V% (70 vol%).
本発明で配合するポリオールの好ましいものとしては、ポリエチレングリコール（マクロゴール）、プロピレングリコール、１，３−ブチレングリコール、グリセリンなどがあげられる。 Preferable polyols blended in the present invention include polyethylene glycol (macrogol), propylene glycol, 1,3-butylene glycol, glycerin and the like.
本発明においてポリオールの配合量は、低級アルコールの種類と配合量により変化し、塩酸テルビナフィンの溶解を確認しながら実験的に配合量を決定することができる。また、ポリオールを多量に配合しすぎると、皮膚塗布時にべたつき、使用感が非常に悪くなるため、通常の配合量は、製剤全体（エアゾールの場合は原液中）の１０〜３０Ｗ／Ｖ％であり、好ましくは１５〜２５Ｗ／Ｖ％である。また、２種類以上のポリオールを混合して用いることもできる。ここで、例として低級アルコールにエタノールを用い、配合量が製剤全体の４７．７Ｗ／Ｖ％（６０体積％）の場合にはポリオールの配合量は２５〜３０Ｗ／Ｖ％であり、エタノールの配合量が５５．７Ｗ／Ｖ％（７０体積％）の場合にはポリオールの配合量は１０〜３０Ｗ／Ｖ％である。 In the present invention, the blending amount of the polyol varies depending on the type and blending amount of the lower alcohol, and the blending amount can be experimentally determined while confirming dissolution of terbinafine hydrochloride. In addition, if too much polyol is blended, it becomes sticky when applied to the skin and the feeling of use becomes very bad. , Preferably 15 to 25 W / V%. Also, two or more types of polyols can be mixed and used. Here, as an example, when ethanol is used as the lower alcohol and the blending amount is 47.7 W / V% (60% by volume) of the whole preparation, the blending amount of the polyol is 25 to 30 W / V%. When the amount is 55.7 W / V% (70% by volume), the blending amount of the polyol is 10 to 30 W / V%.
製剤のｐＨは塩酸テルビナフィンが分子型で存在する領域であり、解離定数（ｐＫａ）７．１３を超える中性〜アルカリ性領域であるが、アルカリ性が強すぎると、皮膚にダメージを与えるため、ｐＨ７．５〜９．０の範囲が好ましい。 The pH of the preparation is a region where terbinafine hydrochloride exists in a molecular form and is a neutral to alkaline region exceeding the dissociation constant (pKa) of 7.13. However, if the alkalinity is too strong, the skin is damaged, so that the pH is 7. A range of 5 to 9.0 is preferred.
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、ローション剤、乳剤、チンキ剤、クリーム剤、水性ゲル剤、エアゾール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 conventional additives as necessary to prepare external preparations such as liquids, lotions, emulsions, tinctures, creams, aqueous gels, aerosols, etc. Can do.
本発明により、塩酸テルビナフィンの角質移行性をより高めることができ、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った。 According to the present invention, it is possible to further improve the keratin transfer property of terbinafine hydrochloride and to provide an antifungal agent that is extremely effective against dermatophytes.
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 by way of examples and test examples.
（ローション）
塩酸テルビナフィン １．０ｇ
塩化ベンザルコニウム ０．０５ｇ
グリチルリチン酸二カリウム ０．５ｇ
ｌ−メントール １．０ｇ
ポリエチレングリコール４００ ２０．０ｇ
エタノール ５０．０ｇ
ＢＨＴ ０．０５ｇ
ジイソプロパノールアミン 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（ジイソプロパノールアミンにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Benzalkonium chloride 0.05g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
Polyethylene glycol 400 20.0g
Ethanol 50.0g
BHT 0.05g
Diisopropanolamine appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
（ローション）
塩酸テルビナフィン １．０ｇ
リドカイン ２．０ｇ
塩化デカリニウム ０．１ｇ
グリチルリチン酸二カリウム ０．５ｇ
ｌ−メントール １．０ｇ
ポリエチレングリコール４００ ２０．０ｇ
エタノール ５０．０ｇ
ＢＨＴ ０．０５ｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（水酸化ナトリウムにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Decalinium chloride 0.1g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
Polyethylene glycol 400 20.0g
Ethanol 50.0g
BHT 0.05g
Sodium hydroxide appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with sodium hydroxide).
（ゲル剤）
塩酸テルビナフィン １．０ｇ
リドカイン ２．０ｇ
プロピレングリコール １５．０ｇ
カルボキシビニルポリマー １．０ｇ
ＥＤＴＡ−２Ｎａ ０．１ｇ
エタノール ５０．０ｇ
ジイソプロパノールアミン 適量
精製水 全１００ｇ
水、プロピレングリコールにカルボキシビニルポリマーを溶解し、室温で放置し、カルボキシビニルポリマーを膨潤させた。これにエタノール、塩酸テルビナフィン、リドカインおよびＥＤＴＡ−２Ｎａを添加した。さらにジイソプロパノールアミンを加え、製剤のｐＨを約８に調整し、ゲルを製造した。(Gel agent)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Propylene glycol 15.0g
Carboxyvinyl polymer 1.0g
EDTA-2Na 0.1g
Ethanol 50.0g
Diisopropanolamine appropriate amount purified water 100g
The carboxyvinyl polymer was dissolved in water and propylene glycol and allowed to stand at room temperature to swell the carboxyvinyl polymer. To this was added ethanol, terbinafine hydrochloride, lidocaine and EDTA-2Na. Further, diisopropanolamine was added to adjust the pH of the preparation to about 8 to produce a gel.
（エアゾール剤）
原液：
塩酸テルビナフィン １．０ｇ
塩化ベンザルコニウム ０．０５ｇ
グリチルリチン酸二カリウム ０．５ｇ
１，３ブチレングリコール ２０．０ｇ
エタノール ５０．０ｇ
ジイソプロパノールアミン 適量
精製水 全１００ｍＬ
噴射剤：
ＤＭＥ ５０ｍＬ
エタノール、精製水の基剤に他の原液成分を溶解後、ジイソプロパノールアミンにて製剤のｐＨを約８に調整し、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。(Aerosol)
Stock solution:
Terbinafine hydrochloride 1.0 g
Benzalkonium chloride 0.05g
Dipotassium glycyrrhizinate 0.5g
1,3 butylene glycol 20.0g
Ethanol 50.0g
Diisopropanolamine appropriate amount purified water 100mL
Propellant:
DME 50mL
The other stock solution components were dissolved in a base of ethanol and purified water, and then the pH of the preparation was adjusted to about 8 with diisopropanolamine to produce a stock solution. After filling the container, a valve was attached and a propellant was filled to produce an aerosol.
（ローション）
塩酸テルビナフィン １．０ｇ
ポリエチレングリコール４００ ２５．０ｇ
エタノール ４７．７ｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（水酸化ナトリウムにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Polyethylene glycol 400 25.0g
47.7g of ethanol
Sodium hydroxide appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with sodium hydroxide).
比較例１
（ローション）
塩酸テルビナフィン １．０ｇ
ポリエチレングリコール４００ ２５．０ｇ
エタノール ４７．７ｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（水酸化ナトリウムにて製剤のｐＨを約５に調整した）。Comparative Example 1
(lotion)
Terbinafine hydrochloride 1.0 g
Polyethylene glycol 400 25.0g
47.7g of ethanol
Sodium hydroxide appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 5 with sodium hydroxide).
（ローション）
塩酸テルビナフィン １．０ｇ
リドカイン ２．０ｇ
塩化ベンザルコニウム ０．０５ｇ
グリチルリチン酸二カリウム ０．５ｇ
ｌ−メントール １．０ｇ
１，３ブチレングリコール １０．０ｇ
エタノール ５５．０ｇ
ジイソプロパノールアミン 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（ジイソプロパノールアミンにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Benzalkonium chloride 0.05g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
1,3 Butylene glycol 10.0 g
Ethanol 55.0g
Diisopropanolamine appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
（ローション）
塩酸テルビナフィン １．０ｇ
ジブカイン ０．５ｇ
塩化ベンゼトニウム ０．５ｇ
グリチルリチン酸二カリウム ０．５ｇ
ｌ−メントール １．０ｇ
１，３ブチレングリコール ２０．０ｇ
エタノール ５０．０ｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（水酸化ナトリウムにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Dibucaine 0.5g
Benzethonium chloride 0.5g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
1,3 butylene glycol 20.0g
Ethanol 50.0g
Sodium hydroxide appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with sodium hydroxide).
（ローション）
塩酸テルビナフィン １．０ｇ
塩酸リドカイン ２．０ｇ
塩化ベンゼトニウム ０．５ｇ
グリチルリチン酸二カリウム ０．５ｇ
ｌ−メントール １．０ｇ
プロピレングリコール ２０．０ｇ
エタノール ５０．０ｇ
ジイソプロパノールアミン 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（ジイソプロパノールアミンにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine hydrochloride 2.0g
Benzethonium chloride 0.5g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
Propylene glycol 20.0g
Ethanol 50.0g
Diisopropanolamine appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
（ローション）
塩酸テルビナフィン １．０ｇ
リドカイン ２．０ｇ
塩化ベンザルコニウム ０．０５ｇ
グリチルリチン酸二カリウム ０．５ｇ
ｌ−メントール １．０ｇ
１，３ブチレングリコール １０．０ｇ
エタノール ４５．０ｇ
イソプロピルアルコール １０．０ｇ
ジイソプロパノールアミン 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（ジイソプロパノールアミンにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Benzalkonium chloride 0.05g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
1,3 Butylene glycol 10.0 g
Ethanol 45.0g
Isopropyl alcohol 10.0g
Diisopropanolamine appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
（ローション）
塩酸テルビナフィン １．０ｇ
リドカイン ２．０ｇ
塩化デカリニウム ０．１ｇ
グリチルリチン酸二カリウム ０．５ｇ
ｌ−メントール １．０ｇ
１，３ブチレングリコール １０．０ｇ
ポリエチレングリコール４００ １０．０ｇ
エタノール ５０．０ｇ
ジイソプロパノールアミン 適量
精製水 全１００ｍＬ
上記処方で、常法によりローション剤を製造した（ジイソプロパノールアミンにて製剤のｐＨを約８に調整した）。(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Decalinium chloride 0.1g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
1,3 Butylene glycol 10.0 g
Polyethylene glycol 400 10.0g
Ethanol 50.0g
Diisopropanolamine appropriate amount purified water 100mL
With the above formulation, a lotion preparation was produced by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
試験例１
塩酸テルビナフィンの溶解性試験
（試験方法）
「水：エタノール：ＰＥＧ４００」比率の異なる溶液への塩酸テルビナフィン（１Ｗ／Ｖ％）の溶解性を目視により確認した。なお、ｐＨは水酸化ナトリウムにより調整した。Test example 1
Solubility test of terbinafine hydrochloride (test method)
The solubility of terbinafine hydrochloride (1 W / V%) in solutions having different ratios of “water: ethanol: PEG400” was visually confirmed. The pH was adjusted with sodium hydroxide.
表１にエタノール３９．８重量％（５０体積％）配合処方におけるＰＥＧ４００配合量に対する塩酸テルビナフィンの溶解性、表２にエタノール４７．７重量％（６０体積％）配合処方におけるＰＥＧ４００配合量に対する塩酸テルビナフィンの溶解性、表３にエタノール５５．７重量％（７０体積％）配合処方におけるＰＥＧ４００配合量に対する塩酸テルビナフィンの溶解性をそれぞれ示した。なお、表中○は溶解し、×は溶解しなかったことを示す。 Table 1 shows the solubility of terbinafine hydrochloride with respect to the blending amount of PEG 400 in the formulation containing 39.8% by weight (50% by volume) of ethanol. Table 3 shows the solubility of terbinafine hydrochloride with respect to the blending amount of PEG 400 in the blending formulation of 55.7% by weight (70% by volume) of ethanol. In the table, ○ indicates that it was dissolved, and X indicates that it was not dissolved.
表から明らかなように、通常、塩酸テルビナフィンはｐＫａ７．１３を超えるｐＨ以上での溶解性は極めて悪いが、本発明の処方は、ｐＨ７．５以上であっても、塩酸テルビナフィン（１重量％）を溶解することが可能であった。 As is apparent from the table, terbinafine hydrochloride usually has very poor solubility at a pH higher than pKa7.13, but the formulation of the present invention has terbinafine hydrochloride (1% by weight) even at pH 7.5 or higher. It was possible to dissolve.
試験例２（塩酸テルビナフィンのヘアレスラット角質移行性試験）
（実験方法）
ヘアレスラット（日本クレア，雄，１１〜１５週齢）を背位固定し、腹部を電気シェーバーで除毛後、汚れをふき取った。各サンプル（実施例５および比較例１）２０μＬをマイクロピペットで量り、腹部（１．８×２．５ｃｍ）に均一に塗布した。塗布６時間後または塗布２４時間後に、７０％エタノールを染み込ませた脱脂綿を用いて皮膚表面に残存するサンプルを十分に拭き取った。その後、塗布部位に市販の粘着テープを貼付し、圧着して角質層を剥離した。この角質層剥離操作を１０回繰り返した。角質層の剥離に用いた粘着テープ１０枚からメタノールにより塩酸テルビナフィンを抽出し、高速液体クロマトグラフィーで角質移行量を測定した。Test Example 2 (Terbinafine hydrochloride hairless rat keratin migration test)
(experimental method)
A hairless rat (Claire Japan, male, 11-15 weeks old) was fixed in the dorsal position, and after removing the abdomen with an electric shaver, the dirt was wiped off. 20 μL of each sample (Example 5 and Comparative Example 1) was weighed with a micropipette and uniformly applied to the abdomen (1.8 × 2.5 cm). Six hours after application or 24 hours after application, the sample remaining on the skin surface was thoroughly wiped with absorbent cotton soaked with 70% ethanol. Thereafter, a commercially available adhesive tape was applied to the application site, and the stratum corneum was peeled off by pressure bonding. This stratum corneum peeling operation was repeated 10 times. Terbinafine hydrochloride was extracted with methanol from 10 pressure-sensitive adhesive tapes used for exfoliating the stratum corneum, and the amount of stratum corneum transferred was measured by high performance liquid chromatography.
結果を図１に示した。なお、結果は各試料について試験を３回行った平均値である。 The results are shown in FIG. The results are average values obtained by performing the test three times for each sample.
図１から明らかなように、ｐＨを８に調整した実施例５の製剤は、ｐＨを５に調整した比較例１の製剤よりも高い角質移行性を示すことが確認された。 As is clear from FIG. 1, it was confirmed that the preparation of Example 5 having the pH adjusted to 8 showed higher keratin transferability than the preparation of Comparative Example 1 having the pH adjusted to 5.
本発明は、水虫、いんきんたむし、ぜにたむしまたは爪白癬の治療薬として利用可能である。 INDUSTRIAL APPLICABILITY The present invention can be used as a therapeutic agent for athlete's foot, snails, colander, or onychomycosis.
Claims (7)
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| WO2010086727A1 (en) * | 2009-01-30 | 2010-08-05 | Galderma Pharma Sa | Stable compositions for nail onychomycosis treatment |
| WO2016144121A2 (en) * | 2015-03-12 | 2016-09-15 | 동아제약 주식회사 | Pharmaceutical composition for treating fungal infectious diseases of ketratin tissue |
| KR101690765B1 (en) * | 2015-04-17 | 2016-12-28 | 동아제약 주식회사 | Transdermal formulation comprising antifungal agent |
| JP7198573B2 (en) * | 2017-06-26 | 2023-01-04 | 小林製薬株式会社 | Aqueous formulation |
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| JPH0585929A (en) * | 1991-03-08 | 1993-04-06 | L'oreal Sa | Use of hydrophillic penetrant in dermatological composition for treating nail mycosis and equivalent composition |
| JPH05132419A (en) * | 1991-05-20 | 1993-05-28 | Sandoz Ag | Medicinal composition |
| JP2001518879A (en) * | 1997-03-31 | 2001-10-16 | ジョンソン・アンド・ジョンソン・コンシューマー・カンパニーズ・インコーポレイテッド | Solvent system for improved penetration of drug compounds |
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| WO2005002561A1 (en) | 2005-01-13 |
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