JP2023099672A - External pharmaceutical composition - Google Patents
External pharmaceutical composition Download PDFInfo
- Publication number
- JP2023099672A JP2023099672A JP2023084246A JP2023084246A JP2023099672A JP 2023099672 A JP2023099672 A JP 2023099672A JP 2023084246 A JP2023084246 A JP 2023084246A JP 2023084246 A JP2023084246 A JP 2023084246A JP 2023099672 A JP2023099672 A JP 2023099672A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- ethyl ether
- minoxidil
- pantothenyl ethyl
- panthenol
- 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
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 29
- MRAMPOPITCOOIN-VIFPVBQESA-N (2r)-n-(3-ethoxypropyl)-2,4-dihydroxy-3,3-dimethylbutanamide Chemical compound CCOCCCNC(=O)[C@H](O)C(C)(C)CO MRAMPOPITCOOIN-VIFPVBQESA-N 0.000 claims abstract description 45
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims abstract description 42
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229960003632 minoxidil Drugs 0.000 claims abstract description 40
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 33
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims abstract description 30
- 229940101267 panthenol Drugs 0.000 claims abstract description 30
- 235000020957 pantothenol Nutrition 0.000 claims abstract description 30
- 239000011619 pantothenol Substances 0.000 claims abstract description 30
- 229940058015 1,3-butylene glycol Drugs 0.000 claims abstract description 21
- 235000019437 butane-1,3-diol Nutrition 0.000 claims abstract description 21
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 18
- 235000011187 glycerol Nutrition 0.000 claims description 15
- 239000000203 mixture Substances 0.000 abstract description 21
- 238000001556 precipitation Methods 0.000 abstract description 14
- 239000013078 crystal Substances 0.000 abstract description 12
- 238000000354 decomposition reaction Methods 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 26
- 230000000052 comparative effect Effects 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 13
- 235000011007 phosphoric acid Nutrition 0.000 description 13
- 239000008213 purified water Substances 0.000 description 13
- 238000009472 formulation Methods 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
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- 239000004480 active ingredient Substances 0.000 description 4
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
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- 239000002253 acid Substances 0.000 description 2
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- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
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- 229940098465 tincture Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
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- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- ZIMGGGWCDYVHOY-UHFFFAOYSA-N 3-hydroxy-2-imino-6-(1-piperidinyl)-4-pyrimidinamine Chemical group N=C1N(O)C(N)=CC(N2CCCCC2)=N1 ZIMGGGWCDYVHOY-UHFFFAOYSA-N 0.000 description 1
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- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 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
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960000716 tonics Drugs 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
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 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
- 229930007845 β-thujaplicin Natural products 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
Abstract
Description
本発明は、ミノキシジル、及びパントテニールエチルエーテル及び／又はパンテノールを有効成分とする外用医薬組成物に関する。更に詳細には、ミノキシジル由来の析出とパントテニールエチルエーテル又はパンテノールの経時的な分解を抑制した外用医薬組成物に関する。 The present invention relates to an external pharmaceutical composition containing minoxidil and pantothenyl ethyl ether and/or panthenol as active ingredients. More particularly, it relates to an external pharmaceutical composition that inhibits minoxidil-derived precipitation and decomposition of pantothenyl ethyl ether or panthenol over time.
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。 Minoxidil, whose chemical name is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, is known to be applied as a hair restorer (Patent Document 1), and has excellent hair growth and growth effects. There are many reports as a drug that exerts
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）。頭皮からのミノキシジルの吸収性を確保するためには、製剤中のミノキシジルが溶解状態で存在することが好ましく、製剤中で結晶析出等が生じないことが求められる。ミノキシジルは水やほとんどの油に対して溶解性が悪く、特に５ｗ／ｖ％以上の高濃度のミノキシジルの溶解性を確保するため、リン酸やクエン酸などの酸を配合して製剤のｐＨを調整することが広く行われている（特許文献３、４）。
一方、パントテニールエチルエーテル又はパンテノールは、細胞賦活剤又は毛包賦活剤として知られる成分である（特許文献５、特許文献６）
The basic performance required for a hair restorer containing minoxidil is excellent absorbability of minoxidil from the scalp (Patent Document 2). In order to ensure the absorbability of minoxidil from the scalp, it is preferable that minoxidil in the formulation exists in a dissolved state, and it is required that no crystal precipitation or the like occurs in the formulation. Minoxidil has poor solubility in water and most oils. In order to ensure the solubility of minoxidil at a high concentration of 5 w/v% or more, an acid such as phosphoric acid or citric acid is added to adjust the pH of the formulation. Adjustment is widely performed (Patent Documents 3 and 4).
On the other hand, pantothenyl ethyl ether or panthenol is a component known as a cell activator or hair follicle activator (Patent Documents 5 and 6).
本発明者らは、５ｗ／ｖ％以上のミノキシジルを配合した育毛剤に、パントテニールエチルエーテル又はパンテノールを配合したところ、パントテニールエチルエーテル又はパンテノールが経時的に分解することがわかった。そこで、ｐＨを８以上に調整すると、パントテニールエチルエーテル又はパンテノールの分解を抑制することはできたが、低温保存中に結晶が析出しやすいという課題があることが分かった。
本発明は、ミノキシジル、及びパントテニールエチルエーテル及び／又はパンテノールを含有した外用組成物において、パントテニールエチルエーテル及び／又はパンテノールの経時的な分解と低温保管時の結晶析出を抑制する外用医薬組成物を提供することを課題とする。
When the present inventors added pantothenyl ethyl ether or panthenol to a hair restorer containing 5 w/v% or more of minoxidil, they found that pantothenyl ethyl ether or panthenol degraded over time. Therefore, it was found that when the pH was adjusted to 8 or more, the decomposition of pantothenyl ethyl ether or panthenol could be suppressed, but there was a problem that crystals tended to precipitate during low-temperature storage.
The present invention is a topical pharmaceutical composition containing minoxidil and pantothenyl ethyl ether and/or panthenol that suppresses the decomposition of pantothenyl ethyl ether and/or panthenol over time and the precipitation of crystals during low-temperature storage. An object is to provide a composition.
本発明者らは、上記課題を解決すべく鋭意検討を重ねた結果、意外なことに、１，３－ブチレングリコール及びグリセリンを配合し、ｐＨを６．５より大きく８以下に調整することにより、ミノキシジル及びパントテニールエチルエーテル及び／又はパンテノールを含有した外用医薬組成物において、パントテニールエチルエーテル及び／又はパンテノールの経時的な分解と低温保管時の結晶析出を抑制できることを見出し、本発明を完成するに至った。 The present inventors have made intensive studies to solve the above problems, and surprisingly, by blending 1,3-butylene glycol and glycerin and adjusting the pH to greater than 6.5 and 8 or less, , in an external pharmaceutical composition containing minoxidil and pantothenyl ethyl ether and / or panthenol, it was found that the decomposition of pantothenyl ethyl ether and / or panthenol over time and crystal precipitation during low temperature storage can be suppressed, and the present invention was completed.
すなわち本発明は、
（１）（ａ）ミノキシジル、（ｂ）パントテニールエチルエーテル及び／又はパンテノール、（ｃ）１，３－ブチレングリコール及びグリセリンを含有し、ｐＨが６．５より大きく８以下であることを特徴とする外用医薬組成物、
（２）（ｃ）１，３－ブチレングリコール及びグリセリンの合計量が、外用医薬組成物全体に対して１２～３０ｗ／ｖ％である、（１）に記載の外用医薬組成物、
（３）（ａ）ミノキシジルの濃度が５ｗ／ｖ％以上である、（１）に記載の外用医薬組成物、
である。
That is, the present invention
(1) characterized by containing (a) minoxidil, (b) pantothenyl ethyl ether and/or panthenol, (c) 1,3-butylene glycol and glycerin, and having a pH greater than 6.5 and 8 or less A pharmaceutical composition for external use,
(2) The topical pharmaceutical composition according to (1), wherein the total amount of (c) 1,3-butylene glycol and glycerin is 12 to 30 w/v% of the entire topical pharmaceutical composition;
(3) (a) The topical pharmaceutical composition according to (1), wherein the concentration of minoxidil is 5 w/v% or more;
is.
本発明により、製剤中のパントテニールエチルエーテル及び／又はパンテノールの経時的な分解を抑制し、かつ低温保管時の結晶析出を抑制したミノキシジル及びパントテニールエチルエーテル及び／又はパンテノール含有外用医薬組成物を提供することが可能になった。 また、優れた使用感を有する前記外用医薬組成物の提供が可能となった。 According to the present invention, an external pharmaceutical composition containing minoxidil and pantothenyl ethyl ether and/or panthenol, which suppresses the decomposition of pantothenyl ethyl ether and/or panthenol in the formulation over time and suppresses the precipitation of crystals during low-temperature storage I was able to provide items. In addition, it has become possible to provide the external pharmaceutical composition having an excellent feeling of use.
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低温保管時の結晶析出の課題と溶解性の課題が大きくなるため、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％以上が好ましく、より好ましくは５ｗ／ｖ％以上であり、上限は１５ｗ／ｖ％である。 Minoxidil used in the topical pharmaceutical composition of the present invention can be appropriately used in quality that is commonly used in pharmaceuticals. In addition, in the topical pharmaceutical composition of the present invention, as the content of minoxidil increases, the problem of crystal precipitation and the problem of solubility during low-temperature storage increase, so the higher the concentration of minoxidil in the topical pharmaceutical composition, It is of great significance to carry out the present invention. Specifically, it is preferably 3 w/v % or more, more preferably 5 w/v % or more, and the upper limit is 15 w/v % in the topical pharmaceutical composition of the present invention.
本発明の外用医薬組成物中におけるパントテニールエチルエーテル又はパンテノールの含有量は、本発明の効果の点から全組成物中好ましくは０．１～３ｗ／ｖ％であり、より好ましくは０．５～１．５ｗ／ｖ％以上であり、更に好ましくは１．０～１．５ｗ／ｖ％である。 The content of pantothenyl ethyl ether or panthenol in the topical pharmaceutical composition of the present invention is preferably 0.1 to 3 w/v%, more preferably 0.1 to 3 w/v% of the entire composition from the viewpoint of the effects of the present invention. It is 5 to 1.5 w/v% or more, more preferably 1.0 to 1.5 w/v%.
本発明の外用医薬組成物中における１，３－ブチレングリコールとグリセリンの含有量は、本発明の低温保管時における結晶析出抑制の効果の点から、合計量として１２ｗ／ｖ％以上が好ましく、より好ましくは１５ｗ／ｖ％以上であり、更に好ましくは２０ｗ／ｖ％以上である。また、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これら合計量として３０ｗ／ｖ％以下が好ましく、より好ましくは２５ｗ／ｖ％以下である。また、１，３－ブチレングリコールの含有量は、全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、グリセリンの含有量は、全組成物中好ましくは５ｗ／ｖ％以上、より好ましくは１０ｗ／ｖ％以上である。また、１，３－ブチレングリコール及びグリセリンの含有比率は、重量比として３．５：１～１：３．５が好ましい。また、本発明の外用医薬組成物中には、プロピレングリコール、ジプロピレングリコールは含まないものとすることが好ましい。
本発明の外用医薬組成物のｐＨは、本発明の効果の点から６．５より大きく、８以下である。
本発明の組成物のｐＨ調整は、通常使用されるｐＨ調整剤を使用することができ、具体的には、例えば、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。
The content of 1,3-butylene glycol and glycerin in the topical pharmaceutical composition of the present invention is preferably 12 w/v% or more as a total amount from the viewpoint of the effect of suppressing crystal precipitation during low-temperature storage of the present invention, and more. It is preferably 15 w/v % or more, more preferably 20 w/v % or more. Further, the upper limit is preferably 30 w/v% or less, more preferably 25 w/v% or less as the total amount in consideration of feeling during use such as less stickiness. In addition, the content of 1,3-butylene glycol is preferably 5 w/v% or more, more preferably 10 w/v% or more in the entire composition, and the content of glycerin is preferably 5 w/v% or more in the entire composition. v % or more, more preferably 10 w/v % or more. Also, the content ratio of 1,3-butylene glycol and glycerin is preferably 3.5:1 to 1:3.5 as a weight ratio. Moreover, it is preferable that the external pharmaceutical composition of the present invention does not contain propylene glycol or dipropylene glycol.
The pH of the topical pharmaceutical composition of the present invention is greater than 6.5 and 8 or less from the viewpoint of the effects of the present invention.
The pH of the composition of the present invention can be adjusted using a commonly used pH adjuster. Specifically, examples include organic acids such as citric acid, malic acid, lactic acid and tartaric acid, phosphoric acid, hydrochloric acid, Inorganic acids such as sulfuric acid may be mentioned.
本発明の外用医薬組成物は、更に必要により水を配合することができる。水の含有量は、２～７５ｗ／ｖ％が好ましく、より好ましくは５～５０ｗ／ｖ％であり、更に好ましくは５～３０ｗ／ｖ％である。 The external pharmaceutical composition of the present invention can further contain water if necessary. The water content is preferably 2 to 75 w/v%, more preferably 5 to 50 w/v%, still more preferably 5 to 30 w/v%.
本発明の外用医薬組成物、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、本発明の着色抑制の効果の観点より、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。 The topical pharmaceutical composition of the present invention may optionally contain a lower alcohol. As the lower alcohol, those having 1 to 5 carbon atoms are preferred, such as ethanol and isopropanol, and these may be used in combination. The content of the lower alcohol in the topical pharmaceutical composition of the present invention is preferably 20 w/v% or more, more preferably 30 w/v% or more in the entire composition, from the viewpoint of the coloring suppression effect of the present invention, It is more preferably 35 w/v % or more, still more preferably 50 w/v % or more. The upper limit is preferably 80 w/v%.
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り、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, the addition of surfactants may affect the feeling of use and the skin absorption of minoxidil, so it is preferable to be substantially free of surfactants.
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。 In addition to the components described above, the pharmaceutical composition for topical application of the present invention can contain necessary active ingredients and auxiliary ingredients within a range that does not impair the effects of the present invention. Pharmaceutically active ingredients that are preferably added to or blended with the topical 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.
これら選択成分の添加量は、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。 The amount of these optional ingredients to be added is not particularly limited, and can be determined experimentally while considering the feel of use, the stability of minoxidil, the composition of the solvent system, 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（尿素、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（酢酸レチノール、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 topical pharmaceutical composition of the present invention, in addition to the above-described ingredients, various active ingredients and auxiliary ingredients used in general topical preparations can be blended within a range that does not impair the effects of the present invention. For example, excipients, hair-growth ingredients (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, Hekkei bird, etc.), vasodilators (carpronium chloride, benzyl nicotinate, assembly extract, panax ginseng extract, ginseng tincture, Capsicum tincture, etc.), antihistamines (isothipendyl hydrochloride, etc.), anti-inflammatory agents (guaiazulene, etc.), keratolytic agents (urea, salicylic acid, etc.), bactericides (chlorhexidine gluconate, isopropylmethylphenol, quaternary ammonium salts, piroctoneola) min, etc.), moisturizing agents (hyaluronic acid or its salts, chondroitin sulfate, etc.), various animals and plants (yew, botanpi, licorice, hypericum perforatum, Bushi, loquat, artemisia var. , Seymong, hops, placenta, saw palmetto, pumpkin seed, etc.), vitamins (retinol acetate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), antioxidants (dibutylhydroxytoluene, sodium pyrosulfite, tocopherol, edet sodium acid, ascorbic acid, isopropyl gallate, etc.), solubilizers (diisopropyl adipate, isopropyl myristate, various vegetable oils, various animal oils, alkyl glyceryl ethers, hydrocarbons, etc.), metabolic activators, gelling agents (highly water-soluble molecules, etc.), adhesives, fragrances, refreshing agents (mint oil, camphor, etc.), dyes, and other commonly used ingredients can be blended.
また、本発明の外用医薬組成物は、液状の製剤であることが好ましく、例えばローション剤、エアゾール剤、トニック剤、ゲル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 a liquid preparation, and can be made into suitable external pharmaceutical compositions such as lotions, aerosols, tonics, and gels.
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 pharmaceutical composition for external application of the present invention is prepared according to a conventional method by containing each of the above components.
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 thus-obtained external pharmaceutical composition of the present invention can be used as a skin preparation such as a hair preparation, eyelash preparation, and eyebrow preparation.
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。 EXAMPLES Examples, comparative examples and test examples are given below to describe the present invention in more detail, but the present invention is not limited by these examples.
（実施例１）
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、グリセリン１０ｇ、リン酸０．０２ｇ、エタノール５４ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ７．５４の外用医薬組成物を得た。
(Example 1)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 10 g of 1,3-butylene glycol, 10 g of glycerin, 0.02 g of phosphoric acid, 54 g of ethanol, and purified water were added to bring the total amount to 100 mL, and dissolved with stirring to prepare an external pharmaceutical composition of pH 7.54. Obtained.
（実施例２）
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、グリセリン１０ｇ、リン酸０．２ｇ、エタノール５３ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．７０の外用医薬組成物を得た。
(Example 2)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 10 g of 1,3-butylene glycol, 10 g of glycerin, 0.2 g of phosphoric acid, 53 g of ethanol, and purified water were added to bring the total volume to 100 mL, and dissolved with stirring to prepare an external pharmaceutical composition of pH 6.70. Obtained.
（実施例３）
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、グリセリン１０ｇ、リン酸０．０２ｇ、エタノール５４ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ７．６５の外用医薬組成物を得た。
(Example 3)
5 g of minoxidil, 1 g of panthenol, 10 g of 1,3-butylene glycol, 10 g of glycerin, 0.02 g of phosphoric acid, 54 g of ethanol, and purified water were added to bring the total amount to 100 mL, and dissolved with stirring to obtain an external pharmaceutical composition having a pH of 7.65. .
（実施例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１０ｇ、グリセリン１０ｇ、リン酸０．２ｇ、エタノール５３ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．７０の外用医薬組成物を得た。
(Example 4)
5 g of minoxidil, 1 g of panthenol, 10 g of 1,3-butylene glycol, 10 g of glycerin, 0.2 g of phosphoric acid, 53 g of ethanol, and purified water were added to bring the total amount to 100 mL, and dissolved with stirring to obtain an external pharmaceutical composition having a pH of 6.70. .
（比較例１）
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２０ｇ、リン酸適量、エタノール５２ｇ、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。
(Comparative example 1)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 20 g of 1,3-butylene glycol, an appropriate amount of phosphoric acid, 52 g of ethanol, and purified water were added to bring the total volume to 100 mL, and dissolved with stirring to obtain an external pharmaceutical composition with a pH of 6.19.
（比較例２）
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２０ｇ、リン酸適量、エタノール５３ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．４９の外用医薬組成物を得た。
(Comparative example 2)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 20 g of 1,3-butylene glycol, an appropriate amount of phosphoric acid, 53 g of ethanol, and purified water were added to bring the total volume to 100 mL, and dissolved with stirring to obtain an external pharmaceutical composition having a pH of 6.49.
（比較例３）
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２０ｇ、リン酸適量、エタノール５３ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ７．０３の外用医薬組成物を得た。
(Comparative Example 3)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 20 g of 1,3-butylene glycol, an appropriate amount of phosphoric acid, 53 g of ethanol, and purified water were added to bring the total volume to 100 mL, and dissolved with stirring to obtain an external pharmaceutical composition of pH 7.03.
（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１０ｇ、ジプロピレングリコール１０ｇ、リン酸０．０２ｇ、エタノール５２ｇ、精製水で全量を１００ｍＬとし、撹拌した。撹拌後も固形物が溶解せず、澄明な製剤は調製できなかった。
(Comparative Example 4)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 10 g of 1,3-butylene glycol, 10 g of dipropylene glycol, 0.02 g of phosphoric acid, 52 g of ethanol, and purified water were added to bring the total volume to 100 mL, followed by stirring. The solid matter did not dissolve even after stirring, and a clear formulation could not be prepared.
（比較例５）
ミノキシジル５ｇ、パンテノール１ｇ、プロピレングリコール１０ｇ、エタノール６０ｇ、精製水で全量を１００ｍＬとし、撹拌した。撹拌後も固形物が溶解せず、澄明な製剤は調製できなかった。
(Comparative Example 5)
5 g of minoxidil, 1 g of panthenol, 10 g of propylene glycol, 60 g of ethanol, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred. The solid matter did not dissolve even after stirring, and a clear formulation could not be prepared.
（比較例６）
ミノキシジル５ｇ、１，３－ブチレングリコール２０ｇ、リン酸適量、エタノール５２ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ６．１４の外用医薬組成物を得た。
(Comparative Example 6)
5 g of minoxidil, 20 g of 1,3-butylene glycol, an appropriate amount of phosphoric acid, 52 g of ethanol, and purified water were added to bring the total volume to 100 mL, and dissolved with stirring to obtain an external pharmaceutical composition having a pH of 6.14.
実施例１～４、比較例１～６の処方及び調製後のｐＨを表１に示す。 Table 1 shows the formulations of Examples 1 to 4 and Comparative Examples 1 to 6 and the pH after preparation.
表１から明らかなように、比較例４、５の製剤は、ミノキシジルを溶解することができなかった。
＜試験例１‐１：パントテニールエチルエーテル含量の評価＞
実施例１～２、比較例１～３に関し、試験開始時及び６５℃条件下１４日経過後のパントテニールエチルエーテル含量をＨＰＬＣにより測定した。下記の式に従い、パントテニールエチルエーテルの含量を算出した。その結果を表２に示す。
パントテニールエチルエーテル含量（％）＝（６５℃条件下１４日経過後のパントテニールエチルエーテル含量／試験開始時のパントテニールエチルエーテル含量）×１００
As is clear from Table 1, the formulations of Comparative Examples 4 and 5 were unable to dissolve minoxidil.
<Test Example 1-1: Evaluation of pantothenyl ethyl ether content>
Regarding Examples 1 and 2 and Comparative Examples 1 and 3, the pantothenyl ethyl ether content was measured by HPLC at the start of the test and after 14 days under the condition of 65°C. The content of pantothenyl ethyl ether was calculated according to the following formula. Table 2 shows the results.
Pantothenyl ethyl ether content (%) = (pantothenyl ethyl ether content after 14 days at 65°C/pantothenyl ethyl ether content at the start of the test) x 100
＜試験例１‐２：パンテノール含量の評価＞
実施例３～４に関し、試験開始時及び６５℃条件下１４日経過後のパンテノール含量をＨＰＬＣにより測定した。下記の式に従い、パンテノールの含有量を算出した。その結果を表２に示す。
パンテノール含量（％）＝（６５℃条件下１４日経過後のパンテノール含量／試験開始時のパンテノール含量）×１００
<Test Example 1-2: Evaluation of panthenol content>
Regarding Examples 3 and 4, the panthenol content was measured by HPLC at the start of the test and after 14 days at 65°C. The content of panthenol was calculated according to the following formula. Table 2 shows the results.
Panthenol content (%) = (panthenol content after 14 days at 65°C/panthenol content at the start of the test) x 100
＜試験例２：低温安定性の評価＞
実施例１～４、比較例１～３及び比較例６をそれぞれ３０ｍＬの透明ペットボトル容器に２０ｍＬずつ充填し、５℃１４日間保管後の結晶析出の有無を目視で評価した。その結果を表２に示す。
<Test Example 2: Evaluation of low temperature stability>
20 mL of each of Examples 1 to 4, Comparative Examples 1 to 3, and Comparative Example 6 was filled in a 30 mL transparent PET bottle container, and the presence or absence of crystal precipitation after storage at 5° C. for 14 days was visually evaluated. Table 2 shows the results.
表２から明らかなように、比較例１及び比較例２ではパントテニールエチルエーテルの含有量が９０％を下回り、商品性に問題があると判断された。また、比較例３の製剤は、低温保管後に結晶の析出が確認され、商品性に問題があると判断された。一方、実施例１～４の製剤はパントテニールエチルエーテル又はパンテノールの含量が低下せず、かつ低温保管時の析出が認められなかったことから、商品性に問題ないと判断された。 As is clear from Table 2, in Comparative Examples 1 and 2, the content of pantothenyl ethyl ether was less than 90%, and it was judged that there was a problem with marketability. In the preparation of Comparative Example 3, precipitation of crystals was confirmed after low-temperature storage, and it was determined that there was a problem with marketability. On the other hand, the formulations of Examples 1 to 4 did not decrease in the content of pantothenyl ethyl ether or panthenol, and no precipitation was observed during storage at low temperature.
（実施例５）
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５ｇ、グリセリン１６ｇ、クエン酸０．１ｇ、エタノール５２ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ７．０４の外用医薬組成物を得た。
(Example 5)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 5 g of 1,3-butylene glycol, 16 g of glycerin, 0.1 g of citric acid, 52 g of ethanol, and purified water were added to bring the total amount to 100 mL, and dissolved with stirring to prepare an external pharmaceutical composition of pH 7.04. Obtained.
（実施例６）
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１５ｇ、グリセリン６ｇ、リン酸０．０４ｇ、乳酸０．０６ｇ、酒石酸０．０１ｇ、エタノール５３ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ７．０２の外用医薬組成物を得た。
(Example 6)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 15 g of 1,3-butylene glycol, 6 g of glycerin, 0.04 g of phosphoric acid, 0.06 g of lactic acid, 0.01 g of tartaric acid, 53 g of ethanol, and purified water to bring the total amount to 100 mL, and dissolved with stirring. to obtain an external pharmaceutical composition with a pH of 7.02.
（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３ｇ、グリセリン３ｇ、プロピレングリコール３ｇ、ジプロピレングリコール３ｇ、リン酸適量、エタノール５０ｇ、精製水で全量を１００ｍＬとし、撹拌溶解してｐＨ５．８０の外用医薬組成物を得た。
(Comparative Example 7)
5 g of minoxidil, 1 g of pantothenyl ethyl ether, 3 g of 1,3-butylene glycol, 3 g of glycerin, 3 g of propylene glycol, 3 g of dipropylene glycol, an appropriate amount of phosphoric acid, 50 g of ethanol, and purified water to bring the total volume to 100 mL, and dissolve with stirring to pH 5.0. 80 topical pharmaceutical compositions were obtained.
実施例５～６、比較例７の処方及び調製後のｐＨを表３に示す。 Table 3 shows the formulations of Examples 5 to 6 and Comparative Example 7 and the pH after preparation.
＜試験例３：パントテニールエチルエーテル含量の評価＞
実施例５～６、比較例７に関し、試験開始時及び６５℃条件下１４日経過後のパントテニールエチルエーテル含量をＨＰＬＣにより測定した。下記の式に従い、パントテニールエチルエーテルの含量を算出した。その結果を表４に示す。
パントテニールエチルエーテル含量（％）＝（６５℃条件下１４日経過後のパントテニールエチルエーテル含量／試験開始時のパントテニールエチルエーテル含量）×１００
<Test Example 3: Evaluation of pantothenyl ethyl ether content>
Regarding Examples 5 and 6 and Comparative Example 7, the pantothenyl ethyl ether content was measured by HPLC at the start of the test and after 14 days under the condition of 65°C. The content of pantothenyl ethyl ether was calculated according to the following formula. Table 4 shows the results.
Pantothenyl ethyl ether content (%) = (pantothenyl ethyl ether content after 14 days at 65°C/pantothenyl ethyl ether content at the start of the test) x 100
＜試験例４：低温安定性の評価＞
実施例５～６、比較例７及び比較例６をそれぞれ３０ｍＬの透明ペットボトル容器に２０ｍＬずつ充填し、５℃１４日間保管後の結晶析出の有無を目視で評価した。その結果を表４に示す。
<Test Example 4: Evaluation of low temperature stability>
20 mL of each of Examples 5 and 6 and Comparative Examples 7 and 6 was filled in a 30 mL transparent PET bottle container, and the presence or absence of crystal precipitation after storage at 5° C. for 14 days was visually evaluated. Table 4 shows the results.
表４から明らかなように、比較例７ではパントテニールエチルエーテルの含有量が９０％を下回り、商品性に問題があると判断された。一方、実施例５～６の製剤はパントテニールエチルエーテルの含量が低下せず、かつ低温保管時の析出が認められなかったことから、商品性に問題ないと判断された。 As is clear from Table 4, in Comparative Example 7, the content of pantothenyl ethyl ether was less than 90%, and it was judged that there was a problem with marketability. On the other hand, the preparations of Examples 5 and 6 did not decrease in the pantothenyl ethyl ether content and no precipitation was observed during low-temperature storage, so it was judged that there was no problem with marketability.
本発明により、ミノキシジル、及びパントテニールエチルエーテル及び／又はパンテノールを含有した外用組成物において、パントテニールエチルエーテル及び／又はパンテノールの経時的な分解と低温保管時の結晶析出を抑制する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, in a composition for external use containing minoxidil and pantothenyl ethyl ether and/or panthenol, an external medicine that suppresses the decomposition of pantothenyl ethyl ether and/or panthenol over time and the precipitation of crystals during low-temperature storage It is now possible to provide compositions.
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