JP2021123586A - Pharmaceutical composition for external use - Google Patents
Pharmaceutical composition for external use Download PDFInfo
- Publication number
- JP2021123586A JP2021123586A JP2021008000A JP2021008000A JP2021123586A JP 2021123586 A JP2021123586 A JP 2021123586A JP 2021008000 A JP2021008000 A JP 2021008000A JP 2021008000 A JP2021008000 A JP 2021008000A JP 2021123586 A JP2021123586 A JP 2021123586A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- minoxidil
- external pharmaceutical
- composition according
- acid
- 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 85
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 claims abstract description 62
- 229960003632 minoxidil Drugs 0.000 claims abstract description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical compound C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229950004580 benzyl nicotinate Drugs 0.000 claims abstract description 17
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims abstract description 16
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims abstract description 11
- 241000723346 Cinnamomum camphora Species 0.000 claims abstract description 11
- 229960001716 benzalkonium Drugs 0.000 claims abstract description 11
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960000846 camphor Drugs 0.000 claims abstract description 11
- 229930008380 camphor Natural products 0.000 claims abstract description 11
- 239000006210 lotion Substances 0.000 claims abstract description 5
- 230000001256 tonic effect Effects 0.000 claims abstract description 5
- 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 70
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 38
- 239000007788 liquid Substances 0.000 claims description 37
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 35
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 35
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 33
- 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 18
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- 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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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 8
- 150000005846 sugar alcohols Polymers 0.000 claims description 7
- 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 4
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- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 claims description 3
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- 235000011090 malic acid Nutrition 0.000 claims description 3
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- 238000003756 stirring Methods 0.000 description 11
- 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
- 235000013772 propylene glycol Nutrition 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
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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 5
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
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- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
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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 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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- 235000006708 antioxidants Nutrition 0.000 description 2
- FUWUEFKEXZQKKA-UHFFFAOYSA-N beta-thujaplicin Chemical compound CC(C)C=1C=CC=C(O)C(=O)C=1 FUWUEFKEXZQKKA-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 2
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- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 2
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 2
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229940037001 sodium edetate Drugs 0.000 description 2
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
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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）。
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、製剤中のミノキシジルが溶解状態で存在し、結晶などが生じないことが好ましい。そして、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、水分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。
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。
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).
In order for minoxidil in the preparation containing minoxidil to be efficiently absorbed from the scalp, it is preferable that the minoxidil in the preparation is present in a dissolved state and crystals and the like are not formed. It is important that the preparation containing minoxidil blends into the surface of the scalp and spreads. However, since the surface free energy acts between the formulation containing a large amount of water 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.
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 topical 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）５ｗ／ｖ％以上のミノキシジル、（ｂ）カンフル、ニコチン酸ベンジル、マレイン酸クロルフェニラミン、ベンザルコニウム及び／又はその塩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。
すなわち本発明は、
（１）（ａ）５ｗ／ｖ％以上のミノキシジル、（ｂ）カンフル、ニコチン酸ベンジル、マレイン酸クロルフェニラミン、ベンザルコニウム及び／又はその塩からなる群から選ばれる少なくとも１種、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）（ａ）ミノキシジルの含有量が、５〜１５ｗ／ｖ％である、（１）に記載の外用医薬組成物。
（３）さらに低級アルコールを含有する、（１）又は（２）に記載の外用医薬組成物、
（４）さらに多価アルコールを含有する、（１）〜（３）のいずれかに記載の外用医薬組成物、
（５）さらにｐＨ調整剤を含有する、（１）〜（４）のいずれかに記載の外用医薬組成物、
（６）低級アルコールが炭素数１〜５の低級アルコールである、（３）に記載の外用医薬組成物、
（７）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、（４）に記載の外用医薬組成物、
（８）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、（５）に記載の外用医薬組成物、
（９）水の含有量が、５〜７５ｗ／ｗ％である、（１）に記載の外用医薬組成物、
（１０）剤形が、液剤、ローション剤、トニック剤、ゲル剤、又はエアゾール剤である、（１）〜（９）のいずれかに記載の外用医薬組成物、
（１１）５ｗ／ｖ％以上のミノキシジルを含有する外用医薬組成物の製造のための、カンフル、ニコチン酸ベンジル、マレイン酸クロルフェニラミン、ベンザルコニウム及び／又はその塩からなる群から選ばれる少なくとも１種の使用、
（１２）５ｗ／ｖ％以上のミノキシジルを含有する外用医薬組成物の肌なじみを向上させるための、カンフル、ニコチン酸ベンジル、マレイン酸クロルフェニラミン、ベンザルコニウム及び／又はその塩からなる群から選ばれる少なくとも１種の使用、
である。
In order to solve the above problems, the present invention is at least selected from (a) minoxidil of 5 w / v% or more, (b) camphor, benzyl nicotinate, chlorpheniramine maleate, benzalkonium and / or a salt thereof. An external pharmaceutical composition containing (c) water is provided.
That is, the present invention
(1) At least one selected from the group consisting of (a) 5 w / v% or more minoxidil, (b) camphor, benzyl nicotinate, chlorpheniramine maleate, benzalkonium and / or a salt thereof, and (c). ) Topical pharmaceutical composition, characterized by containing water,
(2) The external pharmaceutical composition according to (1), wherein the content of (a) minoxidil is 5 to 15 w / v%.
(3) The external pharmaceutical composition according to (1) or (2), which further contains a lower alcohol.
(4) The external pharmaceutical composition according to any one of (1) to (3), which further contains a polyhydric alcohol.
(5) The external pharmaceutical composition according to any one of (1) to (4), which further contains a pH adjuster.
(6) The external pharmaceutical composition according to (3), wherein the lower alcohol is a lower alcohol having 1 to 5 carbon atoms.
(7) The external pharmaceutical composition according to (4), 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. ,
(8) The external pharmaceutical composition according to (5), 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.
(9) The external pharmaceutical composition according to (1), wherein the water content is 5 to 75 w / w%.
(10) The external pharmaceutical composition according to any one of (1) to (9), wherein the dosage form is a liquid agent, a lotion agent, a tonic agent, a gel agent, or an aerosol agent.
(11) At least selected from the group consisting of camphor, benzyl nicotinate, chlorpheniramine maleate, benzalkonium and / or a salt thereof for the production of a topical pharmaceutical composition containing 5 w / v% or more of minoxidil. Use of one kind,
(12) From the group consisting of camphor, benzyl nicotinate, chlorpheniramine maleate, benzalkonium and / or salts thereof for improving the skin compatibility of topical pharmaceutical compositions containing 5 w / v% or more of minoxidil. Use of at least one selected,
Is.
本発明により、（ａ）５ｗ／ｖ％以上のミノキシジル、（ｂ）カンフル、ニコチン酸ベンジル、マレイン酸クロルフェニラミン、ベンザルコニウム及び/又はその塩からなる群から選ばれる少なくとも１種、（ｃ）水を併用して配合することにより、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 of 5 w / v% or more, (b) camphor, benzyl nicotinate, chlorpheniramine maleate, benzalkonium and / or a salt thereof, (c). ) By blending with water in combination, it has become possible to provide a minoxidil-containing topical 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、肌なじみの課題が大きくなる５ｗ／ｖ％以上である。具体的には５〜１５ｗ／ｖ％が好ましく、より好ましくは５〜１０ｗ／ｖ％である。 As the minoxidil used in the external pharmaceutical composition of the present invention, the quality usually used for pharmaceutical products can be appropriately used. In addition, the content of minoxidil used in the present invention is 5 w / v% or more, which increases the problem of skin familiarity with respect to the entire external pharmaceutical composition. Specifically, it is preferably 5 to 15 w / v%, more preferably 5 to 10 w / v%.
本発明のカンフルは、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。本発明においてカンフルの含有量は、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。 As the camphor of the present invention, a quality usually used for pharmaceutical products can be appropriately used. In the present invention, the content of camphor 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. ..
本発明のニコチン酸ベンジルは、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。本発明において、ニコチン酸ベンジルの含有量は、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。 As the benzyl nicotinate of the present invention, a benzyl nicotinate having a quality usually used for pharmaceutical products can be appropriately used. In the present invention, the content of benzyl nicotinate 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. %.
本発明のマレイン酸クロルフェニラミ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。本発明においてマレイン酸クロルフェニラミンの含有量は、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０．０５〜５ｗ／ｖ％である。 As the chlorpheniramine maleate of the present invention, a quality usually used for pharmaceutical products can be appropriately used. In the present invention, the content of chlorpheniramine maleate is preferably 0.01 to 10 w / v%, more preferably 0.05 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%.
本発明のベンザルコニウム及び／又はその塩としては、例えば塩化ベンザルコニウムが挙げられる。本発明のベンザルコニウム及び／又はその塩は、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ザルコニウム及び／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０．００１〜２ｗ／ｖ％であり、より好ましくは０．０１〜１ｗ／ｖ％である。 Examples of the benzalkonium and / or a salt thereof of the present invention include benzalkonium chloride. As the benzalkonium and / or a salt thereof of the present invention, those having the quality usually used for pharmaceutical products can be appropriately used. In the present invention, the content of benzalconium and / or a salt thereof is preferably 0.001 to 2 w / v%, more preferably 0.01, in the external pharmaceutical composition of the present invention from the viewpoint of the effect of the present invention. ~ 1w / 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１５〜３０ｗ／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 15 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、より好ましくは５．６〜７に調整することが好ましい。 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 5.6 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い。低級アルコールは２種以上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、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％が好ましい。 If necessary, a lower alcohol can be added to the external pharmaceutical composition of the present invention. As an example of the lower alcohol, those having 1 to 5 carbon atoms are preferable, and for example, ethanol and isopropanol are preferable. Two or more kinds of lower alcohols may be used in combination. The content of the lower alcohol in the external pharmaceutical composition of the present invention is preferably 20 w / v% or more, more preferably 30 w / v% or more, still more preferably 35 w / v% or more in the total composition. More preferably, it is 50 w / v% or more. The upper limit is preferably 80 w / v%.
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、好ましいのは１，３−ブチレングリコール、プロピレングリコール、グリセリンであり、より好ましいのは１，３−ブチレングリコールである。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、本発明の外用医薬組成物中好ましくは３ｗ／ｖ％以上、より好ましくは５ｗ／ｖ％以上、より好ましくは８ｗ／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 the polyhydric alcohol include 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin, polyethylene glycol and the like, and 1,3-butylene glycol, propylene glycol and glycerin are preferable, and more preferable. Is 1,3-butylene glycol. These may be used alone or in combination of two or more. The content of the polyhydric alcohol is preferably 3 w / v% or more, more preferably 5 w / v% or more, more preferably 8 w / v% or more, more preferably 10 w / v% or more in the external pharmaceutical composition of the present invention. 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、更に必要により界面活性剤を配合することができる。しかしながら、界面活性剤の添加は、使用感やミノキシジルの皮膚吸収に影響を与える可能性があるため、 実質的に界面活性剤を含まないものとすることが好ましい。 The external pharmaceutical composition of the present invention may further contain a surfactant, if necessary. However, since the addition of the surfactant may affect the feeling of use and the skin absorption of minoxidil, it is preferable that the addition of the surfactant is substantially free of the surfactant.
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、必要により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１種又は２種以上の成分が挙げられる。これらの添加量は、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, an active ingredient and an auxiliary ingredient can be added as necessary without impairing the effects of the present invention. The medicinal ingredient preferably added to or blended with the external pharmaceutical composition of the present invention is one or more selected from the group consisting of menthol, vitamin E acetate, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, and diphenhydramine hydrochloride. Ingredients are mentioned. 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、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, hydrochloric acid, hair-growth component (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, ascorbic acid, etc.), vasodilator (carpronium chloride, assembly extract, otane carrot extract, chixetsu carrot tincture, tocopherol 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, Hop, Placenta , Nokogiri palm, pumpkin seed, etc.), vitamins (ascorbic acid, thiamine nitrate, cyanocobalamine, biotin, etc.), antioxidants (dibutylhydroxytoluene, sodium pyrosulfate, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.) ), Dissolution aids (diisopropyl adipate, isopropyl myristate, various vegetable oils, various animal oils, alkylglyceryl ethers, hydrocarbons, etc.), metabolism activators, gelling agents (water-soluble polymers, etc.), adhesives, fragrances, etc. Commonly used ingredients such as a cooling agent (such as peppermint oil) and a dye 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、ゲル剤、エアゾール剤などの適当な外用医薬組成物とすることができ、好ましくは、液剤、ローション剤、トニック剤である。 Further, 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, a tonic agent, a gel agent, or an aerosol agent, and is preferable. , Liquids, lotions, tonics.
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、参考例、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、比較例、及び参考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, Reference Examples, and Test Examples, but the present invention is not limited to these Examples and the like. The water content of Examples, Comparative Examples, and Reference Examples was measured by a Karl Fischer titer.
（実施例１）
ミノキシジル５ｇ、dl-カンフル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（液剤）を得た。
(Example 1)
Minoxidil 5 g, dl-camfur 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 (liquid preparation) having a pH of 6.17.
（実施例２）
ミノキシジル５ｇ、ニコチン酸ベンジル０．１２５ｇ、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（液剤）を得た。
(Example 2)
Minoxidil 5 g, benzyl nicotinate 0.125 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 (liquid preparation) having a pH of 6.15. rice field.
（実施例３）
ミノキシジル５ｇ、マレイン酸クロルフェニラミン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ｐＨ６．０５の外用医薬組成物（液剤）を得た。
(Example 3)
Minoxidil 5 g, chlorpheniramine maleate 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 is stirred and dissolved to obtain an external pharmaceutical composition (liquid preparation) having a pH of 6.05. rice field.
（実施例４）
ミノキシジル５ｇ、ベンザルコニウム塩化物０．３ｇ、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（液剤）を得た。
(Example 4)
Minoxidil 5g, benzalconium chloride 0.3g, 1,3-butylene glycol 10g, ethanol 60g, phosphoric acid appropriate amount, purified water to make the total volume 100mL, and dissolved by stirring to make an external pharmaceutical composition (liquid) with pH 6.12. Got
（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（液剤）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 (liquid preparation) 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（液剤）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 (liquid preparation) having a pH of 6.15.
実施例１〜４、比較例１〜２の処方及び調製後の水分含量、ｐＨを表１に示す。 Table 1 shows the water content and pH after formulation and preparation of Examples 1 to 4 and Comparative Examples 1 and 2.
（肌なじみ評価）
実施例１〜４、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。
［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
(Skin familiarity evaluation)
Each test solution of Examples 1 to 4 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.
[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１〜４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 4 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).
（参考例１）
ミノキシジル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ｐＨ５．８１の外用医薬組成物（液剤）を得た。
（参考例２）
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ｐＨ６．１３の外用医薬組成物（液剤）を得た。
(Reference example 1)
Minoxidil 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 (liquid preparation) having a pH of 5.81.
(Reference example 2)
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 (liquid preparation) having a pH of 6.13.
参考例１及び２の処方及び調製後の水分含量、ｐＨを表３に示す。 Table 3 shows the water content and pH after the formulation and preparation of Reference Examples 1 and 2.
参考例１及び参考例２の肌なじみ評価を実施した結果，参考例２の肌なじみスコアは参考例１と比較して８８％と低く，ミノキシジルの濃度が高い程肌なじみが悪くなるという結果が得られた。 As a result of performing the skin familiarity evaluation of Reference Example 1 and Reference Example 2, the skin familiarity score of Reference Example 2 was as low as 88% as compared with Reference Example 1, and the result was that the higher the concentration of minoxidil, the worse the skin familiarity. Obtained.
（実施例５）
ミノキシジル５ｇ、ｄｌ−カンフル１ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１４ｇ、精製水１３ｇ、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（液剤）を得た。
(Example 5)
Minoxidil 5 g, dl-camfur 1 g, 1,3-butylene glycol 14 g, propylene glycol 14 g, purified water 13 g, tartrate acid appropriate amount, ethanol to make a total volume of 100 mL, and the mixture is stirred and dissolved to prepare an external pharmaceutical composition (liquid preparation) having a pH of 6.75. Obtained.
（実施例６）
ミノキシジル５ｇ、ニコチン酸ベンジル０．１２５ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１４ｇ、精製水１３ｇ、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（液剤）を得た。
(Example 6)
Minoxidil 5 g, benzyl nicotinate 0.125 g, 1,3-butylene glycol 14 g, propylene glycol 14 g, purified water 13 g, tartrate acid appropriate amount, ethanol to make the total volume 100 mL, and dissolve with stirring to make an external pharmaceutical composition (liquid preparation) with pH 6.75. ) Was obtained.
（実施例７）
ミノキシジル５ｇ、マレイン酸クロルフェニラミン１ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１４ｇ、精製水１３ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．６１の外用医薬組成物（液剤）を得た。
(Example 7)
Minoxidil 5 g, chlorpheniramine maleate 1 g, 1,3-butylene glycol 14 g, propylene glycol 14 g, purified water 13 g, tartaric acid appropriate amount, ethanol to make a total volume of 100 mL, dissolve with stirring to make an external pharmaceutical composition (liquid) with pH 6.61. ) Was obtained.
（実施例８）
ミノキシジル５ｇ、ベンザルコニウム塩化物０．３ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１４ｇ、精製水１３ｇ、酒石酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．６９の外用医薬組成物（液剤）を得た。
(Example 8)
Minoxidil 5 g, benzalconium chloride 0.3 g, 1,3-butylene glycol 14 g, propylene glycol 14 g, purified water 13 g, tartrate acid appropriate amount, ethanol to make a total volume of 100 mL, and the composition is stirred and dissolved to make an external pharmaceutical composition having a pH of 6.69. (Liquid) was obtained.
（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１４ｇ、精製水１３ｇ、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（液剤）を得た。
(Comparative Example 3)
Minoxidil 5 g, 1,3-butylene glycol 14 g, propylene glycol 14 g, purified water 13 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 (liquid preparation) having a pH of 6.75.
（比較例４）
ミノキシジル５ｇ、パントテニールエチルエーテル１ｇ、１，３−ブチレングリコール１４ｇ、プロピレングリコール１４ｇ、精製水１３ｇ、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（液剤）を得た。
(Comparative Example 4)
Minoxidil 5 g, pantotenil ethyl ether 1 g, 1,3-butylene glycol 14 g, propylene glycol 14 g, purified water 13 g, tartrate acid appropriate amount, ethanol to make a total volume of 100 mL, and the mixture is stirred and dissolved to make a pH 6.75 external pharmaceutical composition (liquid). Got
（比較例５）
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１４ｇ、精製水１３ｇ、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（液剤）を得た。
(Comparative Example 5)
Minoxidil 5 g, panthenol 1 g, 1,3-butylene glycol 14 g, propylene glycol 14 g, purified water 13 g, tartrate acid appropriate amount, ethanol to make the total volume 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition (liquid preparation) having a pH of 6.76. rice field.
実施例５〜８、比較例３〜５の処方及び調製後の水分含量、ｐＨを表４に示す。 Table 4 shows the water content and pH after formulation and preparation of Examples 5 to 8 and Comparative Examples 3 to 5.
（肌なじみ評価）
実施例５〜８、比較例３〜５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５に示す。
［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
(Skin familiarity evaluation)
Each test solution of Examples 5 to 8 and Comparative Examples 3 to 5 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 5.
[Equation 2] Skin familiarity improvement rate (%) = (skin familiarity score of each test solution / skin familiarity score of Comparative Example 3) × 100
表５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５〜８の外用医薬組成物は肌なじみが改善した。
As shown in Table 5, the external pharmaceutical compositions of Examples 5 to 8 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９）
ミノキシジル５ｇ、ｄｌ−カンフル１ｇ、１，３−ブチレングリコール１ｇ、グリセリン１３ｇ、精製水１２ｇ、乳酸適量、クエン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ７．０２の外用医薬組成物（液剤）を得た。
(Example 9)
Minoxidil 5 g, dl-camfur 1 g, 1,3-butylene glycol 1 g, glycerin 13 g, purified water 12 g, lactic acid appropriate amount, citric acid appropriate amount, ethanol to make a total volume of 100 mL, and the mixture is stirred and dissolved to make an external pharmaceutical composition having a pH of 7.02. Liquid) was obtained.
（実施例１０）
ミノキシジル５ｇ、ニコチン酸ベンジル０．１２５ｇ、１，３−ブチレングリコール１ｇ、グリセリン１３ｇ、精製水１２ｇ、乳酸適量、クエン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ７．０３の外用医薬組成物（液剤）を得た。
(Example 10)
Minoxidil 5 g, benzyl nicotinate 0.125 g, 1,3-butylene glycol 1 g, glycerin 13 g, purified water 12 g, lactic acid appropriate amount, citric acid appropriate amount, ethanol to make the total volume 100 mL, dissolve with stirring to make an external pharmaceutical composition of pH 7.03. A product (liquid agent) was obtained.
（実施例１１）
ミノキシジル５ｇ、マレイン酸クロルフェニラミン１ｇ、１，３−ブチレングリコール１ｇ、グリセリン１３ｇ、精製水１２ｇ、乳酸適量、クエン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．８５の外用医薬組成物（液剤）を得た。
(Example 11)
Minoxidil 5 g, chlorpheniramine maleate 1 g, 1,3-butylene glycol 1 g, glycerin 13 g, purified water 12 g, lactic acid appropriate amount, citric acid appropriate amount, ethanol to make the total volume 100 mL, dissolve with stirring to make an external pharmaceutical composition of pH 6.85. A product (liquid agent) was obtained.
（実施例１２）
ミノキシジル５ｇ、ベンザルコニウム塩化物０．３ｇ、１，３−ブチレングリコール１ｇ、グリセリン１３ｇ、精製水１２ｇ、乳酸適量、クエン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．９１の外用医薬組成物（液剤）を得た。
(Example 12)
Minoxidil 5 g, benzalconium chloride 0.3 g, 1,3-butylene glycol 1 g, glycerin 13 g, purified water 12 g, lactic acid appropriate amount, citric acid appropriate amount, ethanol to make the total volume 100 mL, dissolve by stirring and dissolve at pH 6.91 for external use. A pharmaceutical composition (liquid preparation) was obtained.
（比較例６）
ミノキシジル５ｇ、１，３−ブチレングリコール１ｇ、グリセリン１３ｇ、精製水１２ｇ、乳酸適量、クエン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．９９の外用医薬組成物（液剤）を得た。
(Comparative Example 6)
Minoxidil 5 g, 1,3-butylene glycol 1 g, glycerin 13 g, purified water 12 g, lactic acid appropriate amount, citric acid appropriate amount, and ethanol to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition (liquid preparation) having a pH of 6.99. ..
（比較例７）
ミノキシジル５ｇ、パントテニールエチルエーテル１ｇ、１，３−ブチレングリコール１ｇ、グリセリン１３ｇ、精製水１２ｇ、乳酸適量、クエン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ７．０３の外用医薬組成物（液剤）を得た。
(Comparative Example 7)
Minoxidil 5 g, pantotenil ethyl ether 1 g, 1,3-butylene glycol 1 g, glycerin 13 g, purified water 12 g, lactic acid appropriate amount, citric acid appropriate amount, ethanol to make a total volume of 100 mL, and the composition is stirred and dissolved to make an external pharmaceutical composition having a pH of 7.03. (Liquid) was obtained.
（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１ｇ、グリセリン１３ｇ、精製水１２ｇ、乳酸適量、クエン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ７．０５の外用医薬組成物（液剤）を得た。
(Comparative Example 8)
Minoxidil 5 g, pantenol 1 g, 1,3-butylene glycol 1 g, glycerin 13 g, purified water 12 g, lactic acid appropriate amount, citric acid appropriate amount, ethanol to make a total volume of 100 mL, and the mixture is stirred and dissolved to make a pH 7.05 external pharmaceutical composition (liquid preparation). ) Was obtained.
実施例９〜１２、比較例６〜８の処方及び調製後の水分含量、ｐＨを表６に示す。 Table 6 shows the water content and pH after formulation and preparation of Examples 9 to 12 and Comparative Examples 6 to 8.
（肌なじみ評価）
実施例９〜１２、比較例６〜８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３］に従い、肌なじみ改善率を算出した。算出した結果は、表７に示す。
［式３］肌なじみ改善率（％）＝（各試験液の肌なじみスコア／比較例６の肌なじみスコア）×１００
(Skin familiarity evaluation)
Each test solution of Examples 9 to 12 and Comparative Examples 6 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 3]. The calculated results are shown in Table 7.
[Equation 3] Skin familiarity improvement rate (%) = (skin familiarity score of each test solution / skin familiarity score of Comparative Example 6) × 100
表７に示した通り（ｂ）成分を含有していない比較例６の外用医薬組成物に対して、本発明の実施例９〜１２の外用医薬組成物は肌なじみが改善した。
As shown in Table 7, the external pharmaceutical compositions of Examples 9 to 12 of the present invention had improved skin compatibility with respect to the external pharmaceutical compositions of Comparative Example 6 which did not contain the component (b).
（実施例１３）
ミノキシジル５ｇ、ｄｌ−カンフル１ｇ、１，３−ブチレングリコール１０ｇ、精製水１５ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．１１の外用医薬組成物（液剤）を得た。
(Example 13)
Minoxidil 5 g, dl-camfur 1 g, 1,3-butylene glycol 10 g, purified water 15 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 (liquid preparation) having a pH of 6.11.
（実施例１４）
ミノキシジル５ｇ、ニコチン酸ベンジル０．１２５ｇ、１，３−ブチレングリコール１０ｇ、精製水１５ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．１０の外用医薬組成物（液剤）を得た。
(Example 14)
Minoxidil 5 g, benzyl nicotinate 0.125 g, 1,3-butylene glycol 10 g, purified water 15 g, phosphoric acid appropriate amount, ethanol to make the total volume 100 mL, and the mixture is stirred and dissolved to obtain an external pharmaceutical composition (liquid preparation) having a pH of 6.10. rice field.
（実施例１５）
ミノキシジル５ｇ、マレイン酸クロルフェニラミン１ｇ、１，３−ブチレングリコール１０ｇ、精製水１５ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．００の外用医薬組成物（液剤）を得た。
(Example 15)
Minoxidil 5 g, chlorpheniramine maleate 1 g, 1,3-butylene glycol 10 g, purified water 15 g, an appropriate amount of phosphoric acid, and ethanol to make a total volume of 100 mL, and the mixture is stirred and dissolved to obtain an external pharmaceutical composition (liquid preparation) having a pH of 6.00. rice field.
（実施例１６）
ミノキシジル５ｇ、ベンザルコニウム塩化物０．３ｇ、１，３−ブチレングリコール１０ｇ、精製水１５ｇ、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（液剤）を得た。
(Example 16)
Minoxidil 5 g, benzalconium chloride 0.3 g, 1,3-butylene glycol 10 g, purified water 15 g, phosphoric acid appropriate amount, ethanol to make the total volume 100 mL, dissolve with stirring to make an external pharmaceutical composition (liquid) with pH 6.05. Got
（比較例９）
ミノキシジル５ｇ、１，３−ブチレングリコール１０ｇ、精製水１５ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．１０の外用医薬組成物（液剤）を得た。
(Comparative Example 9)
Minoxidil 5 g, 1,3-butylene glycol 10 g, purified water 15 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 (liquid preparation) having a pH of 6.10.
（比較例１０）
ミノキシジル５ｇ、パントテニールエチルエーテル１ｇ、１，３−ブチレングリコール１０ｇ、精製水１５ｇ、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（液剤）を得た。
(Comparative Example 10)
Minoxidil 5 g, pantotenil ethyl ether 1 g, 1,3-butylene glycol 10 g, purified water 15 g, an appropriate amount of phosphoric acid, and ethanol to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition (liquid preparation) having a pH of 6.09. ..
（比較例１１）
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１５ｇ、リン酸適量、エタノールで全量を１００ｍＬとし、撹拌溶解してｐＨ６．１１の外用医薬組成物（液剤）を得た。
(Comparative Example 11)
Minoxidil 5 g, pantenol 1 g, 1,3-butylene glycol 10 g, purified water 15 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 (liquid preparation) having a pH of 6.11.
実施例１３〜１６、比較例９〜１１の処方及び調製後の水分含量、ｐＨを表８に示す。 Table 8 shows the water content and pH after formulation and preparation of Examples 13 to 16 and Comparative Examples 9 to 11.
（肌なじみ評価）
実施例１３〜１６、比較例９〜１１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９に示す。
［式４］肌なじみ改善率（％）＝（各試験液の肌なじみスコア／比較例９の肌なじみスコア）×１００
(Skin familiarity evaluation)
Each test solution of Examples 13 to 16 and Comparative Examples 9 to 11 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 9.
[Equation 4] Skin familiarity improvement rate (%) = (skin familiarity score of each test solution / skin familiarity score of Comparative Example 9) × 100
表９に示した通り（ｂ）成分を含有していない比較例９の外用医薬組成物に対して、本発明の実施例１３〜１６の外用医薬組成物は肌なじみが改善した。
As shown in Table 9, the external pharmaceutical compositions of Examples 13 to 16 of the present invention had improved skin compatibility with respect to the external pharmaceutical compositions of Comparative Example 9 which did not contain the component (b).
また、別の態様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０．００１〜１ｗ／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％、ｄｌ−カンフル０．１〜１ｗ／ｖ％、ニコチン酸ベンジル０．０１〜０．１２５ｗ／ｖ％、マレイン酸クロルフェニラミン０．０５〜１ｗ／ｖ％、ベンザルコニウム及び／又はその塩０．０２〜０．３ｗ／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 embodiment, for example, minoxidyl 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 to 1 w / v%, and the like. Pyridoxin hydrochloride 0.001-1w / v%, Hinokithiol 0.001-1w / v%, Glycyrrhetinic acid 0.001-1w / v%, Diphenhydramine hydrochloride 0.001-1w / v%, Pantotenil ethyl ether or Pantenol 0.1 to 5 w / v%, dl-camfur 0.1 to 1 w / v%, benzyl nicotinate 0.01 to 0.125 w / v%, chlorpheniramine maleate 0.05 to 1 w / v%, benza Luconium and / or its salt 0.02 to 0.3 w / v%, 1,3-butylene glycol 2 to 30 w / v%, glycerin 1 to 30 w / v%, ethanol 20 to 70 w / v%, antioxidant (Dibutylhydroxytoluene, dibutylhydroxyanisole, sodium pyrosulfate, sodium edetate, or pyropillate ascorbic acid) 0.001 to 1 w / v%, appropriate amount of phosphoric acid, glycine 0.00001 to 1 w / v%, L-arginine 0. Examples thereof include those in which 0.0001 to 1 w / v% and 0.000001 to 1 w / v% of ascorbic acid 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 10 shows a formulation example of this external composition.
本発明により、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が可能になった。 INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a minoxidil-containing topical pharmaceutical composition that is familiar to the skin.
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