JP2022167158A - Percutaneous absorption promoter - Google Patents
Percutaneous absorption promoter Download PDFInfo
- Publication number
- JP2022167158A JP2022167158A JP2021072756A JP2021072756A JP2022167158A JP 2022167158 A JP2022167158 A JP 2022167158A JP 2021072756 A JP2021072756 A JP 2021072756A JP 2021072756 A JP2021072756 A JP 2021072756A JP 2022167158 A JP2022167158 A JP 2022167158A
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- JP
- Japan
- Prior art keywords
- percutaneous absorption
- absorption enhancer
- acid
- log
- hydrophilic drug
- 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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Abstract
Description
本発明は、経皮吸収促進剤に関する。 TECHNICAL FIELD The present invention relates to a percutaneous absorption enhancer.
毛穴縮小効果を有するグリシルグリシンや、抗炎症および美白効果を有するトラネキサム酸等の親水性薬剤は親水性が高く、結晶化しやすい性質がある。親水性薬剤の肌効果を向上させるために、親水性薬剤の肌への浸透効果をより高めることが求められている。 Hydrophilic agents such as glycylglycine, which has a pore-shrinking effect, and tranexamic acid, which has anti-inflammatory and whitening effects, are highly hydrophilic and tend to crystallize. In order to improve the effect of a hydrophilic drug on the skin, it is required to further enhance the effect of the hydrophilic drug on the skin.
これまでに、炭素原子数４～８の１，２－アルカンジオール類の混合物を水溶性の皮膚外用薬効成分に配合してなる経皮吸収促進性皮膚外用組成物（特許文献１参照）、溶解度パラメータが１６以上の水溶性の不揮発性液状物質からなる、皮膚外用剤中のイソブチルレゾルシンの経皮吸収促進剤（特許文献２参照）、ダイフラクトース アンハイドライドを有効成分とする経皮吸収促進剤（特許文献３参照）、および親水性ポリグリセリン変性シリコーンからなる経皮吸収促進剤若しくは経皮吸収コントロール剤（特許文献４参照）などの多種多様な経皮吸収を促進するための組成物や剤が知られているが、特に親水性薬剤の経皮吸収の促進の観点からは更なる改良が求められている。 So far, a percutaneous absorption-enhancing composition for external skin application (see Patent Document 1) obtained by blending a mixture of 1,2-alkanediols having 4 to 8 carbon atoms with a water-soluble medicinal ingredient for external skin application, solubility A percutaneous absorption enhancer for isobutylresorcinol in external skin preparations (see Patent Document 2), a percutaneous absorption enhancer containing difructose anhydride as an active ingredient, which consists of a water-soluble non-volatile liquid substance with a parameter of 16 or more Patent Document 3), and a wide variety of compositions and agents for promoting percutaneous absorption, such as transdermal absorption enhancers or transdermal absorption control agents made of hydrophilic polyglycerin-modified silicones (see Patent Document 4). However, there is a demand for further improvement particularly from the viewpoint of promotion of percutaneous absorption of hydrophilic drugs.
また、特定の有機酸と、特定の界面活性剤と、特定の抗肌荒れ性成分を組み合わせることで、肌荒れを起こさずに効果的に角栓の再生を抑えることができることが知られているが（特許文献５参照）、α－ヒドロキシ酸が親水性薬剤の経皮吸収を促進できることについては全く知られていない。 It is also known that by combining a specific organic acid, a specific surfactant, and a specific anti-roughness ingredient, it is possible to effectively suppress the regeneration of keratotic plugs without causing rough skin ( See Patent Document 5), it is completely unknown that α-hydroxy acids can promote percutaneous absorption of hydrophilic drugs.
本発明者らは、驚くべきことに、α－ヒドロキシ酸が親水性薬剤の経皮吸収を促進できることを見出した。本発明はこれらの知見に基づくものである。 The inventors have surprisingly found that α-hydroxy acids can enhance percutaneous absorption of hydrophilic drugs. The present invention is based on these findings.
本発明によれば、以下の発明が提供される。
（１）α－ヒドロキシ酸を有効成分として含有する、親水性薬剤の経皮吸収促進剤。
（２）前記親水性薬剤が、水／オクタノール分配係数を表すｌｏｇＰ値が２．０以下の親水性薬剤である、（１）に記載の経皮吸収促進剤。
（３）前記親水性薬剤がグリシルグリシン、トラネキサム酸、およびニコチン酸アミドからなる群から選択される一種類以上を含む、（１）または（２）に記載の経皮吸収促進剤。
（４）前記親水性薬剤がグリシルグリシンおよびトラネキサム酸を含有する、（１）～（３）のいずれかに記載の経皮吸収促進剤。
（５）前記α－ヒドロキシ酸が、グリコール酸、乳酸、およびクエン酸からなる群から選択される一種以上である、（１）～（４）のいずれかに記載の経皮吸収促進剤。
（６）前記グリコール酸の配合量が、経皮吸収促進剤の全量に対して、０．１～２質量％である、（５）に記載の経皮吸収促進剤。
（７）前記乳酸の配合量が、経皮吸収促進剤の全量に対して、０．１～３質量％である、（５）または（６）に記載の経皮吸収促進剤。
（８）前記クエン酸の配合量が、経皮吸収促進剤の全量に対して、０．１～４質量％である、（５）～（７）のいずれかに記載の経皮吸収促進剤。
（９）前記親水性薬剤の配合量が、経皮吸収促進剤の全量に対して、１～６質量％である、（１）～（８）のいずれかに記載の経皮吸収促進剤。
（１０）前記親水性薬剤と前記α－ヒドロキシ酸との質量比（経皮吸収促進剤中の親水性薬剤の配合量：経皮吸収促進剤中のα－ヒドロキシ酸の配合量）が、１：４～３：７であり、かつ
前記親水性薬剤がグリシルグリシンまたはトラネキサム酸である、
（１）～（９）のいずれかに記載の経皮吸収促進剤。
（１１）ｐＨが５以下である、（１）～（１０）のいずれかに記載の経皮吸収促進剤。
（１２）α－ヒドロキシ酸を有効成分として含有する、親水性薬剤の経皮吸収促進用組成物。
（１３）皮膚外用組成物である、（１２）に記載の組成物。
According to the present invention, the following inventions are provided.
(1) A percutaneous absorption enhancer for a hydrophilic drug containing an α-hydroxy acid as an active ingredient.
(2) The percutaneous absorption enhancer according to (1), wherein the hydrophilic drug has a logP value representing the water/octanol partition coefficient of 2.0 or less.
(3) The percutaneous absorption enhancer according to (1) or (2), wherein the hydrophilic drug contains one or more selected from the group consisting of glycylglycine, tranexamic acid, and nicotinamide.
(4) The percutaneous absorption enhancer according to any one of (1) to (3), wherein the hydrophilic drug contains glycylglycine and tranexamic acid.
(5) The percutaneous absorption enhancer according to any one of (1) to (4), wherein the α-hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, and citric acid.
(6) The transdermal absorption enhancer according to (5), wherein the amount of glycolic acid is 0.1 to 2% by mass relative to the total amount of the transdermal absorption enhancer.
(7) The percutaneous absorption enhancer according to (5) or (6), wherein the amount of lactic acid is 0.1 to 3% by mass relative to the total amount of the percutaneous absorption enhancer.
(8) The transdermal absorption enhancer according to any one of (5) to (7), wherein the amount of citric acid is 0.1 to 4% by mass with respect to the total amount of the transdermal absorption enhancer. .
(9) The percutaneous absorption enhancer according to any one of (1) to (8), wherein the amount of the hydrophilic drug compounded is 1 to 6% by mass relative to the total amount of the percutaneous absorption enhancer.
(10) The mass ratio of the hydrophilic drug and the α-hydroxy acid (the amount of the hydrophilic drug in the percutaneous absorption enhancer: the amount of the α-hydroxy acid in the transdermal absorption enhancer) is 1. : 4 to 3:7, and the hydrophilic drug is glycylglycine or tranexamic acid,
(1) The percutaneous absorption enhancer according to any one of (9).
(11) The transdermal absorption enhancer according to any one of (1) to (10), which has a pH of 5 or less.
(12) A composition for promoting percutaneous absorption of a hydrophilic drug containing an α-hydroxy acid as an active ingredient.
(13) The composition according to (12), which is an external skin composition.
本発明の経皮吸収促進剤を用いることにより、グリシルグリシンや、トラネキサム酸等の親水性薬剤の経皮吸収を促進することができる点で有利である。 Use of the percutaneous absorption enhancer of the present invention is advantageous in that it can promote percutaneous absorption of hydrophilic drugs such as glycylglycine and tranexamic acid.
本発明は、α－ヒドロキシ酸を有効成分として含有する親水性薬剤の経皮吸収促進剤が提供される。 The present invention provides a percutaneous absorption enhancer for a hydrophilic drug containing an α-hydroxy acid as an active ingredient.
＜α－ヒドロキシ酸＞
本発明の経皮吸収促進剤は、有効成分としてα－ヒドロキシ酸を含む。α－ヒドロキシ酸は、従来から、化粧料や洗浄剤の緩衝剤や中和剤として用いられており、また、角質の柔軟化または細胞賦活化等の目的で各種化粧料に配合されている。本発明の化粧料に配合されるα－ヒドロキシ酸は、特に限定はされるものではないが、例えば、グリコール酸、乳酸、リンゴ酸、酒石酸、クエン酸、グリセリン酸、ピルビン酸、マンデル酸等が挙げられ、単独でも２種以上を組み合わせて配合してもよいが、これらの中でも、グリコール酸、乳酸、およびクエン酸からなる群から選択される一種以上であることが好ましく、グリコール酸、乳酸、およびクエン酸を組み合わせて用いることがより好ましい。
<α-hydroxy acid>
The percutaneous absorption enhancer of the present invention contains an α-hydroxy acid as an active ingredient. α-Hydroxy acids have been conventionally used as buffering agents and neutralizing agents in cosmetics and cleansers, and are blended in various cosmetics for the purpose of softening keratin, activating cells, and the like. The α-hydroxy acid blended in the cosmetic composition of the present invention is not particularly limited, but examples thereof include glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, glyceric acid, pyruvic acid, mandelic acid, and the like. and may be blended alone or in combination of two or more. Among these, one or more selected from the group consisting of glycolic acid, lactic acid, and citric acid is preferable. and citric acid are more preferably used in combination.
本発明の経皮吸収促進剤で用いられるα－ヒドロキシ酸の配合量は、特に限定されるものではないが、好ましくは、経皮吸収促進剤の全量に対して、１．５～５質量％であり、より好ましくは、経皮吸収促進剤の全量に対して、２～４質量％である。 The amount of the α-hydroxy acid used in the percutaneous absorption enhancer of the present invention is not particularly limited, but is preferably 1.5 to 5% by mass with respect to the total amount of the percutaneous absorption enhancer. and more preferably 2 to 4% by mass relative to the total amount of the percutaneous absorption enhancer.
本発明の経皮吸収促進剤で用いられるα－ヒドロキシ酸がグリコール酸を含む場合、グリコール酸の配合量は、特に限定されるものではないが、好ましくは、経皮吸収促進剤の全量に対して、０．１～２質量％であり、より好ましくは、経皮吸収促進剤の全量に対して、０．３～１．５質量％である。 When the α-hydroxy acid used in the percutaneous absorption enhancer of the present invention contains glycolic acid, the amount of glycolic acid is not particularly limited, but is preferably 0.1 to 2% by mass, more preferably 0.3 to 1.5% by mass based on the total amount of the percutaneous absorption enhancer.
本発明の経皮吸収促進剤で用いられるα－ヒドロキシ酸が乳酸を含む場合、乳酸の配合量は、特に限定されるものではないが、好ましくは、経皮吸収促進剤の全量に対して、０．１～３質量％であり、より好ましくは、経皮吸収促進剤の全量に対して、０．５～１．５質量％である。 When the α-hydroxy acid used in the percutaneous absorption enhancer of the present invention contains lactic acid, the amount of lactic acid is not particularly limited, but is preferably It is 0.1 to 3% by mass, more preferably 0.5 to 1.5% by mass relative to the total amount of the percutaneous absorption enhancer.
本発明の経皮吸収促進剤で用いられるα－ヒドロキシ酸がクエン酸を含む場合、クエン酸の配合量は、特に限定されるものではないが、好ましくは、経皮吸収促進剤の全量に対して、０．１～４質量％であり、より好ましくは、経皮吸収促進剤の全量に対して、１～２質量％である。 When the α-hydroxy acid used in the transdermal absorption enhancer of the present invention contains citric acid, the amount of citric acid is not particularly limited, but is preferably based on the total amount of the transdermal absorption enhancer. is 0.1 to 4% by mass, more preferably 1 to 2% by mass based on the total amount of the percutaneous absorption enhancer.
＜親水性薬剤＞
本発明は、α－ヒドロキシ酸を有効成分として含有する親水性薬剤の経皮吸収促進剤である。α－ヒドロキシ酸を有効成分として含有することにより経皮吸収が促進される薬剤は、親水性であれば特に限定されるものではないが、好ましくは、水／オクタノール分配係数を表すｌｏｇＰ値が２．０以下の親水性薬剤であり、より好ましくは、アルブチン（ＬｏｇＰ＝－０．６）、Ｌ－アスコルビン酸（ＬｏｇＰ＝－１．６）、ハイドロキノン（ＬｏｇＰ＝－０．６）、グルタチオン（ＬｏｇＰ＝－４．５）、パントテン酸（ＬｏｇＰ＝－１．１）、トラネキサム酸（ＬｏｇＰ＝－２）、コウジ酸（ＬｏｇＰ＝－０．９）、Ｌ－システイン（ＬｏｇＰ＝－２．５）、エラグ酸（ＬｏｇＰ＝１．１）、レゾルシン（ＬｏｇＰ＝０．８）、ルチン（ＬｏｇＰ＝－１．３）、トリプトファン（ＬｏｇＰ＝－１．１）、ヒスチジン（ＬｏｇＰ＝－３．２）、グリシルグリシン（ｌｏｇＰ＝－２．３）、クエルセチン（ＬｏｇＰ＝１．５）やクエルシトリン（ＬｏｇＰ＝０．９）などのフラボノイド類、カテキン（ＬｏｇＰ＝０．４）没食子酸（ＬｏｇＰ＝０．７）、カイネチン（ＬｏｇＰ＝１）、α－リポ酸（ＬｏｇＰ＝１．７）、エリソルビン酸（ＬｏｇＰ＝－１．６）、チオタウリン（ＬｏｇＰ＝－０．１）、尿素（ＬｏｇＰ＝－１．４）、ニコチン（ＬｏｇＰ＝１．２）、ニコチン酸（ＬｏｇＰ＝０．４）、ニコチン酸アミド（ｌｏｇＰ＝－０．４）、ヒドロキシプロリン（ＬｏｇＰ＝－３．３）、セリン（ＬｏｇＰ＝－３．１）、グルタミン酸（ＬｏｇＰ＝－３．７）、アルギニン（ＬｏｇＰ＝－４．２）、アラニン（ＬｏｇＰ＝－３）、ミノキシジル（ＬｏｇＰ＝１．２）、Ｄ－グルコサミン（ＬｏｇＰ＝－２．８）、Ｎ－アセチル－Ｄ－グルコサミン（ＬｏｇＰ＝－１．７）、ヒアルロン酸（ＬｏｇＰ＝－７．４）、ラフィノース（ＬｏｇＰ＝－５．８）、アゼライン酸（ＬｏｇＰ＝１．６）、γ－アミノ酪酸（ＬｏｇＰ＝－３．２）、アラントイン（ＬｏｇＰ＝－２．２）、Ｌ－カルニチン（ＬｏｇＰ＝－０．２）、およびビオチン（ＬｏｇＰ＝０．３）からなる群から選択される一種類以上を含む親水性薬剤であり、さらに好ましくは、グリシルグリシン、トラネキサム酸、およびニコチン酸アミドからなる群から選択される一種類以上を含む親水性薬剤であり、さらに好ましくは、グリシルグリシンおよびトラネキサム酸を含有する親水性薬剤である。ここで、ｌｏｇＰ値とは、Ｃｈｅｍｉｃａｌ Ｒｅｖｉｅｗｓ ｖｏｌ７１（６），５２５（１９７１）などで定義されている水とオクタノールへの物質の分配のしやすさにより、極性を表す係数である。
<Hydrophilic drug>
The present invention is a percutaneous absorption enhancer for a hydrophilic drug containing an α-hydroxy acid as an active ingredient. The drug whose percutaneous absorption is promoted by containing an α-hydroxy acid as an active ingredient is not particularly limited as long as it is hydrophilic, but preferably has a logP value of 2, which represents the water/octanol partition coefficient. .0 or less hydrophilic drug, more preferably arbutin (LogP = -0.6), L-ascorbic acid (LogP = -1.6), hydroquinone (LogP = -0.6), glutathione (LogP = -4.5), pantothenic acid (LogP = -1.1), tranexamic acid (LogP = -2), kojic acid (LogP = -0.9), L-cysteine (LogP = -2.5), Ellagic acid (Log P = 1.1), resorcin (Log P = 0.8), rutin (Log P = -1.3), tryptophan (Log P = -1.1), histidine (Log P = -3.2), glycine Cylglycine (log P = -2.3), flavonoids such as quercetin (Log P = 1.5) and quercitrin (Log P = 0.9), catechin (Log P = 0.4), gallic acid (Log P = 0.7 ), kinetin (Log P = 1), α-lipoic acid (Log P = 1.7), erythorbic acid (Log P = -1.6), thiotaurine (Log P = -0.1), urea (Log P = -1.4 ), nicotine (Log P = 1.2), nicotinic acid (Log P = 0.4), nicotinamide (log P = -0.4), hydroxyproline (Log P = -3.3), serine (Log P = -3 .1), glutamic acid (Log P = -3.7), arginine (Log P = -4.2), alanine (Log P = -3), minoxidil (Log P = 1.2), D-glucosamine (Log P = -2. 8), N-acetyl-D-glucosamine (Log P = -1.7), hyaluronic acid (Log P = -7.4), raffinose (Log P = -5.8), azelaic acid (Log P = 1.6), selected from the group consisting of γ-aminobutyric acid (Log P=−3.2), allantoin (Log P=−2.2), L-carnitine (Log P=−0.2), and biotin (Log P=0.3) More preferably, it is a hydrophilic drug containing one or more selected from the group consisting of glycylglycine, tranexamic acid, and nicotinamide, and more preferably glycylglycine. It is a hydrophilic drug containing cilglycine and tranexamic acid. Here, the logP value is a coefficient representing polarity according to the easiness of partitioning of a substance into water and octanol as defined in Chemical Reviews vol71(6), 525 (1971).
本発明の経皮吸収促進剤により経皮吸収が促進される親水性薬剤の配合量は、特に限定されるものではないが、好ましくは、経皮吸収促進剤の全量に対して、１～６質量％であり、より好ましくは、経皮吸収促進剤の全量に対して、１～３質量％である。 The amount of the hydrophilic drug whose transdermal absorption is promoted by the percutaneous absorption enhancer of the present invention is not particularly limited, but is preferably 1 to 6 relative to the total amount of the percutaneous absorption enhancer. % by mass, more preferably 1 to 3% by mass relative to the total amount of the percutaneous absorption enhancer.
本発明の経皮吸収促進剤において、親水性薬剤とα－ヒドロキシ酸との質量比（経皮吸収促進剤中の親水性薬剤の配合量：経皮吸収促進剤中のα－ヒドロキシ酸の配合量）は、特に限定されるものではないが、好ましくは、１：１～１：４であり、より好ましくは、１：１．２～１：３．５である。 In the transdermal absorption enhancer of the present invention, the mass ratio of the hydrophilic drug and the α-hydroxy acid (the amount of the hydrophilic drug in the transdermal absorption enhancer: the amount of α-hydroxy acid in the transdermal absorption enhancer amount) is not particularly limited, but is preferably 1:1 to 1:4, more preferably 1:1.2 to 1:3.5.
本発明の経皮吸収促進剤の好ましい態様によれば、α－ヒドロキシ酸を有効成分として含有する親水性薬剤の経皮吸収促進剤であって、前記親水性薬剤と前記α－ヒドロキシ酸との質量比（経皮吸収促進剤中の親水性薬剤の配合量：経皮吸収促進剤中のα－ヒドロキシ酸の配合量）が、１：１～１：４であり、かつ前記親水性薬剤がグリシルグリシンまたはトラネキサム酸である経皮吸収促進剤が提供される。 According to a preferred embodiment of the percutaneous absorption enhancer of the present invention, the percutaneous absorption enhancer for a hydrophilic drug containing an α-hydroxy acid as an active ingredient, wherein the hydrophilic drug and the α-hydroxy acid are The mass ratio (amount of hydrophilic drug in transdermal absorption enhancer:amount of α-hydroxy acid in transdermal absorption enhancer) is 1:1 to 1:4, and the hydrophilic drug is A percutaneous absorption enhancer is provided that is glycylglycine or tranexamic acid.
本発明の経皮吸収促進剤のｐＨは、特に限定されるものではないが、好ましくは５以下である。本発明の経皮吸収促進剤のｐＨは、例えば、ｐＨメーター等により測定することができる。 Although the pH of the percutaneous absorption enhancer of the present invention is not particularly limited, it is preferably 5 or less. The pH of the percutaneous absorption enhancer of the present invention can be measured, for example, with a pH meter or the like.
本発明の経皮吸収促進剤において、コハク酸を含むことが好ましい。コハク酸の配合量は、特に限定されるものではないが、好ましくは、経皮吸収促進剤の全量に対して、０．１～６質量％であり、より好ましくは、経皮吸収促進剤の全量に対して、０．１～１質量％である。 The percutaneous absorption enhancer of the present invention preferably contains succinic acid. The amount of succinic acid is not particularly limited, but is preferably 0.1 to 6% by mass, more preferably 0.1 to 6% by mass, based on the total amount of the percutaneous absorption enhancer. It is 0.1 to 1% by mass with respect to the total amount.
本発明の経皮吸収促進剤には、上記の成分以外に、例えば、粉末成分、油性成分、紫外線吸収剤、各種水性溶媒、金属イオン封鎖剤、単糖、オリゴ糖、アミノ酸、有機アミン、高分子エマルジョン、アルコール類、ｐＨ調整剤、分散剤、酸化防止剤、香料、防腐剤、安定化剤等を必要に応じて適宜配合してよい。 In addition to the above components, the percutaneous absorption enhancer of the present invention includes, for example, powder components, oily components, ultraviolet absorbers, various aqueous solvents, sequestering agents, monosaccharides, oligosaccharides, amino acids, organic amines, high Molecular emulsions, alcohols, pH adjusters, dispersants, antioxidants, fragrances, preservatives, stabilizers, etc. may be added as needed.
本発明の別の態様によれば、α－ヒドロキシ酸を有効成分として含有する親水性薬剤の経皮吸収促進用組成物が提供される。当該経皮吸収促進用組成物は、好ましくは皮膚外用組成物である。 According to another aspect of the present invention, there is provided a composition for promoting percutaneous absorption of a hydrophilic drug containing an α-hydroxy acid as an active ingredient. The percutaneous absorption enhancing composition is preferably an external skin composition.
上記の本発明の経皮吸収促進剤、経皮吸収促進用組成物、および皮膚外用組成物は、化粧料、医薬品、および医薬部外品に広く応用することが可能である。例えば、応用可能なものとしては、例えば、ファンデーション、化粧下地、美容液、乳液、クリーム、口紅、アイシャドー、アイライナー、マスカラ、スプレー、ムース、皮膚科用軟膏等の製品が挙げられる。 The percutaneous absorption enhancer, percutaneous absorption enhancer composition, and external skin composition of the present invention described above can be widely applied to cosmetics, pharmaceuticals, and quasi-drugs. For example, applicable products include foundations, makeup bases, serums, emulsions, creams, lipsticks, eye shadows, eyeliners, mascara, sprays, mousses, dermatological ointments, and the like.
＜経皮吸収促進方法＞
本発明の別の態様によれば、α－ヒドロキシ酸を対象に投与することを含む、親水性薬剤の経皮吸収促進方法が提供される。本発明の別の好ましい態様によれば、α－ヒドロキシ酸を対象に投与することを含む、親水性薬剤の経皮吸収促進方法（ヒトに対する医療行為を除く）が提供される。ここで、「ヒトに対する医療行為」とは、医師等の処方を必要として、ヒトに対して医薬品を摂取させる（投与する）行為などを意味する。また、α－ヒドロキシ酸および親水性薬剤を投与する対象は、ヒトであっても、ヒト以外の動物であってもよいが、ヒトであることが好ましい。ヒト以外の動物としては、例えば、馬、牛などの家畜、犬、猫などの愛玩動物、動物園などで飼育されている鑑賞動物などが挙げられる。
<Method for Promoting Percutaneous Absorption>
According to another aspect of the present invention, there is provided a method for enhancing percutaneous absorption of a hydrophilic drug comprising administering an α-hydroxy acid to a subject. According to another preferred aspect of the present invention, there is provided a method for promoting percutaneous absorption of a hydrophilic drug (excluding medical practice for humans) comprising administering an α-hydroxy acid to a subject. Here, "medical practice on humans" means the practice of ingesting (administering) pharmaceuticals to humans, etc., requiring a prescription from a doctor or the like. Moreover, the subject to which the α-hydroxy acid and the hydrophilic drug are administered may be either humans or animals other than humans, but humans are preferred. Animals other than humans include, for example, domestic animals such as horses and cows, pet animals such as dogs and cats, and ornamental animals kept in zoos and the like.
本発明の別の態様によれば、親水性薬剤の経皮吸収促進剤（または経皮吸収促進用組成物）の製造のための、α－ヒドロキシ酸の使用が提供される。 According to another aspect of the present invention, there is provided the use of an α-hydroxy acid for the manufacture of a percutaneous absorption enhancer (or transdermal absorption enhancer composition) of a hydrophilic drug.
本発明の別の態様によれば、親水性薬剤の経皮吸収促進のための、α－ヒドロキシ酸の使用が提供される。 According to another aspect of the invention, there is provided the use of alpha-hydroxy acids for enhancing percutaneous absorption of hydrophilic drugs.
以下の例に基づいて本発明を具体的に説明するが、本発明はこれらの例に限定されるものではない。含有量は特記しない限り、質量％で示す。 The present invention will be specifically described based on the following examples, but the present invention is not limited to these examples. Unless otherwise specified, the contents are shown in % by mass.
試験例１：経皮吸収確認試験
下記の実施例１～３および比較例１～４の処方（表１参照）について、フランツセルを用いて、in vitroでの経皮吸収性を確認した。その経皮吸収の結果を図１および２に表す。
Test Example 1: Percutaneous Absorption Confirmation Test The in vitro percutaneous absorbability of the formulations of Examples 1 to 3 and Comparative Examples 1 to 4 (see Table 1) was confirmed using a Franz cell. The percutaneous absorption results are presented in FIGS.
下記で調製した組成物についてのグリシルグリシンおよびトラネキサム酸の経皮吸収性は、無限閉鎖系においてフランツセルを用いた経時的な測定をすることで確認した。 The percutaneous absorbability of glycylglycine and tranexamic acid for the compositions prepared below was confirmed by measuring over time using a Franz cell in an infinitely closed system.
より詳細には、静置型フランツセル（垂直型ガラス製拡散セル、開口部直径１０ｍｍ、レシーバー容量 ４．０ｍＬ＜パーメギア社製＞）に、撹拌子を入れ、さらに富士フイルム和光純薬株式会社製のＰＢＳを４ｍＬ注入して、フランツセルとすり付きガラスドナーの間にＳｔｒａｔ－Ｍ（商標）（メルク社製）メンブレンを挟み、クリップで固定した。無限閉鎖系にするため、ガラスドナーに試験サンプル（組成物）を載せ、パラフィルムでサンプルの蒸発による変化を防いだ。 More specifically, a stationary Franz cell (vertical glass diffusion cell, opening diameter 10 mm, receiver capacity 4.0 mL <manufactured by Permegia>) was placed with a stirrer, and further agitator manufactured by FUJIFILM Wako Pure Chemical Co., Ltd. 4 mL of PBS was injected, and a Strat-M™ (manufactured by Merck) membrane was sandwiched between the Franz cell and the ground glass donor and fixed with clips. To create an infinitely closed system, a test sample (composition) was mounted on a glass donor, and parafilm was applied to prevent the sample from changing due to evaporation.
恒温槽を３７℃に設定し、シリコンチューブで恒温槽とフランツセル同士を直列に繋ぎ、リザーバー溶液が一定温度に保たれるようにした。各フランツセルを攪拌機にセットし、攪拌を開始し、試験開始とした。攪拌開始時から一定時間後（１時間後、２時間後、３時間後、６時間後、９時間後、および２４時間後）に０．５ｍＬずつのリザーバー溶液を採取して、ＬＣ／ＭＳにてリザーバー溶液中のグリシルグリシン含有量およびトラネキサム酸量を定量し、グリシルグリシンの累積透過量（ｎｍｏｌ／ｃｍ２）（図１参照）およびトラネキサム酸の累積透過量（ｎｍｏｌ／ｃｍ２）（図２参照）を求めた。 The constant temperature bath was set to 37° C., and the constant temperature bath and the Franz cell were connected in series with a silicon tube so that the reservoir solution was maintained at a constant temperature. Each Franz cell was set in a stirrer and stirring was started to start the test. After a certain period of time from the start of stirring (1 hour, 2 hours, 3 hours, 6 hours, 9 hours, and 24 hours), 0.5 mL of the reservoir solution was collected and analyzed by LC/MS. The glycylglycine content and the amount of tranexamic acid in the reservoir solution were quantified using the 2) was obtained.
分析条件
グリシルグリシン
ＬＣ／ＭＳ＿ ＭＲＭ １３０．９０＞７３．９ ｎｅｇａｔｉｖｅ（Ｓｈｉｍａｄｚｕ ＭＳ８０５０）を定量して検出した。
トラネキサム酸
ＬＣ／ＭＳ＿ ＳＩＭ ｍ／ｚ １５８＿ｐｏｓｉｔｉｖｅ （Ｓｈｉｍａｄｚｕ ＭＳ８０５０）を定量して検出した。
Analysis conditions
Glycylglycine LC/MS_MRM 130.90>73.9 negative (Shimadzu MS8050) was quantified and detected.
Tranexamic acid
LC/MS_SIM m/z 158_positive (Shimadzu MS8050) was quantified and detected.
グリシルグリシンの累積透過量を表す図１について、実施例３と比較例２との間、および実施例３と比較例１の間、および実施例３と実施例１との間でチューキー・クレーマー(Ｔｕｋｅｙ－Ｋｒａｍｅｒ)法により多重比較を行ったところ、いずれもｐ＜０．０５であり、有意差があることが分かった。 Tukey-Kramer When multiple comparison was performed by the (Tukey-Kramer) method, p<0.05 was found for both, indicating a significant difference.
トラネキサム酸の累積透過量を表す図２について、実施例３と比較例４との間、および実施例３と実施例２の間、および実施例３と比較例３の間でチューキー・クレーマー(Ｔｕｋｅｙ－Ｋｒａｍｅｒ)法により多重比較を行ったところ、ｐ＜０．０５であり、有意差があることが分かった。 Tukey-Kramer -Kramer) method, p < 0.05, indicating a significant difference.
化粧品、医薬部外品に用いられる水溶性活性成分としては、美白剤、抗老化剤、抗酸化
剤、保湿剤、育毛剤、細胞賦活剤、ビタミン類、アミノ酸類などが挙げられる。具体的に
は、アルブチン（ＬｏｇＰ＝－０．６）、Ｌ－アスコルビン酸（ＬｏｇＰ＝－１．６）、
ハイドロキノン（ＬｏｇＰ＝－０．６）、グルタチオン（ＬｏｇＰ＝－４．５）、パントテン酸（ＬｏｇＰ＝－１．１）、トラネキサム酸（ＬｏｇＰ＝－２）、コウジ酸（ＬｏｇＰ＝－０．９）、Ｌ－システイン（ＬｏｇＰ＝－２．５）、エラグ酸（ＬｏｇＰ＝１．１）、レゾルシン（ＬｏｇＰ＝０．８）、ルチン（ＬｏｇＰ＝－１．３）、トリプトファン（ＬｏｇＰ＝－１．１）、ヒスチジン（ＬｏｇＰ＝－３．２）、グリシルグリシン（ｌｏｇＰ＝－２．３）、クエルセチン（ＬｏｇＰ＝１．５）やクエルシトリン（ＬｏｇＰ＝０．９）などのフラボノイド類、カテキン（ＬｏｇＰ＝０．４）没食子酸（ＬｏｇＰ＝０．７）、カイネチン（ＬｏｇＰ＝１）、α－リポ酸（ＬｏｇＰ＝１．７）、エリソルビン酸（ＬｏｇＰ＝－１．６）、チオタウリン（ＬｏｇＰ＝－０．１）、尿素（ＬｏｇＰ＝－１．４）、ニコチン（ＬｏｇＰ＝１．２）、ニコチン酸（ＬｏｇＰ＝０．４）、ニコチン酸アミド（ｌｏｇＰ＝－０．４）、ヒドロキシプロリン（ＬｏｇＰ＝－３．３）、セリン（ＬｏｇＰ＝－３．１）、グルタミン酸（ＬｏｇＰ＝－３．７）、アルギニン（ＬｏｇＰ＝－４．２）、アラニン（ＬｏｇＰ＝－３）、ミノキシジル（ＬｏｇＰ＝１．２）、Ｄ－グルコサミン（ＬｏｇＰ＝－２．８）、Ｎ－アセチル－Ｄ－グルコサミン（ＬｏｇＰ＝－１．７）、ヒアルロン酸（ＬｏｇＰ＝－７．４）、ラフィノース（ＬｏｇＰ＝－５．８）、アゼライン酸（ＬｏｇＰ＝１．６）、γ－アミノ酪酸（ＬｏｇＰ＝－３．２）、アラントイン（ＬｏｇＰ＝－２．２）、Ｌ－カルニチン（ＬｏｇＰ＝－０．２）、ビオチン（ＬｏｇＰ＝０．３）が挙げられる。
Water-soluble active ingredients used in cosmetics and quasi-drugs include whitening agents, anti-aging agents, antioxidants, moisturizing agents, hair restorers, cell activators, vitamins, and amino acids. Specifically, arbutin (LogP = -0.6), L-ascorbic acid (LogP = -1.6),
Hydroquinone (Log P = -0.6), Glutathione (Log P = -4.5), Pantothenic acid (Log P = -1.1), Tranexamic acid (Log P = -2), Kojic acid (Log P = -0.9) , L-cysteine (Log P = -2.5), ellagic acid (Log P = 1.1), resorcin (Log P = 0.8), rutin (Log P = -1.3), tryptophan (Log P = -1.1 ), histidine (LogP = -3.2), glycylglycine (logP = -2.3), flavonoids such as quercetin (LogP = 1.5) and quercitrin (LogP = 0.9), catechin (LogP = 0.4) gallic acid (Log P = 0.7), kinetin (Log P = 1), α-lipoic acid (Log P = 1.7), erythorbic acid (Log P = -1.6), thiotaurine (Log P = - 0.1), urea (Log P = -1.4), nicotine (Log P = 1.2), nicotinic acid (Log P = 0.4), nicotinamide (log P = -0.4), hydroxyproline (Log P = -3.3), serine (LogP = -3.1), glutamic acid (LogP = -3.7), arginine (LogP = -4.2), alanine (LogP = -3), minoxidil (LogP = 1 .2), D-glucosamine (Log P = -2.8), N-acetyl-D-glucosamine (Log P = -1.7), hyaluronic acid (Log P = -7.4), raffinose (Log P = -5. 8), azelaic acid (Log P = 1.6), γ-aminobutyric acid (Log P = -3.2), allantoin (Log P = -2.2), L-carnitine (Log P = -0.2), biotin ( LogP=0.3).
Claims (13)
前記親水性薬剤がグリシルグリシンまたはトラネキサム酸である、
請求項１～９のいずれか一項に記載の経皮吸収促進剤。 The mass ratio of the hydrophilic drug and the α-hydroxy acid (the amount of the hydrophilic drug in the percutaneous absorption enhancer: the amount of the α-hydroxy acid in the transdermal absorption enhancer) is from 1:1 to 1:4, and the hydrophilic drug is glycylglycine or tranexamic acid.
The percutaneous absorption enhancer according to any one of claims 1 to 9.
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| JP2021072756A JP2022167158A (en) | 2021-04-22 | 2021-04-22 | Percutaneous absorption promoter |
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| JP2021072756A JP2022167158A (en) | 2021-04-22 | 2021-04-22 | Percutaneous absorption promoter |
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| JP2022167158A true JP2022167158A (en) | 2022-11-04 |
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