WO2020158643A1 - External preparation - Google Patents

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Publication number
WO2020158643A1
WO2020158643A1 PCT/JP2020/002689 JP2020002689W WO2020158643A1 WO 2020158643 A1 WO2020158643 A1 WO 2020158643A1 JP 2020002689 W JP2020002689 W JP 2020002689W WO 2020158643 A1 WO2020158643 A1 WO 2020158643A1
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Prior art keywords
acid
tranexamic acid
derivatives
external preparation
tranexamic
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PCT/JP2020/002689
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French (fr)
Japanese (ja)
Inventor
良 池田
圭悟 鳥家
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丸善製薬株式会社
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Priority to JP2020569605A priority Critical patent/JPWO2020158643A1/en
Priority to CN202080011197.2A priority patent/CN113347968A/en
Publication of WO2020158643A1 publication Critical patent/WO2020158643A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair

Definitions

  • the present invention relates to an external preparation containing tranexamic acid.
  • Tranexamic acid has hemostatic and anti-inflammatory effects, and is widely used in dentifrices and pharmaceuticals. Further, it has a rough skin improving action and a whitening action, and is also used as an external preparation for the skin or hair of cosmetics and the like.
  • tranexamic acid is water-soluble, it has extremely high crystallinity, and there is a problem that crystals are easily precipitated by evaporation of water.
  • phytic acid Patent Document 1: JP-A-2018-48097
  • polyhydroxy acid Patent Document 2: JP-A-2013-121955
  • a method has been proposed.
  • the present invention has been made in view of the above circumstances, and an object thereof is to provide an external preparation having an effect of suppressing crystallization of tranexamic acid.
  • the present inventors have conducted intensive studies to achieve the above-mentioned object, and as a result, they have found that a concomitant use of a specific amino acid has a remarkable crystallization-inhibiting effect on tranexamic acid, and have completed the present invention. It is a thing.
  • the present invention provides the following external preparations.
  • the cosmetic label may be used as the ingredient name.
  • component (B) is one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, ⁇ -aminobutyric acid, theanine, pyrrolidonecarboxylic acid, and salts thereof.
  • the present invention it is possible to provide an external preparation having a remarkable effect of inhibiting crystallization of tranexamic acid. As a result, the effect of tranexamic acid can be sufficiently exerted, and the external preparation also has a good appearance and a good feeling in use.
  • the component (A) is at least one selected from tranexamic acid, tranexamic acid derivatives and salts thereof, and may be used alone or in combination of two or more.
  • Tranexamic acid is trans-4-aminomethylcyclohexane-1-carboxylic acid.
  • the tranexamic acid derivative include ester derivatives such as cetyl tranexamic acid and amide derivatives such as tranexamic acid methylamide.
  • the salt is not particularly limited, and examples thereof include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, metal salts such as aluminum, iron and zinc, ammonium, monoethanolamine, diethanolamine, and trisalt. Examples thereof include organic amine salts such as ethanolamine and stearylamine.
  • the content of the component (A) is not particularly limited, but is preferably 1 to 5 mass% in the external preparation, more preferably 1 to 2 mass %.
  • the component (B) is one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, ⁇ -aminobutyric acid, derivatives thereof, and salts of these and these derivatives, and one kind alone. Or two or more of them may be used in appropriate combination.
  • arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine and ⁇ -aminobutyric acid are amino acids and may be D-form, L-form or DL-form.
  • Examples of these derivatives include ester derivatives in which a hydrogen atom in an amino acid is substituted with an alkyl group, an alkenyl group, an aryl group, etc.; an ester derivative in which a hydrogen atom of a hydroxyl group is substituted with an acyl group; a hydrogen atom of a hydroxyl group, Ether derivatives substituted with alkyl groups, alkenyl groups, aryl groups, etc.; Amido derivatives substituted with hydrogen atoms of amino groups with acyl groups; Hydrogen atoms of amino groups substituted with alkyl groups, alkenyl groups, aryl groups, etc. And the like. Specific examples include glutamic acid derivatives such as theanine and pyrrolidonecarboxylic acid.
  • the salt of the amino acid salt and the amino acid derivative is not particularly limited, and examples thereof include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, metal salts such as aluminum, iron and zinc, and ammonium, Examples thereof include organic amine salts such as monoethanolamine, diethanolamine, triethanolamine and stearylamine.
  • arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, ⁇ -aminobutyric acid, theanine, pyrrolidonecarboxylic acid, and salts thereof are preferable from the viewpoint of the crystallization inhibitory effect of tranexamic acid. ..
  • the content of the component (B) is not particularly limited, it is preferably 0.05 to 5% by mass, more preferably 0.125 to 2% by mass, and further preferably 0.25 to 1% by mass in the external preparation. Within this range, the crystallization suppressing effect of tranexamic acid is further improved.
  • Arginine or its salt 0.5-2% by mass Aspartic acid: 0.125 to 1 mass%
  • Glutamic acid 0.125 to 1 mass%
  • Glycine 0.75 to 1.25 mass%
  • Proline 1-2% by mass Serine: 0.25 to 1 mass%
  • Threonine 0.5-1% by mass
  • Theanine 0.125 to 0.25 mass%
  • ⁇ -Aminobutyric acid 0.125 to 0.25% by mass
  • Pyrrolidonecarboxylic acid 0.25 to 0.5 mass%
  • the content mass ratio of the component (A) and the component (B) represented by (A):(B) is preferably 20:1 to 0.5:1, more preferably 16:1 to 1:1, More preferred is 8:1 to 2:1. Within this range, the crystallization suppressing effect of tranexamic acid is further improved.
  • the external preparation of the present invention may contain an appropriate amount of components usually used in the external preparation, as long as the effects of the present invention are not impaired.
  • components usually used in the external preparation include whitening agents, anti-aging agents, moisturizers, preservatives, antibacterial agents, enzymes, plant extracts, and other functional ingredients, as well as oil agents, surfactants, fragrances, dyes, and pH adjusters.
  • water such as agents and purified water. Each of these may be used alone or in an appropriate amount by combining two or more thereof.
  • the polyhydric alcohol may be used alone or in combination of two or more kinds.
  • examples of the polyhydric alcohol include isopentyl diol, ethylhexane diol, caprylyl glycol, glycol, (C15-18) glycol, (C20-30) glycol, glycerin, diethylene glycol, diglycerin, dithiaoctane diol, dipropylene glycol, Thioglycerin, 1,10-decanediol, decylene glycol, triethylene glycol, trimethylhydroxymethylcyclohexanol, phytantriol, phenoxypropanediol, 1,2-butanediol, 2,3-butanediol, butylethylpropanediol , BG such as 1,3-butylene glycol, PG, 1,2-hexanediol,
  • a polyhydric alcohol When a polyhydric alcohol is added, its content in the external preparation is preferably 1.0 to 30.0 mass%, more preferably 2.0 to 30.0 mass%.
  • the external preparation is not particularly limited to pharmaceuticals, quasi drugs, cosmetics and the like. Among them, it is suitable as an external preparation for skin and hair.
  • the skin is not particularly limited to the body such as face, scalp, and arm, but does not include the inside of the oral cavity.
  • the form of the external preparation is not particularly limited, and may be a liquid, suspension, emulsion, cream, ointment, gel, lotion, aerosol or the like. Examples of forms in which the crystallization-inhibiting effect of tranexamic acid is expected include liquids and lotions.
  • the pH of the external preparation is not particularly limited, preferably 3 to 8 at 25° C., more preferably 5.0 to 7.0.
  • the present invention provides (A) an external preparation containing at least one member selected from tranexamic acid, tranexamic acid derivatives and salts thereof, and (B) arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, ⁇ -
  • a method for suppressing crystallization of tranexamic acid which comprises blending one or more selected from aminobutyric acid, derivatives thereof, and salts of these and derivatives thereof. Further, it can be used as a crystallization inhibitor of tranexamic acid containing the above-mentioned component (A) and component (B).
  • the suitable components and blending amounts are the same as above.
  • Image analysis/image analysis Scanner Docu Center-IV C5575 (manufactured by Fuji Xerox) Image capture resolution: 300 dpi Image analysis software: ImageJ (ver. 1.50i) The area inside the well of the image was circularly selected by the Oval tool, and the Mean gray value was measured with the Analyze/Measure.
  • Fig. 1 shows a photograph of Asp 0.5%, 0.25%, 0.125%, phytic acid 0.16%, and blank tranexamic acid crystallization inhibitory test after storage at room temperature for 24 hours. It was confirmed that aspartic acid had a higher crystallization inhibitory effect on tranexamic acid than phytic acid.
  • Examples, Comparative Examples It was prepared by mixing and dissolving components other than purified water in purified water to obtain a lotion having the composition shown in Table 4. Enter the cosmetic label. The crystallization suppressing effect of tranexamic acid was evaluated by the same method as above. The results are also shown in the table.

Abstract

According to the present invention, an external preparation is configured to contain (A) one or more substances that are selected from among tranexamic acid, tranexamic acid derivatives and salts of tranexamic acid or tranexamic acid derivatives, and (B) one or more substances that are selected from among arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, derivatives of these compounds, and salts of these compounds or the derivatives of these compounds, thereby being capable of suppressing crystallization of tranexamic acid.

Description

外用剤Topical
　本発明は、トラネキサム酸を含有する外用剤に関するものである。 The present invention relates to an external preparation containing tranexamic acid.
　トラネキサム酸は、止血作用や抗炎症作用を有し、歯磨剤、医薬品等に広く使用されている。また、荒れ肌改善作用や美白作用を有し、化粧品等の皮膚又は毛髪用外用剤としても使用されている。 Tranexamic acid has hemostatic and anti-inflammatory effects, and is widely used in dentifrices and pharmaceuticals. Further, it has a rough skin improving action and a whitening action, and is also used as an external preparation for the skin or hair of cosmetics and the like.
　しかしながら、トラネキサム酸は水溶性である一方で非常に結晶性が高く、水分の蒸発により、容易に結晶が析出するという課題があった。このようなトラネキサム酸の結晶化抑制の方法としては、フィチン酸（特許文献１：特開２０１８－４８０９７号公報）、ポリヒドロキシ酸（特許文献２：特開２０１３－１２１９５５号公報）等を併用する方法が提案されている。しかしながら、トラネキサム酸の結晶化抑制効果にさらに優れた方法が望まれていた。 However, while tranexamic acid is water-soluble, it has extremely high crystallinity, and there is a problem that crystals are easily precipitated by evaporation of water. As such a method for suppressing crystallization of tranexamic acid, phytic acid (Patent Document 1: JP-A-2018-48097), polyhydroxy acid (Patent Document 2: JP-A-2013-121955) and the like are used in combination. A method has been proposed. However, there has been a demand for a method which is more excellent in the effect of suppressing crystallization of tranexamic acid.
特開２０１８－４８０９７号公報JP, 2018-48097, A 特開２０１３－１２１９５５号公報JP, 2013-121955, A
　本発明は上記事情に鑑みなされたもので、トラネキサム酸の結晶化抑制効果を有する外用剤を提供することを目的とする。 The present invention has been made in view of the above circumstances, and an object thereof is to provide an external preparation having an effect of suppressing crystallization of tranexamic acid.
　本発明者らは、上記目的を達成するため鋭意検討した結果、特定のアミノ酸を併用することで、顕著なトラネキサム酸の結晶化抑制効果が得られることを知見し、本発明をなすに至ったものである。 The present inventors have conducted intensive studies to achieve the above-mentioned object, and as a result, they have found that a concomitant use of a specific amino acid has a remarkable crystallization-inhibiting effect on tranexamic acid, and have completed the present invention. It is a thing.
　従って、本発明は下記外用剤を提供する。以下、成分名として化粧品表示名称を使用する場合がある。
１．（Ａ）トラネキサム酸、トラネキサム酸誘導体及びこれらの塩から選ばれる１種以上、及び、
（Ｂ）アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸、これらの誘導体、並びにこれら及びこれらの誘導体の塩から選ばれる１種以上
を含有する外用剤。
２．（Ｂ）成分が、アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸、テアニン、ピロリドンカルボン酸、及びこれらの塩から選ばれる１種以上である１記載の外用剤。 Therefore, the present invention provides the following external preparations. Hereinafter, the cosmetic label may be used as the ingredient name.
1. (A) one or more selected from tranexamic acid, tranexamic acid derivatives and salts thereof, and
(B) An external preparation containing at least one selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, their derivatives, and salts of these and their derivatives.
2. The external preparation according to 1, wherein the component (B) is one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, theanine, pyrrolidonecarboxylic acid, and salts thereof.
　本発明によれば、顕著なトラネキサム酸の結晶化抑制効果を有する外用剤を提供することができる。これにより、トラネキサム酸の効果が十分に発揮できると共に、外用剤の外観も良く、使用感も良好なものとなる。 According to the present invention, it is possible to provide an external preparation having a remarkable effect of inhibiting crystallization of tranexamic acid. As a result, the effect of tranexamic acid can be sufficiently exerted, and the external preparation also has a good appearance and a good feeling in use.
Ａｓｐ０．５質量％、０．２５質量％、０．１２５質量％、フィチン酸０．１６質量％、ブランクのトラネキサム酸の結晶化抑制試験における、室温で２４時間保存後の写真である。It is a photograph after storing at room temperature for 24 hours in a crystallization inhibition test of Asp 0.5% by mass, 0.25% by mass, 0.125% by mass, phytic acid 0.16% by mass, and blank tranexamic acid.
　以下、本発明について詳細に説明する。
[（Ａ）成分]
　（Ａ）成分は、トラネキサム酸、トラネキサム酸誘導体及びこれらの塩から選ばれる１種以上であり、１種単独で又は２種以上を適宜組み合わせて用いることができる。トラネキサム酸は、トランス－４－アミノメチルシクロヘキサン－１－カルボン酸である。トラネキサム酸誘導体としては、トラネキサム酸セチルエステル等のエステル誘導体、トラネキサム酸メチルアミド等のアミド誘導体等が挙げられる。塩としては、特に限定されず、例えば、ナトリウム、カリウム等のアルカリ金属塩、カルシウム、マグネシウム等のアルカリ土類金属塩、アルミニウム、鉄、亜鉛等の金属塩、アンモニウム、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、ステアリルアミン等の有機アミン塩等が挙げられる。 Hereinafter, the present invention will be described in detail.
[(A) component]
The component (A) is at least one selected from tranexamic acid, tranexamic acid derivatives and salts thereof, and may be used alone or in combination of two or more. Tranexamic acid is trans-4-aminomethylcyclohexane-1-carboxylic acid. Examples of the tranexamic acid derivative include ester derivatives such as cetyl tranexamic acid and amide derivatives such as tranexamic acid methylamide. The salt is not particularly limited, and examples thereof include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, metal salts such as aluminum, iron and zinc, ammonium, monoethanolamine, diethanolamine, and trisalt. Examples thereof include organic amine salts such as ethanolamine and stearylamine.
　（Ａ）成分の含有量は特に限定されないが、外用剤中１～５質量％が好ましく、１～２質量％がより好ましい。 The content of the component (A) is not particularly limited, but is preferably 1 to 5 mass% in the external preparation, more preferably 1 to 2 mass %.
［（Ｂ）成分］
　（Ｂ）成分は、アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸、これらの誘導体、並びにこれら及びこれらの誘導体の塩から選ばれる１種以上であり、１種単独で又は２種以上を適宜組み合わせて用いることができる。 [(B) component]
The component (B) is one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, derivatives thereof, and salts of these and these derivatives, and one kind alone. Or two or more of them may be used in appropriate combination.
　上記アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸（ＧＡＢＡ）は、アミノ酸であり、Ｄ体、Ｌ体又はＤＬ体でもよい。これらの誘導体としては、アミノ酸中の水素原子が、アルキル基、アルケニル基、アリール基等で置換されたエステル誘導体；水酸基の水素原子が、アシル基で置換されたエステル誘導体；水酸基の水素原子が、アルキル基、アルケニル基、アリール基等で置換されたエーテル誘導体；アミノ基の水素原子が、アシル基で置換されたアミド誘導体；アミノ基の水素原子が、アルキル基、アルケニル基、アリール基等で置換されたアミン誘導体等が挙げられる。具体的には、グルタミン酸の誘導体である、テアニン、ピロリドンカルボン酸等が挙げられる。 The above-mentioned arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine and γ-aminobutyric acid (GABA) are amino acids and may be D-form, L-form or DL-form. Examples of these derivatives include ester derivatives in which a hydrogen atom in an amino acid is substituted with an alkyl group, an alkenyl group, an aryl group, etc.; an ester derivative in which a hydrogen atom of a hydroxyl group is substituted with an acyl group; a hydrogen atom of a hydroxyl group, Ether derivatives substituted with alkyl groups, alkenyl groups, aryl groups, etc.; Amido derivatives substituted with hydrogen atoms of amino groups with acyl groups; Hydrogen atoms of amino groups substituted with alkyl groups, alkenyl groups, aryl groups, etc. And the like. Specific examples include glutamic acid derivatives such as theanine and pyrrolidonecarboxylic acid.
　上記アミノ酸塩及びアミノ酸誘導体の塩としては、特に限定されず、例えば、ナトリウム、カリウム等のアルカリ金属塩、カルシウム、マグネシウム等のアルカリ土類金属塩、アルミニウム、鉄、亜鉛等の金属塩、アンモニウム、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、ステアリルアミン等の有機アミン塩等が挙げられる。 The salt of the amino acid salt and the amino acid derivative is not particularly limited, and examples thereof include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, metal salts such as aluminum, iron and zinc, and ammonium, Examples thereof include organic amine salts such as monoethanolamine, diethanolamine, triethanolamine and stearylamine.
　（Ｂ）成分としては、トラネキサム酸の結晶化抑制効果の点から、アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸、テアニン、ピロリドンカルボン酸、及びこれらの塩が好ましい。 As the component (B), arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, theanine, pyrrolidonecarboxylic acid, and salts thereof are preferable from the viewpoint of the crystallization inhibitory effect of tranexamic acid. ..
　グルタミン酸又はその塩と、γ－アミノ酪酸又はその塩との組み合わせ、γ－アミノ酪酸又はその塩とテアニンとの組み合わせにより、トラネキサム酸の結晶化抑制効果の相乗効果を得ることができる点から、これらの組み合わせが好ましい。 By combining glutamic acid or a salt thereof with γ-aminobutyric acid or a salt thereof, or combining γ-aminobutyric acid or a salt thereof with theanine, a synergistic effect of inhibiting crystallization of tranexamic acid can be obtained. Is preferred.
　（Ｂ）成分の含有量は特に限定されないが、外用剤中０．０５～５質量％が好ましく、０．１２５～２質量％がより好ましく、０．２５～１質量％がさらに好ましい。この範囲とすることで、トラネキサム酸の結晶化抑制効果がより向上する。 Although the content of the component (B) is not particularly limited, it is preferably 0.05 to 5% by mass, more preferably 0.125 to 2% by mass, and further preferably 0.25 to 1% by mass in the external preparation. Within this range, the crystallization suppressing effect of tranexamic acid is further improved.
　特に下記の成分又はその塩の場合は、下記範囲が特に好ましい。
アルギニン又はその塩：０．５～２質量％
アスパラギン酸：０．１２５～１質量％
グルタミン酸：０．１２５～１質量％
グリシン：０．７５～１．２５質量％
プロリン：１～２質量％
セリン：０．２５～１質量％
トレオニン：０．５～１質量％
テアニン：０．１２５～０．２５質量％
γ－アミノ酪酸：０．１２５～０．２５質量％
ピロリドンカルボン酸：０．２５～０．５質量％ Especially in the case of the following components or salts thereof, the following ranges are particularly preferable.
Arginine or its salt: 0.5-2% by mass
Aspartic acid: 0.125 to 1 mass%
Glutamic acid: 0.125 to 1 mass%
Glycine: 0.75 to 1.25 mass%
Proline: 1-2% by mass
Serine: 0.25 to 1 mass%
Threonine: 0.5-1% by mass
Theanine: 0.125 to 0.25 mass%
γ-Aminobutyric acid: 0.125 to 0.25% by mass
Pyrrolidonecarboxylic acid: 0.25 to 0.5 mass%
　（Ａ）：（Ｂ）で表される、（Ａ）成分と（Ｂ）成分との含有質量比は２０：１～０．５：１が好ましく、１６：１～１：１がより好ましく、８：１～２：１がさらに好ましい。この範囲とすることで、トラネキサム酸の結晶化抑制効果がより向上する。 The content mass ratio of the component (A) and the component (B) represented by (A):(B) is preferably 20:1 to 0.5:1, more preferably 16:1 to 1:1, More preferred is 8:1 to 2:1. Within this range, the crystallization suppressing effect of tranexamic acid is further improved.
［任意成分］
　本発明の外用剤には、本発明の効果を損なわない範囲で、外用剤に通常用いられる成分を適量配合することができる。このような成分としては、例えば、美白剤、抗老化剤、保湿剤、防腐剤、抗菌剤、酵素、植物抽出物等の機能性成分の他、油剤、界面活性剤、香料、色素、ｐＨ調整剤、精製水等の水等が挙げられる。これらは、それぞれ１種単独で又は２種以上を適宜組み合わせて、適量を用いることができる。 [Arbitrary ingredients]
The external preparation of the present invention may contain an appropriate amount of components usually used in the external preparation, as long as the effects of the present invention are not impaired. Examples of such components include whitening agents, anti-aging agents, moisturizers, preservatives, antibacterial agents, enzymes, plant extracts, and other functional ingredients, as well as oil agents, surfactants, fragrances, dyes, and pH adjusters. Examples include water such as agents and purified water. Each of these may be used alone or in an appropriate amount by combining two or more thereof.
　中でも、本発明の外用剤には多価アルコールを配合することが好ましい。多価アルコールは１種単独で又は２種以上を適宜組み合わせて用いることができる。多価アルコールとしては、イソペンチルジオール、エチルヘキサンジオール、カプリリルグリコール、グリコール、（Ｃ１５－１８）グリコール、（Ｃ２０－３０）グリコール、グリセリン、ジエチレングリコール、ジグリセリン、ジチアオクタンジオール、ジプロピレングリコール、チオグリセリン、１，１０－デカンジオール、デシレングリコール、トリエチレングリコール、トリメチルヒドロキシメチルシクロヘキサノール、フィタントリオール、フェノキシプロパンジオール、１，２－ブタンジオール、２，３－ブタンジオール、ブチルエチルプロパンジオール、１，３－ブチレングリコール等のＢＧ、ＰＧ、１，２－ヘキサンジオール、ヘキシレングリコール、ペンチレングリコール、メチルプロパンジオール、メンタンジオール、ラウリルグリコール等が挙げられる。 Above all, it is preferable to add a polyhydric alcohol to the external preparation of the present invention. The polyhydric alcohol may be used alone or in combination of two or more kinds. Examples of the polyhydric alcohol include isopentyl diol, ethylhexane diol, caprylyl glycol, glycol, (C15-18) glycol, (C20-30) glycol, glycerin, diethylene glycol, diglycerin, dithiaoctane diol, dipropylene glycol, Thioglycerin, 1,10-decanediol, decylene glycol, triethylene glycol, trimethylhydroxymethylcyclohexanol, phytantriol, phenoxypropanediol, 1,2-butanediol, 2,3-butanediol, butylethylpropanediol , BG such as 1,3-butylene glycol, PG, 1,2-hexanediol, hexylene glycol, pentylene glycol, methylpropanediol, menthanediol, lauryl glycol and the like.
　多価アルコールを配合する場合、その含有量は、外用剤中１．０～３０．０質量％が好ましく、２．０～３０．０質量％がより好ましい。 When a polyhydric alcohol is added, its content in the external preparation is preferably 1.0 to 30.0 mass%, more preferably 2.0 to 30.0 mass%.
　外用剤としては、医薬品、医薬部外品、化粧品等特に限定されない。中でも皮膚用、頭髪用の外用剤に好適である。皮膚は、顔、頭皮、腕等の身体等、特に限定されないが、口腔内は含まない。外用剤の形態としては特に限定されず、液剤、懸濁剤、乳剤、クリーム剤、軟膏剤、ゲル剤、ローション剤、エアゾール剤等にすることができる。トラネキサム酸の結晶化抑制効果が期待される形態としては、液剤、ローション剤等が挙げられる。 The external preparation is not particularly limited to pharmaceuticals, quasi drugs, cosmetics and the like. Among them, it is suitable as an external preparation for skin and hair. The skin is not particularly limited to the body such as face, scalp, and arm, but does not include the inside of the oral cavity. The form of the external preparation is not particularly limited, and may be a liquid, suspension, emulsion, cream, ointment, gel, lotion, aerosol or the like. Examples of forms in which the crystallization-inhibiting effect of tranexamic acid is expected include liquids and lotions.
　外用剤、特に医薬部外品又は化粧品用の外用剤とする場合の用途としては、例えば、化粧水、乳液、クリーム、ジェル、美容液、日焼け止め用化粧料、パック、マスク、ハンドクリーム、ボディローション、ボディークリーム等の基礎化粧料；洗顔料、メイク落とし、ボディーシャンプー等の皮膚洗浄料；シャンプー、リンス、トリートメント等の頭皮及び毛髪化粧料；ファンデーション、リップ、マスカラ等のメイクアップ化粧料等が挙げられる。 When used as an external preparation, particularly as an external preparation for quasi-drugs or cosmetics, for example, lotion, emulsion, cream, gel, beauty essence, sunscreen cosmetic, pack, mask, hand cream, body Basic cosmetics such as lotions and body creams; facial cleansers, makeup removers, skin cleansers such as body shampoos; scalp and hair cosmetics such as shampoos, rinses and treatments; makeup cosmetics such as foundations, lips and mascara. Can be mentioned.
　外用剤のｐＨは特に限定されず、２５℃で３～８が好ましく、５．０～７．０がより好ましい。 The pH of the external preparation is not particularly limited, preferably 3 to 8 at 25° C., more preferably 5.0 to 7.0.
[トラネキサム酸の結晶化抑制方法]
　本発明は、（Ａ）トラネキサム酸、トラネキサム酸誘導体及びこれらの塩から選ばれる１種以上を含有する外用剤に、（Ｂ）アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸、これらの誘導体、並びにこれら及びこれらの誘導体の塩から選ばれる１種以上を配合する、トラネキサム酸の結晶化抑制方法を提供する。また、上記（Ａ）成分と（Ｂ）成分とを含有するトラネキサム酸の結晶化抑制剤とすることもできる。それぞれ、好適な成分、配合量等は上記と同じである。 [Method for suppressing crystallization of tranexamic acid]
The present invention provides (A) an external preparation containing at least one member selected from tranexamic acid, tranexamic acid derivatives and salts thereof, and (B) arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ- Provided is a method for suppressing crystallization of tranexamic acid, which comprises blending one or more selected from aminobutyric acid, derivatives thereof, and salts of these and derivatives thereof. Further, it can be used as a crystallization inhibitor of tranexamic acid containing the above-mentioned component (A) and component (B). The suitable components and blending amounts are the same as above.
　以下、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。なお、下記の例において特に明記のない場合は、組成の「％」は質量％、比率は質量比を示し、表中の各成分の量は純分換算した量である。 Hereinafter, the present invention will be specifically described by showing Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the following examples, unless otherwise specified, “%” in the composition indicates mass %, ratio indicates mass ratio, and the amount of each component in the table is the amount converted to pure content.
　下記成分について、表中に記載の濃度でトラネキサム酸の結晶化抑制試験を行った。結果を表中に併記する。
[試験例：トラネキサム酸の結晶化抑制]
（１）試験サンプル（ｐＨ３～８）
　下記組成の組成物を作製した。
　トラネキサム酸　　　　　　　　２％
　１，３－ブチレングリコール　３０％
　サンプル　　　　　　　　　　表中の記載濃度
　精製水　　　　　　　　　　　　残部　　　　
　合計　　　　　　　　　　　１００％ The following components were subjected to a crystallization inhibition test of tranexamic acid at the concentrations shown in the table. The results are also shown in the table.
[Test Example: Inhibition of crystallization of tranexamic acid]
(1) Test sample (pH 3-8)
A composition having the following composition was produced.
Tranexamic acid 2%
1,3-butylene glycol 30%
Concentration described in the sample table
Purified water balance
Total 100%
（２）試験方法
　上記組成物を下記プレートに３．０ｇ／ウェルで添加し、室温で２４時間保存後に下記（３）に記載の方法で画像解析を行った。
プレート
　株式会社ステム社製
　材質：ＰＳ（ポリスチレン）
　プレートサイズ：１２８×８６×２０ｍｍ
　型番：６穴（平底）
　ウェル径×高さ（ｍｍ）：φ３３．５×１６．７ (2) Test method The above composition was added to the following plate at 3.0 g/well, and after image storage for 24 hours at room temperature, image analysis was performed by the method described in (3) below.
Plate Stem Co., Ltd. Material: PS (polystyrene)
Plate size: 128 x 86 x 20 mm
Model number: 6 holes (flat bottom)
Well diameter x height (mm): φ33.5 x 16.7
（３）画像解析
・画像解析
　スキャナ：Ｄｏｃｕ　Ｃｅｎｔｅｒ－ＩＶ　Ｃ５５７５（Ｆｕｊｉ　Ｘｅｒｏｘ社製）
　画像取り込み解像度：３００ｄｐｉ
　画像解析ソフト：ＩｍａｇｅＪ（ｖｅｒ．　１．５０ｉ）
　画像のウェル内部の領域をＯｖａｌツールによって円形に選択し、Ａｎａｌｙｚｅ／ＭｅａｓｕｒｅでＭｅａｎ　ｇｒａｙ　ｖａｌｕｅを測定した。 (3) Image analysis/image analysis Scanner: Docu Center-IV C5575 (manufactured by Fuji Xerox)
Image capture resolution: 300 dpi
Image analysis software: ImageJ (ver. 1.50i)
The area inside the well of the image was circularly selected by the Oval tool, and the Mean gray value was measured with the Analyze/Measure.
（４）Ｍｅａｎ　ｇｒａｙ　ｖａｌｕｅの結果から、トラネキサム酸の結晶化抑制効果を下記基準で示す。数値が低いほど、トラネキサム酸の結晶化抑制効果が高いことを示す。
＋＋＋：２０未満
＋＋：２０以上４０未満
＋：４０以上６０未満
－：６０以上 (4) From the results of Mean gray value, the crystallization suppressing effect of tranexamic acid is shown by the following criteria. The lower the value, the higher the crystallization-inhibiting effect of tranexamic acid.
++: Less than 20 ++: 20 or more and less than 40 +: 40 or more and less than 60 -: 60 or more
　以下、略称を示す。
Ａｌａ：Ｌ－アラニン
Ａｒｇ：Ｌ－アルギニン
Ａｓｐ：Ｌ－アスパラギン酸
Ｃｙｓ：ＤＬ－システイン
Ｇｌｕ：Ｌ－グルタミン酸
Ｇｌｙ：Ｌ－グリシン
Ｈｉｓ：Ｌ－ヒスチジン
Ｉｌｅ：Ｌ－イソロイシン
Ｐｒｏ：Ｌ－プロリン
Ｓｅｒ：Ｌ－セリン
Ｔｈｒ：ＤＬ－トレオニン
Ｔｙｒ：Ｌ－チロシン
Ｐｏｌｙ－Ｌｙｓ：ポリ－Ｌ－リジン
Ｐｏｌｙ－ＰＡ：ポリリン酸Ｎａ
Ｔｈｅａｎｉｎｅ：Ｌ－テアニン
ＧＡＢＡ：γ－アミノ酪酸
ＰＣＡ：ＤＬ－ピロリドンカルボン酸 The abbreviations are shown below.
Ala:L-alanine Arg:L-arginine Asp:L-aspartic acid Cys:DL-cysteine Glu:L-glutamic acid Gly:L-glycine His:L-histidine Ile:L-isoleucine Pro:L-proline Ser:L- Serine Thr: DL-threonine Tyr: L-tyrosine Poly-Lys: poly-L-lysine Poly-PA: Na polyphosphate
Theanine: L-theanine GABA: γ-aminobutyric acid PCA: DL-pyrrolidone carboxylic acid
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　Ａｓｐ０．５％、０．２５％、０．１２５％、フィチン酸０．１６％、ブランクの上記トラネキサム酸の結晶化抑制試験における、室温で２４時間保存後の写真を図１に示す。アスパラギン酸は、フィチン酸よりも高いトラネキサム酸の結晶化抑制効果を有することが確認された。 Fig. 1 shows a photograph of Asp 0.5%, 0.25%, 0.125%, phytic acid 0.16%, and blank tranexamic acid crystallization inhibitory test after storage at room temperature for 24 hours. It was confirmed that aspartic acid had a higher crystallization inhibitory effect on tranexamic acid than phytic acid.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　上記結果から、アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、テアニン、γ－アミノ酪酸、ピロリドンカルボン酸は、トラネキサム酸の結晶化抑制効果を有することが確認された。 From the above results, it was confirmed that arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, theanine, γ-aminobutyric acid, and pyrrolidonecarboxylic acid have a crystallization inhibiting effect on tranexamic acid.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　上記結果から、アラニン、システイン、ヒスチジン、イソロイシン、チロシン、ポリリジン、ポリリン酸ナトリウムには、トラネキサム酸の結晶化抑制効果は確認されなかった。 From the above results, it was not confirmed that alanine, cysteine, histidine, isoleucine, tyrosine, polylysine, or sodium polyphosphate had an effect of suppressing crystallization of tranexamic acid.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　表３の結果から、Ｇｌｕ：Ｌ－グルタミン酸とＧＡＢＡ：γ－アミノ酪酸とを併用することで、トラネキサム酸の結晶化抑制における相乗効果が確認された。
　表４の結果から、合計量が０．１２５％となるように調整しているので、ＧＡＢＡとＴｈｅａｎｉｎｅとが相加効果の場合は「＋」となるが、「＋＋」となっているので、ＧＡＢＡ：γ－アミノ酪酸と、Ｔｈｅａｎｉｎｅ：Ｌ－テアニンを併用することで、トラネキサム酸の結晶化抑制における相乗効果が確認された。 From the results in Table 3, it was confirmed that the combined use of Glu:L-glutamic acid and GABA:γ-aminobutyric acid has a synergistic effect in suppressing the crystallization of tranexamic acid.
From the results of Table 4, since the total amount is adjusted to be 0.125%, when GABA and Theanine have an additive effect, the result is “+”, but it is “++”. The combined use of GABA:γ-aminobutyric acid and Theanine:L-theanine was confirmed to have a synergistic effect in suppressing crystallization of tranexamic acid.
　　［実施例、比較例］
　精製水に精製水以外の成分を混合溶解して調製し、表４に示す組成の化粧水を得た。化粧品表示名称で記載する。上記と同様の方法でトラネキサム酸の結晶化抑制効果を評価した。結果を表中に併記する。 [Examples, Comparative Examples]
It was prepared by mixing and dissolving components other than purified water in purified water to obtain a lotion having the composition shown in Table 4. Enter the cosmetic label. The crystallization suppressing effect of tranexamic acid was evaluated by the same method as above. The results are also shown in the table.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006

Claims (2)

  1. 　（Ａ）トラネキサム酸、トラネキサム酸誘導体及びこれらの塩から選ばれる１種以上、及び、
    （Ｂ）アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸、これらの誘導体、並びにこれら及びこれらの誘導体の塩から選ばれる１種以上
    を含有する外用剤。     (A) one or more selected from tranexamic acid, tranexamic acid derivatives and salts thereof, and
    (B) An external preparation containing at least one selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, their derivatives, and salts of these and their derivatives.
  2. 　（Ｂ）成分が、アルギニン、アスパラギン酸、グルタミン酸、グリシン、プロリン、セリン、トレオニン、γ－アミノ酪酸、テアニン、ピロリドンカルボン酸、及びこれらの塩から選ばれる１種以上である請求項１記載の外用剤。 The external use according to claim 1, wherein the component (B) is one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, theanine, pyrrolidonecarboxylic acid, and salts thereof. Agent.
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