JP2021167298A - Pharmaceutical composition for external use - Google Patents
Pharmaceutical composition for external use Download PDFInfo
- Publication number
- JP2021167298A JP2021167298A JP2020172262A JP2020172262A JP2021167298A JP 2021167298 A JP2021167298 A JP 2021167298A JP 2020172262 A JP2020172262 A JP 2020172262A JP 2020172262 A JP2020172262 A JP 2020172262A JP 2021167298 A JP2021167298 A JP 2021167298A
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- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- external pharmaceutical
- minoxidil
- composition according
- external
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 96
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229960003632 minoxidil Drugs 0.000 claims abstract description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000000203 mixture Substances 0.000 claims abstract description 36
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims abstract description 19
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 claims abstract description 16
- 229960005274 benzocaine Drugs 0.000 claims abstract description 15
- 239000004202 carbamide Substances 0.000 claims abstract description 15
- 229960003338 crotamiton Drugs 0.000 claims abstract description 14
- 229960004830 cetylpyridinium Drugs 0.000 claims abstract description 11
- NEUSVAOJNUQRTM-UHFFFAOYSA-N cetylpyridinium Chemical compound CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NEUSVAOJNUQRTM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960003872 benzethonium Drugs 0.000 claims abstract description 10
- SIYLLGKDQZGJHK-UHFFFAOYSA-N dimethyl-(phenylmethyl)-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]ammonium Chemical compound C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 SIYLLGKDQZGJHK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 239000006210 lotion Substances 0.000 claims abstract description 4
- 230000001256 tonic effect Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 102
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 66
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 38
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 33
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 33
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 20
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 19
- 235000011007 phosphoric acid Nutrition 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 235000011187 glycerol Nutrition 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 10
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- 235000014655 lactic acid Nutrition 0.000 claims description 10
- 239000004310 lactic acid Substances 0.000 claims description 10
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003002 pH adjusting agent Substances 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
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- 239000002552 dosage form Substances 0.000 claims description 2
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
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- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- FUWUEFKEXZQKKA-UHFFFAOYSA-N beta-thujaplicin Chemical compound CC(C)C=1C=CC=C(O)C(=O)C=1 FUWUEFKEXZQKKA-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
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- 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 5
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229940127557 pharmaceutical product Drugs 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 3
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 3
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 3
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 3
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- 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 3
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 3
- TUFYVOCKVJOUIR-UHFFFAOYSA-N alpha-Thujaplicin Natural products CC(C)C=1C=CC=CC(=O)C=1O TUFYVOCKVJOUIR-UHFFFAOYSA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 3
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- 210000004209 hair Anatomy 0.000 description 3
- 230000003779 hair growth Effects 0.000 description 3
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- 238000000034 method Methods 0.000 description 3
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 3
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 3
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- 239000011764 pyridoxine hydrochloride Substances 0.000 description 3
- 229940037001 sodium edetate Drugs 0.000 description 3
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 3
- -1 sucrose fatty acid ester Chemical class 0.000 description 3
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- 239000004471 Glycine Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
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- 210000002826 placenta Anatomy 0.000 description 1
- TXGSOSAONMOPDL-UHFFFAOYSA-N propan-2-yl 3,4,5-trihydroxybenzoate Chemical compound CC(C)OC(=O)C1=CC(O)=C(O)C(O)=C1 TXGSOSAONMOPDL-UHFFFAOYSA-N 0.000 description 1
- 235000020236 pumpkin seed Nutrition 0.000 description 1
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- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 1
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- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
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- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 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 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ミノキシジルを配合した外用医薬組成物に関する。 The present invention relates to an external pharmaceutical composition containing minoxidil.
ミノキシジルは化学名を６−（１−ピペリジニル）−２、４−ピリミジンジアミン−３−オキサイドと称し、育毛剤としての適応が知られており（特許文献１）、優れた育毛・発毛効果を発揮する薬剤として多数の報告がある。 ミノキシジルを配合した育毛剤に求められる基本的な性能は、頭皮からのミノキシジルの吸収性に優れることである（特許文献２）。 Minoxidil has a chemical name of 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide, and is known to be applied as a hair restorer (Patent Document 1), and has excellent hair growth and hair growth effects. There are many reports as a drug to exert. The basic performance required for a hair restorer containing minoxidil is that it has excellent absorption of minoxidil from the scalp (Patent Document 2).
ミノキシジルを含有する製剤中のミノキシジルが頭皮から効率的に吸収されるためには、ミノキシジルを含有する製剤が頭皮の表面になじみ、広がることが重要である。しかし、水を多く含む製剤は疎水的な皮膚との間に表面自由エネルギーが働くため、滴の状態を保ち、肌表面に広がりにくい。肌なじみを向上する技術として、例えばポリエーテル変性シリコーン又はポリグリセリン変性シリコーン、及びショ糖脂肪酸エステルを利用する方法が提案されている（特許文献３）。また、特許文献４には、ミノキシジルの濃度が高まると、頭皮に製剤が広がる感じが悪化することが示されている。 In order for minoxidil in the preparation containing minoxidil to be efficiently absorbed from the scalp, it is important that the preparation containing minoxidil is familiar with and spreads on the surface of the scalp. However, since the surface free energy acts between the water-rich preparation and the hydrophobic skin, it keeps the state of droplets and is difficult to spread on the skin surface. As a technique for improving skin compatibility, for example, a method using polyether-modified silicone or polyglycerin-modified silicone, and sucrose fatty acid ester has been proposed (Patent Document 3). Further, Patent Document 4 shows that as the concentration of minoxidil increases, the feeling that the preparation spreads on the scalp worsens.
しかしながら、上記特許文献１〜４のいずれにも、肌なじみがよいミノキシジル含有外用医薬組成物である本発明を得るために、本発明の構成を採用することを示唆するような記載はない。 However, none of the above-mentioned Patent Documents 1 to 4 has a description suggesting that the constitution of the present invention is adopted in order to obtain the present invention which is a minoxidil-containing external pharmaceutical composition which is familiar to the skin.
本発明は、肌なじみがよい、ミノキシジル含有外用医薬組成物を提供することを目的とする。 An object of the present invention is to provide a minoxidil-containing external pharmaceutical composition that is familiar to the skin.
上記課題を解決するために、本発明は、（ａ）ミノキシジル、（ｂ）クロタミトン、アミノ安息香酸エチル、尿素、セチルピリジニウム及び/又はその塩、並びに、ベンゼトニウム及び/又はその塩からなる群から選ばれる少なくとも１種、（ｃ）水を含有する外用医薬組成物を提供する。 In order to solve the above problems, the present invention is selected from the group consisting of (a) minoxidil, (b) crotamiton, ethyl aminobenzoate, urea, cetylpyridinium and / or a salt thereof, and benzethonium and / or a salt thereof. Provided is an external pharmaceutical composition containing at least one of (c) water.
すなわち本発明は、
（１）（ａ）ミノキシジル、（ｂ）尿素、セチルピリジニウム及びその塩、アミノ安息香酸エチル、クロタミトン並びに、ベンゼトニウム及びその塩からなる群から選ばれる少なくとも１種、及び（ｃ）水を含有することを特徴とする外用医薬組成物、
（２）成分（ｂ）が尿素である、（１）に記載の外用医薬組成物、
（３）成分（ｂ）がセチルピリジニウム及び／又はその塩である、（１）に記載の外用医薬組成物、
（４）成分（ｂ）がアミノ安息香酸エチルである、（１）に記載の外用医薬組成物、
（５）成分（ｂ）がクロタミトンである、（１）に記載の外用医薬組成物、
（６）成分（ｂ）がベンゼトニウム及び／又はその塩である、（１）に記載の外用医薬組成物、
（７）（ａ）ミノキシジルの含有量が、３〜１５ｗ／ｖ％である、（１）に記載の外用医薬組成物、
（８）さらに低級アルコールを含有する、（１）〜（７）のいずれかに記載の外用医薬組成物、
（９）さらに多価アルコールを含有する、（１）〜（８）のいずれかに記載の外用医薬組成物、
（１０）さらにｐＨ調整剤を含有する、（１）〜（９）のいずれかに記載の外用医薬組成物、
（１１）低級アルコールが炭素数１〜５の低級アルコールである、（８）に記載の外用組成物、
（１２）多価アルコールが、１,３−ブチレングリコール、ジプロピレングリコール、プロピレングリコール、グリセリン、及びポリエチレングリコールからなる群から選択される少なくとも１種である、（９）に記載の外用医薬組成物、
（１３）ｐＨ調整剤が、クエン酸、リンゴ酸、乳酸、酒石酸、リン酸、塩酸、及び硫酸からなる群から選択される少なくとも１種である、（１０）に記載の外用医薬組成物、
（１４）水の含有量が、５〜７５ｗ／ｗ％である、（１）に記載の外用医薬組成物、
（１５）剤形が、液剤、ローション剤又はトニック剤である、（１）〜（１４）のいずれかに記載の外用医薬組成物、
である。
That is, the present invention
(1) Containing at least one selected from the group consisting of (a) minoxidil, (b) urea, cetylpyridinium and salts thereof, ethyl aminobenzoate, crotamiton, benzethonium and salts thereof, and (c) water. External pharmaceutical composition, characterized by
(2) The external pharmaceutical composition according to (1), wherein the component (b) is urea.
(3) The external pharmaceutical composition according to (1), wherein the component (b) is cetylpyridinium and / or a salt thereof.
(4) The external pharmaceutical composition according to (1), wherein the component (b) is ethyl aminobenzoate.
(5) The external pharmaceutical composition according to (1), wherein the component (b) is crotamiton.
(6) The external pharmaceutical composition according to (1), wherein the component (b) is benzethonium and / or a salt thereof.
(7) The external pharmaceutical composition according to (1), wherein the content of (a) minoxidil is 3 to 15 w / v%.
(8) The external pharmaceutical composition according to any one of (1) to (7), which further contains a lower alcohol.
(9) The external pharmaceutical composition according to any one of (1) to (8), which further contains a polyhydric alcohol.
(10) The external pharmaceutical composition according to any one of (1) to (9), which further contains a pH adjuster.
(11) The external composition according to (8), wherein the lower alcohol is a lower alcohol having 1 to 5 carbon atoms.
(12) The external pharmaceutical composition according to (9), wherein the polyhydric alcohol is at least one selected from the group consisting of 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin, and polyethylene glycol. ,
(13) The external pharmaceutical composition according to (10), wherein the pH adjuster is at least one selected from the group consisting of citric acid, malic acid, lactic acid, tartaric acid, phosphoric acid, hydrochloric acid, and sulfuric acid.
(14) The external pharmaceutical composition according to (1), wherein the water content is 5 to 75 w / w%.
(15) The external pharmaceutical composition according to any one of (1) to (14), wherein the dosage form is a liquid agent, lotion agent or tonic agent.
Is.
本発明により、（ａ）ミノキシジル、（ｂ）クロタミトン、アミノ安息香酸エチル、尿素、セチルピリジニウム及び/又はその塩、並びに、ベンゼトニウム及び/又はその塩からなる群から選ばれる少なくとも１種、（ｃ）水を含有ことにより、肌なじみに優れたミノキシジル含有外用医薬組成物を提供することが可能になった。 According to the present invention, at least one selected from the group consisting of (a) minoxidil, (b) crotamiton, ethyl aminobenzoate, urea, cetylpyridinium and / or a salt thereof, and benzethonium and / or a salt thereof, (c). By containing water, it has become possible to provide a minoxidil-containing external pharmaceutical composition having excellent skin compatibility.
本発明の外用医薬組成物において用いるミノキシジルは、通常医薬品に用いられる品質のものを適宜使用することができる。また、本発明に用いるミノキシジルの含有量は、外用医薬組成物全体に対して、１〜１５ｗ／ｖ％が好ましい。本発明における外用医薬組成物において、ミノキシジルの含有量が多くなるにつれ肌なじみの課題も大きくなるため、外用医薬組成物中におけるミノキシジルの濃度が高いほど、本発明を実施する意義が大きい。具体的には、本発明の外用医薬組成物中３ｗ／ｖ％以上がより好ましく、更に好ましくは５ｗ／ｖ％以上であり、上限は１５ｗ／ｖ％以下がより好ましく、更に好ましくは１０ｗ／ｖ％以下である。 As the minoxidil used in the external pharmaceutical composition of the present invention, those of the quality usually used for pharmaceutical products can be appropriately used. The content of minoxidil used in the present invention is preferably 1 to 15 w / v% with respect to the entire external pharmaceutical composition. In the external pharmaceutical composition of the present invention, the problem of skin familiarity increases as the content of minoxidil increases. Therefore, the higher the concentration of minoxidil in the external pharmaceutical composition, the greater the significance of carrying out the present invention. Specifically, 3 w / v% or more is more preferable, more preferably 5 w / v% or more, and the upper limit is more preferably 15 w / v% or less, still more preferably 10 w / v in the external pharmaceutical composition of the present invention. % Or less.
本発明のクロタミトンは、通常医薬品に用いられる品質のものを適宜使用することができる。本発明においてクロタミトンの含有量は、本発明の効果の点から本発明の外用医薬組成物中好ましくは０．０１〜１０ｗ／ｖ％であり、より好ましくは０．１〜５ｗ／ｖ％である。 As the crotamiton of the present invention, those having a quality usually used for pharmaceutical products can be appropriately used. In the present invention, the content of crotamiton is preferably 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v% in the external pharmaceutical composition of the present invention from the viewpoint of the effect of the present invention. ..
本発明のアミノ安息香酸エチルはベンゾカインと呼ばれることもあり、通常医薬品に用いられる品質のものを適宜使用することができる。本発明において、アミノ安息香酸エチルの含有量は、本発明の効果の点から本発明の外用医薬組成物中好ましくは０．０１〜１０ｗ／ｖ％であり、より好ましくは０．１〜５ｗ／ｖ％である。 The ethyl aminobenzoate of the present invention is sometimes called benzocaine, and the quality usually used for pharmaceuticals can be appropriately used. In the present invention, the content of ethyl aminobenzoate is preferably 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v% in the external pharmaceutical composition of the present invention from the viewpoint of the effect of the present invention. It is v%.
本発明の尿素は通常医薬品に用いられる品質のものを適宜使用することができる。本発明において尿素の含有量は、本発明の効果の点から本発明の外用医薬組成物中好ましくは０．０１〜１０ｗ／ｖ％であり、より好ましくは０．１〜５ｗ／ｖ％である。 As the urea of the present invention, the urea of the quality usually used for pharmaceutical products can be appropriately used. In the present invention, the urea content is preferably 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v% in the external pharmaceutical composition of the present invention from the viewpoint of the effect of the present invention. ..
本発明のセチルピリジニウム及び/又はその塩としては、例えばセチルピリジニウム、塩化セチルピリジニウムが挙げられる。これらは、通常医薬品に用いられる品質のものを適宜使用することができる。本発明においてセチルピリジニウム及び/又はその塩の含有量は、本発明の効果の点から本発明の外用医薬組成物中好ましくは０．０１〜２ｗ／ｖ％であり、より好ましくは０．０４〜１ｗ／ｖ％である。 Examples of the cetylpyridinium and / or a salt thereof of the present invention include cetylpyridinium and cetylpyridinium chloride. As these, those of the quality usually used for pharmaceutical products can be appropriately used. In the present invention, the content of cetylpyridinium and / or a salt thereof is preferably 0.01 to 2 w / v%, more preferably 0.04 to 0.04 to the external pharmaceutical composition of the present invention from the viewpoint of the effect of the present invention. It is 1 w / v%.
本発明のベンゼトニウム及び/又はその塩としては、例えば塩化ベンゼトニウムが挙げられる。これらは、通常医薬品に用いられる品質のものを適宜使用することができる。本発明においてベンゼトニウム及び/又はその塩の含有量は、本発明の効果の点から本発明の外用医薬組成物中好ましくは０．０１〜５ｗ／ｖ％であり、より好ましくは０．０２〜０．５ｗ／ｖ％である。 Examples of the benzethonium and / or a salt thereof of the present invention include benzethonium chloride. As these, those of the quality usually used for pharmaceutical products can be appropriately used. In the present invention, the content of benzethonium and / or a salt thereof is preferably 0.01 to 5 w / v%, more preferably 0.02 to 0, in the external pharmaceutical composition of the present invention from the viewpoint of the effect of the present invention. It is .5 w / v%.
本発明の水の含有量は、本発明の効果の点から本発明の外用医薬組成物中１〜７５ｗ／ｗ％が好ましく、より好ましくは５〜５０ｗ／ｗ％であり、更に好ましくは８〜３０ｗ／ｗ％、最も好ましくは１２〜３０ｗ／ｗ％である。本発明の外用医薬組成物中の水の含有量の測定は、カール・フィッシャー法により行うことができる。 The water content of the present invention is preferably 1 to 75 w / w%, more preferably 5 to 50 w / w%, still more preferably 8 to 50% in the external pharmaceutical composition of the present invention from the viewpoint of the effect of the present invention. It is 30 w / w%, most preferably 12 to 30 w / w%. The water content in the external pharmaceutical composition of the present invention can be measured by the Karl Fischer method.
本発明の外用医薬組成物には必要によりｐＨ調整剤を配合することができる。ｐＨ調整剤の例としては、クエン酸、リンゴ酸、乳酸、酒石酸などの有機酸やリン酸、塩酸、硫酸などの無機酸を挙げることができる。本発明の外用医薬組成物のｐＨは、５〜８に調整することが好ましく、５．５〜７．５がさらに好ましく、６〜７が最も好ましい。 A pH adjuster can be added to the external pharmaceutical composition of the present invention, if necessary. Examples of the pH adjuster include organic acids such as citric acid, malic acid, lactic acid and tartaric acid, and inorganic acids such as phosphoric acid, hydrochloric acid and sulfuric acid. The pH of the external pharmaceutical composition of the present invention is preferably adjusted to 5 to 8, more preferably 5.5 to 7.5, and most preferably 6 to 7.
本発明の外用医薬組成物には必要により低級アルコールを配合することができる。低級アルコールの例としては、炭素数１〜５のものが好ましく、例えばエタノールやイソプロパノールなどが好ましく、これらを組み合わせて使用しても良い。本発明の外用医薬組成物中の低級アルコールの含有量は、本発明において特に制限はなく、適宜調製して必要量を決定すればよい。例えば、全組成物中２０ｗ／ｖ％以上が好ましく、より好ましくは３０ｗ／ｖ％以上であり、更に好ましくは３５ｗ／ｖ％以上であり、更に好ましくは５０ｗ／ｖ％以上である。上限は８０ｗ／ｖ％以下がより好ましく、更に好ましくは７０ｗ／ｖ％以下が好ましい。 A lower alcohol can be added to the external pharmaceutical composition of the present invention, if necessary. As an example of the lower alcohol, those having 1 to 5 carbon atoms are preferable, and for example, ethanol and isopropanol are preferable, and these may be used in combination. The content of the lower alcohol in the external pharmaceutical composition of the present invention is not particularly limited in the present invention and may be appropriately prepared to determine the required amount. For example, it is preferably 20 w / v% or more, more preferably 30 w / v% or more, still more preferably 35 w / v% or more, still more preferably 50 w / v% or more in the total composition. The upper limit is more preferably 80 w / v% or less, still more preferably 70 w / v% or less.
本発明の外用医薬組成物には必要により多価アルコールを配合することができる。多価アルコールの例としては、１,３−ブチレングリコール、ジプロピレングリコール、プロピレングリコール、グリセリン、ポリエチレングリコール等が挙げられ、これらを１種又は２種以上組み合わせてもよい。多価アルコールの含有量は、本発明において特に制限はなく、適宜調製して必要量を決定すればよい。例えば、本発明の外用医薬組成物中好ましくは５ｗ／ｖ％以上、より好ましくは１０ｗ／ｖ％以上であり、上限はべたつきが少なくなるなどの使用感も考慮すると３０ｗ／ｖ％以下が好ましい。 A polyhydric alcohol can be added to the external pharmaceutical composition of the present invention, if necessary. Examples of polyhydric alcohols include 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin, polyethylene glycol and the like, and these may be used alone or in combination of two or more. The content of the polyhydric alcohol is not particularly limited in the present invention and may be appropriately prepared to determine the required amount. For example, in the external pharmaceutical composition of the present invention, it is preferably 5 w / v% or more, more preferably 10 w / v% or more, and the upper limit is preferably 30 w / v% or less in consideration of usability such as less stickiness.
本発明の外用医薬組成物は、上記した各成分の他に、本発明の効果を損なわない範囲で、必要な活性成分や補助成分を加えることができる。本発明の外用医薬組成物に添加、配合することが好ましい薬効成分としては、メントール、ビタミンＥアセテート、ヒノキチオール、塩酸ピリドキシン、グリチルレチン酸、塩酸ジフェンヒドラミンから成る群より選ばれた成分が挙げられる。これら添加量は、特に制約はなく、使用感やミノキシジルの安定性又は溶剤系組成等を考慮しながら実験的に定めることができる。 In the external pharmaceutical composition of the present invention, in addition to the above-mentioned components, necessary active ingredients and auxiliary ingredients can be added as long as the effects of the present invention are not impaired. Preferable medicinal ingredients to be added to and blended with the external pharmaceutical composition of the present invention include ingredients selected from the group consisting of menthol, vitamin E acetate, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, and diphenhydramine hydrochloride. The amount of these additions is not particularly limited and can be experimentally determined in consideration of usability, stability of minoxidil, solvent-based composition, and the like.
本発明の外用医薬組成物においては、上記した成分の他、本発明の効果を損なわない範囲で、一般の外用剤に用いられる種々の活性成分や補助成分を配合することができる。例えば、賦形剤、育毛成分（６−ベンジルアミノプリン、アデノシン、ペンタデカン酸グリセリド、何首鳥等）、血管拡張剤（塩化カルプロニウム、ニコチン酸ベンジル、センブリ抽出液、オタネニンジンエキス、チクセツニンジンチンキ、トウガラシチンキ等）、抗ヒスタミン剤（塩酸イソチペンジル等）、抗炎症剤（グアイアズレン等）、角質溶解剤（サリチル酸等）、殺菌剤（グルコン酸クロルヘキシジン、イソプロピルメチルフェノール、第４級アンモニウム塩、ピロクトンオラミン等）、保湿剤（ヒアルロン酸又はその塩、コンドロイチン硫酸等）、各種動植物（イチイ、ボタンピ、カンゾウ、オトギリソウ、附子、ビワ、カワラヨモギ、コンフリー、アシタバ、サフラン、サンシシ、ローズマリー、セージ、モッコウ、セイモッコウ、ホップ、プラセンタ、ノコギリヤシ、パンプキンシード等）の抽出物、ビタミン類（アスコルビン酸、硝酸チアミン、シアノコバラミン、ビオチン等）、抗酸化剤（ジブチルヒドロキシトルエン、ピロ亜硫酸ナトリウム、トコフェロール、エデト酸ナトリウム、アスコルビン酸、イソプロピルガレート等）、溶解補助剤（アジピン酸ジイソプロピル、ミリスチン酸イソプロピル、各種植物油、各種動物油、アルキルグリセリルエーテル、炭化水素類等）、代謝賦活剤、ゲル化剤（水溶性高分子等）、粘着剤、香料、清涼化剤（ハッカ油、カンフル等）、染料等の通常使用される成分を配合することができる。 In the external pharmaceutical composition of the present invention, in addition to the above-mentioned ingredients, various active ingredients and auxiliary ingredients used in general external preparations can be blended as long as the effects of the present invention are not impaired. For example, excipients, hair growth ingredients (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, ascorbic acid, etc.), vasodilators (carpronium chloride, benzyl nicotinate, assembly extract, otane carrot extract, tincture tincture, etc. Togarashi tincture, etc.), antihistamine (isotipendyl hydrochloride, etc.), anti-inflammatory agent (guaizulene, etc.), keratolytic agent (salicylic acid, etc.), bactericide (chlorhexidine gluconate, isopropylmethylphenol, quaternary ammonium salt, pyrocton olamine, etc.) ), Moisturizer (hyaluronic acid or its salt, chondroitin sulfate, etc.), various animals and plants (Ichii, Buttonpi, Kanzo, Otogirisou, Tsukushi, Biwa, Kawarayomogi, Comfrey, Ashitaba, Saffron, Sanshishi, Rosemary, Sage, Mokko, Seimokko , Hops, placentas, sawtooth palms, pumpkin seeds, etc.), vitamins (ascorbic acid, thiamine nitrate, cyanocobalamine, biotin, etc.), antioxidants (dibutylhydroxytoluene, sodium pyrosulfate, tocopherol, sodium edetate, ascorbic acid, etc.) , Isopropyl gallate, etc.), solubilizers (diisopropyl adipate, isopropyl myristate, various vegetable oils, various animal oils, alkylglyceryl ethers, hydrocarbons, etc.), metabolism activators, gelling agents (water-soluble polymers, etc.), adhesive Commonly used ingredients such as agents, fragrances, refreshing agents (such as peppermint oil and camphor), and dyes can be blended.
また、本発明の外用医薬組成物は、液状の剤形であることが好ましく、液剤、ローション剤、トニック剤などの適当な外用医薬組成物とすることができる。 In addition, the external pharmaceutical composition of the present invention is preferably in a liquid dosage form, and can be an appropriate external pharmaceutical composition such as a liquid agent, a lotion agent, or a tonic agent.
本発明の外用医薬組成物の調製は、常法に従い、上記各成分を含有することにより調製される。 The preparation of the external pharmaceutical composition of the present invention is prepared by containing each of the above components according to a conventional method.
かくして得られる本発明の外用医薬組成物は、頭髪用剤、睫毛用剤、眉毛用剤等の皮膚適用製剤等として使用することができる。 The external pharmaceutical composition of the present invention thus obtained can be used as a skin-applied preparation such as a hair agent, an eyelash agent, and an eyebrow agent.
以下に、実施例、比較例及び試験例を記載し、本発明をさらに具体的に説明するが、本発明はこれら実施例等により何ら制約されるものではない。なお、実施例及び比較例の水分含量はカール・フィッシャー水分計により測定した。 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples, but the present invention is not limited to these Examples and the like. The water content of Examples and Comparative Examples was measured by a Karl Fischer titer.
（実施例１）
ミノキシジル５ｇ、クロタミトン１ｇ、１，３−ブチレングリコール１０ｇ、エタノール６０ｇ、リン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．１７の外用医薬組成物を得た。
(Example 1)
Minoxidil 5 g, crotamiton 1 g, 1,3-butylene glycol 10 g, ethanol 60 g, an appropriate amount of phosphoric acid, and purified water were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.17.
（実施例２）
ミノキシジル５ｇ、アミノ安息香酸エチル１ｇ、１，３−ブチレングリコール１０ｇ、エタノール６０ｇ、リン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．１７の外用医薬組成物を得た。
(Example 2)
Minoxidil 5 g, ethyl aminobenzoate 1 g, 1,3-butylene glycol 10 g, ethanol 60 g, phosphoric acid appropriate amount, purified water to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.17.
（実施例３）
ミノキシジル５ｇ、尿素１ｇ、１，３−ブチレングリコール１０ｇ、エタノール６０ｇ、リン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．１９の外用医薬組成物を得た。
(Example 3)
Minoxidil 5 g, urea 1 g, 1,3-butylene glycol 10 g, ethanol 60 g, an appropriate amount of phosphoric acid, and purified water were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.19.
（実施例４）
ミノキシジル５ｇ、セチルピリジニウム塩化物水和物０．２ｇ、１，３−ブチレングリコール１０ｇ、エタノール６０ｇ、リン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．１２の外用医薬組成物を得た。
(Example 4)
Minoxidil 5 g, cetylpyridinium chloride hydrate 0.2 g, 1,3-butylene glycol 10 g, ethanol 60 g, phosphoric acid appropriate amount, purified water to make the total volume 100 mL, and the mixture is stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.12. Obtained.
（実施例５）
ミノキシジル５ｇ、ベンゼトニウム塩化物０．５ｇ、１，３−ブチレングリコール１０ｇ、エタノール６０ｇ、リン酸適量、精製水で全量を１００ｍＬとし撹拌溶解してｐＨ６．１０の外用医薬組成物を得た。
(Example 5)
Minoxidil 5 g, benzethonium chloride 0.5 g, 1,3-butylene glycol 10 g, ethanol 60 g, an appropriate amount of phosphoric acid, and purified water were used to make a total volume of 100 mL and dissolved by stirring to obtain an external pharmaceutical composition having a pH of 6.10.
（比較例１）
ミノキシジル５ｇ、１，３−ブチレングリコール１０ｇ、エタノール６０ｇ、リン酸適量、精製水で全量を１００ｍＬとし撹拌溶解してｐＨ６．１６の外用医薬組成物を得た。
(Comparative Example 1)
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, an appropriate amount of phosphoric acid, and purified water were used to make a total volume of 100 mL and dissolved by stirring to obtain an external pharmaceutical composition having a pH of 6.16.
（比較例２）
ミノキシジル５ｇ、パンテノール１ｇ、１，３−ブチレングリコール１０ｇ、エタノール６０ｇ、リン酸適量、精製水で全量を１００ｍＬとし撹拌溶解してｐＨ６．１５の外用医薬組成物を得た。
(Comparative Example 2)
Minoxidil 5 g, pantenol 1 g, 1,3-butylene glycol 10 g, ethanol 60 g, an appropriate amount of phosphoric acid, and purified water were used to make a total volume of 100 mL and dissolved by stirring to obtain an external pharmaceutical composition having a pH of 6.15.
実施例１〜５、比較例１〜２の処方及び調製後のｐＨを表１に示す。 Table 1 shows the pH after formulation and preparation of Examples 1 to 5 and Comparative Examples 1 and 2.
（肌なじみ評価）
実施例１〜５、比較例１〜２の各試験液をマイクロピペット（エッペンドルフ社製）を用いて１００μＬ量り取り、バイオスキンプレート（＃４０、ビューラックス社製）上に滴下した。滴下３０秒後、広がった液の長径と短径を測定し、掛け合わせた値を肌なじみのスコアとした。下記［式１］に従い、肌なじみ改善率を算出した。算出した結果は、表２に示す。
(Skin familiarity evaluation)
Each test solution of Examples 1 to 5 and Comparative Examples 1 and 2 was weighed in 100 μL using a micropipette (manufactured by Eppendorf) and dropped onto a bioskin plate (# 40, manufactured by Bulux). Thirty seconds after the dropping, the major axis and the minor axis of the spread liquid were measured, and the multiplied value was used as a score familiar to the skin. The skin familiarity improvement rate was calculated according to the following [Equation 1]. The calculated results are shown in Table 2.
［式１］肌なじみ改善率（％）＝（各試験液の肌なじみスコア／比較例１の肌なじみスコア）×１００ [Equation 1] Skin familiarity improvement rate (%) = (skin familiarity score of each test solution / skin familiarity score of Comparative Example 1) × 100
表２に示した通り、（ｂ）成分を含有していない比較例１の外用医薬組成物に対して、本発明の実施例１〜５の外用医薬組成物は肌なじみが改善した。 As shown in Table 2, the external pharmaceutical compositions of Examples 1 to 5 of the present invention had improved skin compatibility with respect to the external pharmaceutical compositions of Comparative Example 1 which did not contain the component (b).
（実施例６）
ミノキシジル５ｇ、クロタミトン１ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１５ｇ、精製水１２ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．７５の外用医薬組成物を得た。
(Example 6)
Minoxidil 5 g, crotamiton 1 g, 1,3-butylene glycol 14 g, propylene glycol 15 g, purified water 12 g, tartrate acid appropriate amount, and ethanol were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.75.
（実施例７）
ミノキシジル５ｇ、アミノ安息香酸エチル１ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１５ｇ、精製水１２ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．７６の外用医薬組成物を得た。
(Example 7)
Minoxidil 5 g, ethyl aminobenzoate 1 g, 1,3-butylene glycol 14 g, propylene glycol 15 g, purified water 12 g, tartrate acid appropriate amount, ethanol to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.76. ..
（実施例８）
ミノキシジル５ｇ、尿素１ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１５ｇ、精製水１２ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．７７の外用医薬組成物を得た。
(Example 8)
Minoxidil 5 g, urea 1 g, 1,3-butylene glycol 14 g, propylene glycol 15 g, purified water 12 g, an appropriate amount of tartaric acid, and ethanol were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.77.
（実施例９）
ミノキシジル５ｇ、セチルピリジニウム塩化物水和物０．２ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１５ｇ、精製水１２ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．７０の外用医薬組成物を得た。
(Example 9)
Minoxidil 5 g, cetylpyridinium chloride hydrate 0.2 g, 1,3-butylene glycol 14 g, propylene glycol 15 g, purified water 12 g, tartrate acid appropriate amount, ethanol to make the total volume 100 mL, dissolve by stirring and dissolve for external use at pH 6.70. The composition was obtained.
（実施例１０）
ミノキシジル５ｇ、ベンゼトニウム塩化物０．５ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１５ｇ、精製水１２ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．６７の外用医薬組成物を得た。
(Example 10)
Minoxidil 5 g, benzethonium chloride 0.5 g, 1,3-butylene glycol 14 g, propylene glycol 15 g, purified water 12 g, tartrate acid appropriate amount, ethanol to make a total volume of 100 mL, and the mixture is stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.67. rice field.
（比較例３）
ミノキシジル５ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１５ｇ、精製水１２ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．７７の外用医薬組成物を得た。
(Comparative Example 3)
Minoxidil 5 g, 1,3-butylene glycol 14 g, propylene glycol 15 g, purified water 12 g, an appropriate amount of tartaric acid, and ethanol were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.77.
（比較例４）
ミノキシジル５ｇ、パンテノール１ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１５ｇ、精製水１２ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．７５の外用医薬組成物を得た。
(Comparative Example 4)
Minoxidil 5 g, panthenol 1 g, 1,3-butylene glycol 14 g, propylene glycol 15 g, purified water 12 g, tartrate acid appropriate amount, and ethanol were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.75.
実施例６〜１０、比較例３〜４の処方及び調製後のｐＨを表３に示す。 Table 3 shows the pH after formulation and preparation of Examples 6 to 10 and Comparative Examples 3 to 4.
（肌なじみ評価）
実施例６〜１０、比較例３〜４の各試験液をマイクロピペット（エッペンドルフ社製）を用いて１００μＬ量り取り、バイオスキンプレート（＃４０、ビューラックス社製）上に滴下した。滴下３０秒後、広がった液の長径と短径を測定し、掛け合わせた値を肌なじみのスコアとした。下記［式２］に従い、肌なじみ改善率を算出した。算出した結果は、表４に示す。
(Skin familiarity evaluation)
Each test solution of Examples 6 to 10 and Comparative Examples 3 to 4 was weighed in 100 μL using a micropipette (manufactured by Eppendorf) and dropped onto a bioskin plate (# 40, manufactured by Bulux). Thirty seconds after the dropping, the major axis and the minor axis of the spread liquid were measured, and the multiplied value was used as a score familiar to the skin. The skin familiarity improvement rate was calculated according to the following [Equation 2]. The calculated results are shown in Table 4.
［式２］肌なじみ改善率（％）＝（各試験液の肌なじみスコア／比較例３の肌なじみスコア）×１００ [Equation 2] Skin familiarity improvement rate (%) = (skin familiarity score of each test solution / skin familiarity score of Comparative Example 3) × 100
表４に示した通り、（ｂ）成分を含有していない比較例３の外用医薬組成物に対して、本発明の実施例６〜１０の外用医薬組成物は肌なじみが改善した。 As shown in Table 4, the external pharmaceutical compositions of Examples 6 to 10 of the present invention had improved skin compatibility with respect to the external pharmaceutical compositions of Comparative Example 3 which did not contain the component (b).
（実施例１１）
ミノキシジル５ｇ、クロタミトン１ｇ、１，３−ブチレングリコール１ｇ、グリセリン１２ｇ、エタノール５５ｇ、乳酸適量、クエン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．９３の外用医薬組成物を得た。
(Example 11)
Minoxidil 5 g, crotamiton 1 g, 1,3-butylene glycol 1 g, glycerin 12 g, ethanol 55 g, lactic acid appropriate amount, citric acid appropriate amount, purified water to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.93. ..
（実施例１２）
ミノキシジル５ｇ、アミノ安息香酸エチル１ｇ、１，３−ブチレングリコール１ｇ、グリセリン１２ｇ、エタノール５５ｇ、乳酸適量、クエン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．９３の外用医薬組成物を得た。
(Example 12)
Minoxidil 5 g, ethyl aminobenzoate 1 g, 1,3-butylene glycol 1 g, glycerin 12 g, ethanol 55 g, lactic acid appropriate amount, citric acid appropriate amount, purified water to make the total volume 100 mL, and dissolved by stirring to make an external pharmaceutical composition having a pH of 6.93. Got
（実施例１３）
ミノキシジル５ｇ、尿素１ｇ、１，３−ブチレングリコール１ｇ、グリセリン１２ｇ、エタノール５５ｇ、乳酸適量、クエン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．９４の外用医薬組成物を得た。
(Example 13)
Minoxidil 5 g, urea 1 g, 1,3-butylene glycol 1 g, glycerin 12 g, ethanol 55 g, lactic acid appropriate amount, citric acid appropriate amount, purified water to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.94. ..
（実施例１４）
ミノキシジル５ｇ、セチルピリジニウム塩化物水和物０．２ｇ、１，３−ブチレングリコール１ｇ、グリセリン１２ｇ、エタノール５５ｇ、乳酸適量、クエン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．８６の外用医薬組成物を得た。
(Example 14)
Minoxidil 5 g, cetylpyridinium chloride hydrate 0.2 g, 1,3-butylene glycol 1 g, glycerin 12 g, ethanol 55 g, lactic acid appropriate amount, citric acid appropriate amount, purified water to make the total volume 100 mL, stir and dissolve to pH 6.86. External pharmaceutical composition was obtained.
（実施例１５）
ミノキシジル５ｇ、ベンゼトニウム塩化物０．５ｇ、１，３−ブチレングリコール１ｇ、グリセリン１２ｇ、エタノール５５ｇ、乳酸適量、クエン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．８５の外用医薬組成物を得た。
(Example 15)
Minoxidil 5 g, benzethonium chloride 0.5 g, 1,3-butylene glycol 1 g, glycerin 12 g, ethanol 55 g, lactic acid appropriate amount, citric acid appropriate amount, purified water to make the total volume 100 mL, and dissolved by stirring to make an external pharmaceutical composition of pH 6.85. I got something.
（比較例５）
ミノキシジル５ｇ、１，３−ブチレングリコール１ｇ、グリセリン１２ｇ、エタノール５５ｇ、乳酸適量、クエン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．９０の外用医薬組成物を得た。
(Comparative Example 5)
Minoxidil 5 g, 1,3-butylene glycol 1 g, glycerin 12 g, ethanol 55 g, lactic acid appropriate amount, citric acid appropriate amount, and purified water were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.90.
（比較例６）
ミノキシジル５ｇ、パンテノール１ｇ、１，３−ブチレングリコール１ｇ、グリセリン１２ｇ、エタノール５５ｇ、乳酸適量、クエン酸適量、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．９１の外用医薬組成物を得た。
(Comparative Example 6)
Minoxidil 5 g, pantenol 1 g, 1,3-butylene glycol 1 g, glycerin 12 g, ethanol 55 g, lactic acid appropriate amount, citric acid appropriate amount, purified water to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.91. rice field.
実施例１１〜１５、比較例５〜６の処方及び調製後のｐＨを表５に示す。 Table 5 shows the pH after formulation and preparation of Examples 11 to 15 and Comparative Examples 5 to 6.
（肌なじみ評価）
実施例１１〜１５、比較例５〜６の各試験液をマイクロピペット（エッペンドルフ社製）を用いて１００μＬ量り取り、バイオスキンプレート（＃４０、ビューラックス社製）上に滴下した。滴下３０秒後、広がった液の長径と短径を測定し、掛け合わせた値を肌なじみのスコアとした。下記［式３］に従い、肌なじみ改善率を算出した。算出した結果は、表６に示す。
(Skin familiarity evaluation)
Each test solution of Examples 11 to 15 and Comparative Examples 5 to 6 was weighed in 100 μL using a micropipette (manufactured by Eppendorf) and dropped onto a bioskin plate (# 40, manufactured by Bulux). Thirty seconds after the dropping, the major axis and the minor axis of the spread liquid were measured, and the multiplied value was used as a score familiar to the skin. The skin familiarity improvement rate was calculated according to the following [Equation 3]. The calculated results are shown in Table 6.
［式３］肌なじみ改善率（％）＝（各試験液の肌なじみスコア／比較例５の肌なじみスコア）×１００ [Equation 3] Skin familiarity improvement rate (%) = (skin familiarity score of each test solution / skin familiarity score of Comparative Example 5) × 100
表６に示した通り、（ｂ）成分を含有していない比較例５の外用医薬組成物に対して、本発明の実施例１１〜１５の外用医薬組成物は肌なじみが改善した。 As shown in Table 6, the external pharmaceutical compositions of Examples 11 to 15 of the present invention had improved skin compatibility with respect to the external pharmaceutical compositions of Comparative Example 5 which did not contain the component (b).
（実施例１６）
ミノキシジル５ｇ、クロタミトン１ｇ、１，３−ブチレングリコール１０ｇ、精製水１７ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．０８の外用医薬組成物を得た。
(Example 16)
Minoxidil 5 g, crotamiton 1 g, 1,3-butylene glycol 10 g, purified water 17 g, an appropriate amount of phosphoric acid, and ethanol were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.08.
（実施例１７）
ミノキシジル５ｇ、アミノ安息香酸エチル１ｇ、１，３−ブチレングリコール１０ｇ、精製水１７ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．０９の外用医薬組成物を得た。
(Example 17)
Minoxidil 5 g, ethyl aminobenzoate 1 g, 1,3-butylene glycol 10 g, purified water 17 g, an appropriate amount of phosphoric acid, and ethanol were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.09.
（実施例１８）
ミノキシジル５ｇ、尿素１ｇ、１，３−ブチレングリコール１０ｇ、精製水１７ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．０９の外用医薬組成物を得た。
(Example 18)
Minoxidil 5 g, urea 1 g, 1,3-butylene glycol 10 g, purified water 17 g, an appropriate amount of phosphoric acid, and ethanol were added to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.09.
（実施例１９）
ミノキシジル５ｇ、セチルピリジニウム塩化物水和物０．２ｇ、１，３−ブチレングリコール１０ｇ、精製水１７ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．０４の外用医薬組成物を得た。
(Example 19)
Minoxydil 5 g, cetylpyridinium chloride hydrate 0.2 g, 1,3-butylene glycol 10 g, purified water 17 g, phosphoric acid appropriate amount, ethanol to make a total volume of 100 mL, and the mixture is stirred and dissolved to obtain an external pharmaceutical composition having a pH of 6.04. Obtained.
（実施例２０）
ミノキシジル５ｇ、ベンゼトニウム塩化物０．５ｇ、１，３−ブチレングリコール１０ｇ、精製水１７ｇ、リン酸適量、エタノールで全量を１００ｍＬとし撹拌溶解してｐＨ６．０２の外用医薬組成物を得た。
(Example 20)
Minoxidil 5 g, benzethonium chloride 0.5 g, 1,3-butylene glycol 10 g, purified water 17 g, an appropriate amount of phosphoric acid, and ethanol were used to make a total volume of 100 mL and dissolved by stirring to obtain an external pharmaceutical composition having a pH of 6.02.
（比較例７）
ミノキシジル５ｇ、１，３−ブチレングリコール１０ｇ、精製水１７ｇ、リン酸適量、エタノールで全量を１００ｍＬとし撹拌溶解してｐＨ６．０５の外用医薬組成物を得た。
(Comparative Example 7)
Minoxidil 5 g, 1,3-butylene glycol 10 g, purified water 17 g, an appropriate amount of phosphoric acid, and ethanol were added to make a total volume of 100 mL and dissolved by stirring to obtain an external pharmaceutical composition having a pH of 6.05.
（比較例８）
ミノキシジル５ｇ、パンテノール１ｇ、１，３−ブチレングリコール１０ｇ、精製水１７ｇ、リン酸適量、エタノールで全量を１００ｍＬとし撹拌溶解してｐＨ６．０８の外用医薬組成物を得た。
(Comparative Example 8)
Minoxidil 5 g, pantenol 1 g, 1,3-butylene glycol 10 g, purified water 17 g, an appropriate amount of phosphoric acid, and ethanol were used to make a total volume of 100 mL and dissolved by stirring to obtain an external pharmaceutical composition having a pH of 6.08.
実施例１６〜２０、比較例７〜８の処方及び調製後のｐＨを表７に示す。 Table 7 shows the pH after formulation and preparation of Examples 16 to 20 and Comparative Examples 7 to 8.
（肌なじみ評価）
実施例１６〜２０、比較例７〜８の各試験液をマイクロピペット（エッペンドルフ社製）を用いて１００μＬ量り取り、バイオスキンプレート（＃４０、ビューラックス社製）上に滴下した。滴下３０秒後、広がった液の長径と短径を測定し、掛け合わせた値を肌なじみのスコアとした。下記［式４］に従い、肌なじみ改善率を算出した。算出した結果は、表８に示す。
(Skin familiarity evaluation)
Each test solution of Examples 16 to 20 and Comparative Examples 7 to 8 was weighed in 100 μL using a micropipette (manufactured by Eppendorf) and dropped onto a bioskin plate (# 40, manufactured by Bulux). Thirty seconds after the dropping, the major axis and the minor axis of the spread liquid were measured, and the multiplied value was used as a score familiar to the skin. The skin familiarity improvement rate was calculated according to the following [Equation 4]. The calculated results are shown in Table 8.
［式４］肌なじみ改善率（％）＝（各試験液の肌なじみスコア／比較例７の肌なじみスコア）×１００ [Equation 4] Skin familiarity improvement rate (%) = (skin familiarity score of each test solution / skin familiarity score of Comparative Example 7) × 100
表８に示した通り、（ｂ）成分を含有していない比較例７の外用医薬組成物に対して、本発明の実施例１６〜２０の外用医薬組成物は肌なじみが改善した。 As shown in Table 8, the external pharmaceutical compositions of Examples 16 to 20 of the present invention had improved skin compatibility with respect to the external pharmaceutical compositions of Comparative Example 7 which did not contain the component (b).
また、別の発明の外用組成物として、例えばミノキシジル０．１〜１０ｗ／ｖ％、活性
成分や補助成分としてメントール０．１〜５ｗ／ｖ％、ビタミンＥアセテート０．００１
〜１ｗ／ｖ％、塩酸ピリドキシン０．００１〜１ｗ／ｖ％、ヒノキチオール０．００１〜
１ｗ／ｖ％、グリチルレチン酸０．００１〜１ｗ／ｖ％、塩酸ジフェンヒドラミン０．０
０１〜１ｗ／ｖ％、パントテニールエチルエーテル又はパンテノール０．１〜５ｗ／ｖ％、１，３−ブチレングリコール２〜３０ｗ／ｖ％、グリセリン１〜３０ｗ／ｖ％、エタノール２０〜８０ｗ／ｖ％、抗酸化剤（ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、ピロ硫酸ナトリウム、エデト酸ナトリウム、又は没食子酸ピロピル）０．００１〜１ｗ／ｖ％、リン酸適量、グリシン０．００００１〜１ｗ／ｖ％、Ｌ−アルギニン０．００００１〜１ｗ／ｖ％、アスコルビン酸０．０００００１〜１ｗ／ｖ％を配合し、残量を水で調製したものが挙げられる。これら活性成分や補助成分は使用感やミノキシジルの安定性あるいは溶剤系組成等を考慮し適宜配合することができる。この外用組成物の処方例を表９に示す。
Further, as an external composition of another invention, for example, minoxidil 0.1 to 10 w / v%, menthol 0.1 to 5 w / v% as an active ingredient or an auxiliary ingredient, vitamin E acetate 0.001
~ 1w / v%, pyridoxine hydrochloride 0.001 ~ 1w / v%, hinokitiol 0.001 ~
1 w / v%, glycyrrhetinic acid 0.001-1 w / v%, diphenhydramine hydrochloride 0.0
01 to 1 w / v%, pantotenyl ethyl ether or pantenol 0.1 to 5 w / v%, 1,3-butylene glycol 2 to 30 w / v%, glycerin 1 to 30 w / v%, ethanol 20 to 80 w / v %, Antioxidants (dibutylhydroxytoluene, dibutylhydroxyanisole, sodium pyrosulfate, sodium edetate, or gallic acid pyropyl) 0.001 to 1 w / v%, phosphoric acid appropriate amount, glycine 0.00001 to 1 w / v%, Examples thereof include those in which L-arginine 0.00001 to 1 w / v% and ascorbic acid 0.000001 to 1 w / v% are blended and the remaining amount is prepared with water. These active ingredients and auxiliary ingredients can be appropriately blended in consideration of usability, stability of minoxidil, solvent-based composition, and the like. Table 9 shows a formulation example of this external composition.
また、別の発明の外用組成物として、例えばミノキシジル０．１〜１０ｗ／ｖ％、活性
成分や補助成分としてメントール０．１〜５ｗ／ｖ％、ビタミンＥアセテート０．００１
〜１ｗ／ｖ％、塩酸ピリドキシン０．００１〜１ｗ／ｖ％、ヒノキチオール０．００１〜
１ｗ／ｖ％、グリチルレチン酸０．００１〜１ｗ／ｖ％、塩酸ジフェンヒドラミン０．０
０１〜１ｗ／ｖ％、パントテニールエチルエーテル又はパンテノール０．１〜５ｗ／ｖ％、クロタミトン１〜５ｗ／ｖ％、アミノ安息香酸エチル０．５〜５ｗ／ｖ％、尿素１〜５ｗ／ｖ％、セチリピリジニウム及び/又はその塩０．０４〜０．２ｗ／ｖ％、ベンゼトニウム及び/又はその塩０．０５〜０．５ｗ／ｖ％、１，３−ブチレングリコール２〜３０ｗ／ｖ％、グリセリン１〜３０ｗ／ｖ％、エタノール２０〜７０ｗ／ｖ％、抗酸化剤（ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、ピロ硫酸ナトリウム、エデト酸ナトリウム、又は没食子酸ピロピル）０．００１〜１ｗ／ｖ％、リン酸適量、グリシン０．００００１〜１ｗ／ｖ％、Ｌ−アルギニン０．００００１〜１ｗ／ｖ％、アスコルビン酸０．０００００１〜１ｗ／ｖ％を配合し、残量を水で調製したものが挙げられる。これら活性成分や補助成分は使用感やミノキシジルの安定性あるいは溶剤系組成等を考慮し適宜配合することができる。この外用組成物の処方例を表１０に示す。
Further, as an external composition of another invention, for example, minoxidil 0.1 to 10 w / v%, menthol 0.1 to 5 w / v% as an active ingredient or an auxiliary ingredient, vitamin E acetate 0.001
~ 1w / v%, pyridoxine hydrochloride 0.001 ~ 1w / v%, hinokitiol 0.001 ~
1 w / v%, glycyrrhetinic acid 0.001-1 w / v%, diphenhydramine hydrochloride 0.0
01 to 1 w / v%, pantotenil ethyl ether or pantenol 0.1 to 5 w / v%, crotamitone 1 to 5 w / v%, ethyl aminobenzoate 0.5 to 5 w / v%, urea 1 to 5 w / v %, Cetylpyridinium and / or its salt 0.04 to 0.2 w / v%, benzethonium and / or its salt 0.05 to 0.5 w / v%, 1,3-butylene glycol 2 to 30 w / v% , Glycerin 1-30 w / v%, Ethanol 20-70 w / v%, Antioxidants (dibutylhydroxytoluene, dibutylhydroxyanisole, sodium pyrosulfate, sodium edetate, or gallic acid pyropyl) 0.001-1 w / v% , Phosphoric acid appropriate amount, glycine 0.00001-1w / v%, L-arginine 0.00001-1w / v%, ascorbic acid 0.000001-1w / v%, and the remaining amount prepared with water. Can be mentioned. These active ingredients and auxiliary ingredients can be appropriately blended in consideration of usability, stability of minoxidil, solvent-based composition, and the like. Table 10 shows a formulation example of this external composition.
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