JP2005036000A - External antifungal composition prevented from being adsorbed by container - Google Patents
External antifungal composition prevented from being adsorbed by container Download PDFInfo
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- JP2005036000A JP2005036000A JP2004196212A JP2004196212A JP2005036000A JP 2005036000 A JP2005036000 A JP 2005036000A JP 2004196212 A JP2004196212 A JP 2004196212A JP 2004196212 A JP2004196212 A JP 2004196212A JP 2005036000 A JP2005036000 A JP 2005036000A
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- Prior art keywords
- terbinafine hydrochloride
- container
- polyethylene
- polyol
- preparation
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Links
- 239000012871 anti-fungal composition Substances 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 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 description 41
- 229960000699 terbinafine hydrochloride Drugs 0.000 claims abstract description 41
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- -1 polyethylene Polymers 0.000 claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 18
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 17
- 229920005862 polyol Polymers 0.000 claims abstract description 17
- 150000003077 polyols Chemical class 0.000 claims abstract description 17
- 239000005038 ethylene vinyl acetate Substances 0.000 claims abstract description 15
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 239000004743 Polypropylene Substances 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 229920001155 polypropylene Polymers 0.000 claims description 12
- 238000001179 sorption measurement Methods 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 8
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 7
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 7
- 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
- 229920005989 resin Polymers 0.000 abstract description 23
- 239000011347 resin Substances 0.000 abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 15
- 230000002378 acidificating effect Effects 0.000 abstract description 7
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 abstract description 5
- 239000007788 liquid Substances 0.000 abstract description 4
- 239000004698 Polyethylene Substances 0.000 abstract description 2
- 229920000573 polyethylene Polymers 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000243 solution Substances 0.000 description 14
- 239000006210 lotion Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 6
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 6
- 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 6
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 229960004194 lidocaine Drugs 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229920013716 polyethylene resin Polymers 0.000 description 3
- 229920000139 polyethylene terephthalate Polymers 0.000 description 3
- 239000005020 polyethylene terephthalate Substances 0.000 description 3
- 239000012508 resin bead Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical group CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical group CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical group CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 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 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- 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 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 229960001777 castor oil Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 1
- 229940043276 diisopropanolamine Drugs 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000004318 erythorbic acid Substances 0.000 description 1
- 235000010350 erythorbic acid Nutrition 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical group CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229940026239 isoascorbic acid Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Chemical group CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Chemical group CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000003566 sealing material Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 201000009862 superficial mycosis Diseases 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Abstract
Description
本発明は、塩酸テルビナフィンの容器への吸着を抑制した外用抗真菌液剤に関する。 The present invention relates to an antifungal solution for external use in which adsorption of terbinafine hydrochloride to a container is suppressed.
塩酸テルビナフィンは、その優れた薬理効果から汎用されている抗真菌剤の一つであり、浅在性真菌症などの治療剤として使用されている。塩酸テルビナフィンは酸性の水には溶解しやすいが、弱酸性〜アルカリ性の水には難溶で、ポリオレフィン、エチレン-酢酸ビニル共重合体製の樹脂容器に吸着しやすい性質を有している。この様な塩酸テルビナフィンを抗真菌製剤に調製するには、薬物が容器に吸着することにより発生する薬物濃度低下の課題を解決する必要がある。 Terbinafine hydrochloride is one of the antifungal agents widely used because of its excellent pharmacological effect, and is used as a therapeutic agent for superficial mycosis. Terbinafine hydrochloride is easily dissolved in acidic water, but hardly soluble in weakly acidic to alkaline water, and has a property of being easily adsorbed to a resin container made of polyolefin or ethylene-vinyl acetate copolymer. In order to prepare such terbinafine hydrochloride as an antifungal preparation, it is necessary to solve the problem of lowering the drug concentration caused by the drug adsorbed on the container.
従来、塩酸テルビナフィン配合液剤は液性を酸性（ｐＨ３位）にして溶解性を高めることにより、薬物の容器への吸着を防止している。しかし、製剤の液性を酸性領域にすると、安定性の面からその他に配合できる成分が限られたものになるため、中性付近で塩酸テルビナフィンを配合した製剤が求められていた。 Conventionally, liquids containing terbinafine hydrochloride have been made acidic (pH 3) to enhance the solubility, thereby preventing the drug from adsorbing to the container. However, when the liquidity of the preparation is in the acidic range, other components that can be blended are limited from the standpoint of stability, and therefore a preparation containing terbinafine hydrochloride in the vicinity of neutrality has been demanded.
従来、容器への吸着を起こしやすい薬物の安定性を向上させるためにポリエチレンテレフタレート性容器を使用する技術が開示されている（特許文献１）。しかし、ポリエチレンテレフタレート樹脂は硬いためキャップ部位のシーリング材などにはポリエチレンテレフタレートが使えず、ポリエチレン、エチレン-酢酸ビニル共重合体、ポリプロピレンなどの柔らかい樹脂を使用する必要があった。 Conventionally, a technique using a polyethylene terephthalate container has been disclosed in order to improve the stability of a drug that easily adsorbs to the container (Patent Document 1). However, since polyethylene terephthalate resin is hard, polyethylene terephthalate cannot be used as a sealing material for the cap portion, and it has been necessary to use soft resin such as polyethylene, ethylene-vinyl acetate copolymer, and polypropylene.
本発明者らは塩酸テルビナフィン配合製剤に、柔らかく使いやすい樹脂であるポリエチレン、エチレン-酢酸ビニル共重合体、ポリプロピレンなどの樹脂製容器を用いることを検討した。しかし、中性付近の液性の場合、それらの樹脂には塩酸テルビナフィンが吸着してしまい、薬物の溶液中での含有率が低下してしまうことがわかった。 The present inventors examined the use of resin containers such as polyethylene, ethylene-vinyl acetate copolymer, and polypropylene, which are soft and easy-to-use resins, for the terbinafine hydrochloride compounded preparation. However, in the case of liquidity near neutrality, it has been found that terbinafine hydrochloride is adsorbed on these resins, and the content of the drug in the solution decreases.
本発明は、弱酸性〜アルカリ性の水に難溶で、かつ樹脂製容器に吸着しやすい性質を有する塩酸テルビナフィンを樹脂容器に充填した抗真菌製剤として提供することを目的とする。 An object of the present invention is to provide an antifungal preparation in which a resin container is filled with terbinafine hydrochloride having a property of being hardly soluble in weakly acidic to alkaline water and easily adsorbing to a resin container.
本発明者らは、弱酸性〜アルカリ性では樹脂製容器に吸着しやすく、かつ、水に難溶な塩酸テルビナフィンを抗真菌製剤に調製する方法について鋭意研究を行った。その結果、抗真菌液剤にポリオールおよび低級アルコールを配合することにより、塩酸テルビナフィンの樹脂製容器への吸着を顕著に抑制できることを見出し、本発明を完成した。 The inventors of the present invention have conducted intensive studies on a method for preparing terbinafine hydrochloride, which is weakly acidic to alkaline and easily adsorbed on a resin container and is hardly soluble in water, as an antifungal preparation. As a result, it was found that the adsorption of terbinafine hydrochloride to a resin container can be remarkably suppressed by blending a polyol and a lower alcohol with the antifungal liquid, and the present invention has been completed.
すなわち本発明は
１．塩酸テルビナフィン、低級アルコール及びポリオールを含み、ｐＨが５〜９である組成物が、ポリエチレン、エチレン−酢酸ビニル共重合体またはポリプロピレン製の容器に充填されていることを特徴とする外用抗真菌製剤。
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、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製剤。
３．低級アルコールがエタノールである、１または２に記載の外用抗真菌製剤。
４．ポリオールの配合量が組成物全体の１０〜３０質量％である１〜３のいずれかに記載の外用抗真菌製剤。
５．塩酸テルビナフィンの配合量が組成物全体の０．０１〜２質量％である１〜４のいずれかに記載の外用抗真菌製剤。
６．低級アルコールおよびポリオールを配合することによる、ポリエチレン、エチレン−酢酸ビニル共重合体またはポリプロピレン製の容器への塩酸テルビナフィンの吸着を抑制する方法。
７．エタノールおよびポリオールを配合することによる、ポリエチレン、エチレン−酢酸ビニル共重合体またはポリプロピレン製の容器への塩酸テルビナフィンの吸着を抑制する方法。
である。
That is, the present invention is 1. An antifungal preparation for external use, wherein a composition comprising terbinafine hydrochloride, a lower alcohol and a polyol and having a pH of 5 to 9 is filled in a container made of polyethylene, ethylene-vinyl acetate copolymer or polypropylene.
2. 2. The antifungal preparation 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 preparation for external use according to 1 or 2, wherein the lower alcohol is ethanol.
4). The antifungal preparation for external use according to any one of 1 to 3, wherein the blending amount of the polyol is 10 to 30% by mass of the whole composition.
5. The antifungal preparation for external use according to any one of 1 to 4, wherein the amount of terbinafine hydrochloride is 0.01 to 2 mass% of the entire composition.
6). A method for suppressing adsorption of terbinafine hydrochloride to a container made of polyethylene, ethylene-vinyl acetate copolymer or polypropylene by blending a lower alcohol and a polyol.
7. A method for suppressing adsorption of terbinafine hydrochloride to a container made of polyethylene, ethylene-vinyl acetate copolymer or polypropylene by blending ethanol and polyol.
It is.
本発明において塩酸テルビナフィンの配合量は組成物中の０．００１〜３質量％であり、好ましくは０．０１〜２質量％である。 In this invention, the compounding quantity of terbinafine hydrochloride is 0.001-3 mass% in a composition, Preferably it is 0.01-2 mass%.
本発明で用いるポリオールとは、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。ポリオールの配合量は、通常、組成物全体（エアゾールの場合は原液中）の１０〜３０質量％であり、好ましくは１０〜２０質量％である。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り、少ないと塩酸テルビナフィンの樹脂容器への吸着防止効果が不十分だからである。 Examples of the polyol used in the present invention include polyethylene glycol (macrogol), propylene glycol, 1,3-butylene glycol, glycerin and the like. The blending amount of the polyol is usually 10 to 30% by mass, preferably 10 to 20% by mass, based on the entire composition (in the case of an aerosol, in the stock solution). If too much polyol is blended, it becomes sticky when applied to the skin and the feeling of use becomes very bad. If it is too little, the effect of preventing adsorption of terbinafine hydrochloride to the resin container is insufficient.
本発明で低級アルコールとは炭素原子数２〜４の外用剤に配合しても安全なアルコール成分であり、好ましいものとして、エタノールおよびイソプロパノールがあげられ、最も好ましいものとしてエタノールをあげることができる。 In the present invention, the lower alcohol is an alcohol component that is safe even when blended with an external preparation having 2 to 4 carbon atoms. Preferred examples include ethanol and isopropanol, and most preferred examples include ethanol.
本発明で、樹脂製容器の材質は、柔らかく薬物が吸着しやすいものであり、具体的にはポリエチレン、エチレン−酢酸ビニル共重合体またはポリプロピレンである。これらの樹脂は高密度樹脂であっても、低密度樹脂であってもよい。また、本発明の効果は、容器の一部にこれらの樹脂を使用したものでも効果を示す。 In the present invention, the material of the resin container is soft and easy to adsorb drugs, and specifically, polyethylene, ethylene-vinyl acetate copolymer or polypropylene. These resins may be high-density resins or low-density resins. Moreover, the effect of this invention shows an effect even if it uses these resins for a part of container.
本発明では、必要に応じて通常の添加剤などを組成物中に混合して、常法により、液剤、ローション剤、乳剤、チンキ剤、水性ゲル剤などの外用組成物とすることができる。また、容器内の一部でポリエチレン、エチレン−酢酸ビニル共重合体またはポリプロピレンを使用しているエアゾール剤などとすることもできる。 In the present invention, if necessary, ordinary additives and the like can be mixed into the composition to obtain external compositions such as liquids, lotions, emulsions, tinctures, and aqueous gels by conventional methods. Moreover, it can also be set as the aerosol agent etc. which are using polyethylene, ethylene-vinyl acetate copolymer, or polypropylene in a part in a container.
本発明では組成物のｐＨは５〜９である必要がある。これよりもｐＨが低ければ、本発明によらなくとも薬物が容器に吸着せず、ｐＨが高いと容器への塩酸テルビナフィン吸着を防止する効果が不十分になるからである。ここで、ｐＨ調整剤としては、クエン酸、水酸化ナトリウム、ジイソプロパノールアミンなどがあげられる。 In the present invention, the pH of the composition needs to be 5-9. If the pH is lower than this, the drug will not be adsorbed to the container even if not according to the present invention, and if the pH is high, the effect of preventing adsorption of terbinafine hydrochloride to the container will be insufficient. Here, examples of the pH adjuster include citric acid, sodium hydroxide, diisopropanolamine and the like.
本発明では必要に応じて組成物中に油性成分（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、スクワラン、中鎖トリグリセライドなど）、高分子（カルボキシビニルポリマー、メチルセルロース、エチルセルロースなど）、抗酸化剤（ジブチルヒドロキシトルエン（ＢＨＴ）、ブチルヒドロキシアニソール（ＢＨＡ）、α−トコフェロール、エリソルビン酸、ピロ亜硫酸ナトリウムなど）、界面活性剤（ポリオキシエチレン硬化ヒマシ油、ソルビタンモノステアレート、ソルビタンモノパルミテート、グリセリンモノステアレート、ソルビタンモノラウレート、ポリオキシエチレンポリオキシプロピレンブロックコポリマー、ポリソルベート類、ラウリル硫酸ナトリウム、ショ糖脂肪酸エステル、レシチンなど）、安定化剤（ＥＤＴＡ−２Ｎａなど）などを配合することができる。 In the present invention, an oily component (diisopropyl adipate, stearyl alcohol, cetanol, squalane, medium chain triglyceride, etc.), polymer (carboxyvinyl polymer, methylcellulose, ethylcellulose, etc.), antioxidant (dibutylhydroxyl, etc.) is optionally contained in the composition. Toluene (BHT), butylhydroxyanisole (BHA), α-tocopherol, erythorbic acid, sodium pyrosulfite, etc., surfactant (polyoxyethylene hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate, glycerin monostearate , Sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymer, polysorbates, sodium lauryl sulfate, sucrose fatty acid ester, lecithin, etc.), stabilization (Such as EDTA-2Na) may be blended like.
本発明により、塩酸テルビナフィンの容器への吸着を防止することができた。 By this invention, adsorption | suction to the container of terbinafine hydrochloride was able to be prevented.
以下、実施例、調製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, Preparation Examples and Test Examples.
（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 ６０．０ｇ
精製水 全１００ｇ
上記処方で、常法によりローション剤を製造した後，ポリエチレン樹脂容器に充填した。
(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 60.0g
100g of purified water
A lotion preparation was produced according to the above-described method and filled in a polyethylene resin container.
（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 ２０．０ｇ
エタノール ５０．０ｇ
精製水 全１００ｇ
上記処方で、常法によりローション剤を製造した後，ポリプロピレン樹脂容器に充填した。
(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 20.0g
Ethanol 50.0g
100g of purified water
A lotion preparation was produced according to the above-described method and filled in a polypropylene resin container.
（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
ポリエチレングリコール４００ ２０．０ｇ
エタノール ５０．０ｇ
精製水 全１００ｇ
上記処方で、常法によりローション剤を製造した後，ポリプロピレン樹脂容器に充填した。
(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Benzalkonium chloride 0.05g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
Polyethylene glycol 400 20.0g
Ethanol 50.0g
100g of purified water
A lotion preparation was produced according to the above-described method and filled in a polypropylene resin container.
（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
プロピレングリコール ２０．０ｇ
エタノール ５０．０ｇ
精製水 全１００ｇ
上記処方で、常法によりローション剤を製造した後，エチレン-酢酸ビニル共重合体樹脂容器に充填した。
(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Decalinium chloride 0.1g
Dipotassium glycyrrhizinate 0.5g
l-Menthol 1.0g
Propylene glycol 20.0g
Ethanol 50.0g
100g of purified water
A lotion preparation was produced in the above-mentioned manner by a conventional method and then filled into an ethylene-vinyl acetate copolymer resin container.
（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 ２０．０ｇ
エタノール ６０．０ｇ
精製水 全１００ｇ
上記処方で、常法によりローション剤を製造した後，ポリエチレン樹脂容器に充填した。
(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 20.0g
Ethanol 60.0g
100g of purified water
A lotion preparation was produced according to the above-described method and filled in a polyethylene resin container.
（ローション）
塩酸テルビナフィン １．０ｇ
リドカイン ２．０ｇ
塩化ベンゼトニウム 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
精製水 全１００ｇ
上記処方で、常法によりローション剤を製造した後，ポリエチレン樹脂容器に充填した。
(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Benzethonium 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
100g of purified water
A lotion preparation was produced according to the above-described method and filled in a polyethylene resin container.
調製例１
塩酸テルビナフィン ０．０１ｇ
ポリエチレングリコール４００ ２５ｇ
ＮａＯＨ 適量（ｐＨ５）
エタノール ５０ｍＬ
水 全１００ｍＬ
上記処方で、常法により液剤を調製した（ＮａＯＨ水溶液でｐＨ５に調整した）。
Preparation Example 1
Terbinafine hydrochloride 0.01g
Polyethylene glycol 400 25g
NaOH proper amount (pH 5)
Ethanol 50mL
100 mL of water
With the above formulation, a solution was prepared by a conventional method (adjusted to pH 5 with an aqueous NaOH solution).
調製例２
塩酸テルビナフィン ０．０１ｇ
ポリエチレングリコール４００ ２５ｇ
ＮａＯＨ 適量（ｐＨ８）
エタノール ５０ｍＬ
水 全１００ｍＬ
上記処方で、常法により液剤を調製した（ＮａＯＨ水溶液でｐＨ８に調整した）。
Preparation Example 2
Terbinafine hydrochloride 0.01g
Polyethylene glycol 400 25g
NaOH proper amount (pH8)
Ethanol 50mL
100 mL of water
With the above formulation, a solution was prepared by a conventional method (adjusted to pH 8 with an aqueous NaOH solution).
比較例１
塩酸テルビナフィン ０．０１ｇ
エタノール ５０ｍＬ
精製水 全１００ｍＬ
上記処方で、常法により液剤を調製した。
Comparative Example 1
Terbinafine hydrochloride 0.01g
Ethanol 50mL
100 mL of purified water
With the above formulation, a solution was prepared by a conventional method.
比較例２
塩酸テルビナフィン ０．０１ｇ
ＮａＯＨ 適量（ｐＨ８）
エタノール ５０ｍＬ
水 全１００ｍＬ
上記処方で、常法により液剤を調製した（ＮａＯＨ水溶液でｐＨ８に調整した）。
Comparative Example 2
Terbinafine hydrochloride 0.01g
NaOH proper amount (pH8)
Ethanol 50mL
100 mL of water
With the above formulation, a solution was prepared by a conventional method (adjusted to pH 8 with an aqueous NaOH solution).
試験例
塩酸テルビナフィンの樹脂ビーズへの吸着試験
＜試験方法＞ガラスバイアル（２０ｍＬ）に調製例１，２及び比較例１，２の溶液１０ｍＬ及び樹脂ビーズ（ポリエチレン、エチレン-酢酸ビニル共重合体）約１ｇを充填し、４０℃で２週間保存した。比較として各処方の溶液において樹脂ビーズなしのサンプルを充填し、４０℃で２週間保存した。溶液中の塩酸テルビナフィンの残存量を高速液体クロマトグラフィー法（以下、ＨＰＬＣ法）にて測定し、各処方の対ビーズなしで残存率を評価した。結果を表１に示した。
Test Example Adsorption test of terbinafine hydrochloride on resin beads <Test method> About 10 mL of the solutions of Preparation Examples 1 and 2 and Comparative Examples 1 and 2 and resin beads (polyethylene, ethylene-vinyl acetate copolymer) in a glass vial (20 mL) 1 g was filled and stored at 40 ° C. for 2 weeks. For comparison, a sample without resin beads was filled in each formulation solution and stored at 40 ° C. for 2 weeks. The residual amount of terbinafine hydrochloride in the solution was measured by a high performance liquid chromatography method (hereinafter, HPLC method), and the residual rate was evaluated without beads for each formulation. The results are shown in Table 1.
表から明らかなように、ポリエチレン製、エチレン-酢酸ビニル共重合体製のいずれの樹脂においても、ポリオールを配合していない比較例１および２に比べて、ポリオールを配合した調製例１または調製例２の方が溶液中の塩酸テルビナフィンの残存率が高く、塩酸テルビナフィンの樹脂製容器への吸着が顕著に抑制された。 As is clear from the table, in both resins made of polyethylene and ethylene-vinyl acetate copolymer, Preparation Example 1 or Preparation Example in which a polyol was blended as compared with Comparative Examples 1 and 2 in which no polyol was blended No. 2 had a higher residual rate of terbinafine hydrochloride in the solution, and the adsorption of terbinafine hydrochloride to the resin container was significantly suppressed.
本発明により、塩酸テルビナフィン配合液剤の容器選択の余地が広がったので、医薬品製剤に応用可能である。 According to the present invention, the room for container selection of a terbinafine hydrochloride compounded solution has been expanded, so that it can be applied to pharmaceutical preparations.
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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 |
| 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 |
| JP2002003364A (en) * | 2000-06-23 | 2002-01-09 | Lion Corp | Eye drop, ophthalmic composition and method for adsorption control |
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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 |
| 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 |
| JP2002003364A (en) * | 2000-06-23 | 2002-01-09 | Lion Corp | Eye drop, ophthalmic composition and method for adsorption control |
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