External preparation

Abstract

By preparing an external preparation containing (A) at least one selected from tranexamic acid, tranexamic acid derivatives, and salts thereof, and (B) at least one selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, their derivatives, and salts of their derivatives, crystallization of tranexamic acid can be inhibited.

Description

Technical Field

[0001] The present invention relates to an external preparation containing tranexamic acid. Background of the Invention

[0003] Tranexamic acid has a hemostatic effect and an anti-inflammatory effect, and is widely used in toothpaste, pharmaceuticals, etc. In addition, it has an effect of improving rough skin and a whitening effect, and is also used as an external preparation for skin or hair such as cosmetics.

[0004] However, although tranexamic acid is water-soluble, on the other hand, there is a problem that it has a very high crystallinity and easily precipitates crystals due to evaporation of moisture. As a method for suppressing such crystallization of tranexamic acid, a method of using phytic acid (Patent Document 1: Japanese Patent Laid-Open No. 2018-48097), polyhydroxy acid (Patent Document 2: Japanese Patent Laid-Open No. 2013-121955), etc. has been proposed. However, a method with further excellent tranexamic acid crystallization suppression effect is desired.

[0005] Prior Art Documents

[0006] Patent Documents

[0007] Patent Document 1: Japanese Patent Laid-Open No. 2018-48097

[0008] Patent Document 2: Japanese Patent Laid-Open No. 2013-121955 Summary of the Invention

[0010] Problems to be Solved by the Invention

[0011] In view of the above circumstances, the present invention aims to provide an external preparation having an effect of suppressing tranexamic acid crystallization.

[0012] Method for Solving the Problems

[0013] In order to achieve the above object, the present inventors conducted in-depth research and found that by using a specific amino acid in combination, a remarkable effect of suppressing tranexamic acid crystallization was obtained, and thus the present invention was completed.

[0014] Therefore, the present invention provides the following external preparation. Hereinafter, the name of a cosmetic may sometimes be used as the name of a component.

[0015] 1. An external preparation containing:

[0016] (A) One or more selected from tranexamic acid, tranexamic acid derivatives, and salts thereof, and

[0017] (B) One or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, their derivatives, and salts of them and their derivatives.

[0018] 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.

[0019] Advantages of the Invention

[0020] According to the present invention, an external preparation having a remarkable effect of inhibiting the crystallization of tranexamic acid can be provided. Thereby, the effect of tranexamic acid can be fully exerted, and the appearance and usability of the external preparation are also good. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Photographs after storing at room temperature for 24 hours in the crystallization inhibition test of tranexamic acid with Asp at 0.5% by mass, 0.25% by mass, 0.125% by mass, phytic acid at 0.16% by mass, and blank. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention will be described in detail below.

[0023] [Component (A)]

[0024] The component (A) is one or more selected from tranexamic acid, tranexamic acid derivatives, and salts thereof, and one kind can be used alone or two or more kinds can be used in appropriate combination. Tranexamic acid is trans-4-aminomethylcyclohexane-1-carboxylic acid. Examples of tranexamic acid derivatives include ester derivatives such as tranexamic acid cetyl ester, and amide derivatives such as tranexamic acid formamide. 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, and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine, and stearylamine.

[0025] The content of the component (A) is not particularly limited, and is preferably 1 to 5% by mass, more preferably 1 to 2% by mass in the external preparation.

[0026] [Component (B)]

[0027] The component (B) is one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, their derivatives, and salts of them and their derivatives, and one kind can be used alone or two or more kinds can be used in appropriate combination.

[0028] The above-mentioned arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid (GABA) are amino acids, and can be of D-type, L-type or DL-type. As their derivatives, examples include: ester derivatives in which the hydrogen atom in the amino acid is replaced by an alkyl group, alkenyl group, aryl group, etc., ester derivatives in which the hydrogen atom of the hydroxyl group is replaced by an acyl group, ether derivatives in which the hydrogen atom of the hydroxyl group is replaced by an alkyl group, alkenyl group, aryl group, etc., amide derivatives in which the hydrogen atom of the amino group is replaced by an acyl group, amine derivatives in which the hydrogen atom of the amino group is replaced by an alkyl group, alkenyl group, aryl group, etc. Specific examples include L-theanine, pyroglutamic acid, etc. as derivatives of glutamic acid.

[0029] The salts of the above-mentioned amino acid salts and amino acid derivatives are not particularly limited, and examples 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 organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine, stearylamine, etc.

[0030] As the component (B), from the viewpoint of the effect of inhibiting the crystallization of tranexamic acid, arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, L-theanine, pyroglutamic acid, and their salts are preferred.

[0031] By using the combination of glutamic acid or its salt and γ-aminobutyric acid or its salt, or the combination of γ-aminobutyric acid or its salt and L-theanine, a synergistic effect of the effect of inhibiting the crystallization of tranexamic acid can be obtained, and from this point, these combinations are preferred.

[0032] The content of the component (B) is not particularly limited, and in the external preparation, 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. By setting it within this range, the effect of inhibiting the crystallization of tranexamic acid is further improved.

[0033] Especially in the case of the following components or their salts, the following ranges are particularly preferred.

[0034] Arginine or its salt: 0.5 to 2% by mass

[0035] Aspartic acid: 0.125 to 1% by mass

[0036] Glutamic acid: 0.125 to 1% by mass

[0037] Glycine: 0.75 to 1.25% by mass

[0038] Proline: 1 to 2% by mass

[0039] Serine: 0.25 to 1% by mass

[0040] Threonine: 0.5 to 1% by mass

[0041] L-Theanine: 0.125 to 0.25% by mass

[0042] γ-Aminobutyric acid: 0.125 to 0.25% by mass

[0043] Pyrrolidonecarboxylic acid: 0.25 to 0.5% by mass

[0044] The mass ratio of component (A) to component (B) represented by (A):(B) is preferably 20:1 to 0.5:1, more preferably 16:1 to 1:1, and still more preferably 8:1 to 2:1. By setting it within this range, the effect of inhibiting tranexamic acid crystallization is better.

[0045] [Optional component]

[0046] In the external preparation of the present invention, components commonly used in external preparations can be appropriately formulated within the range that does not impair the effects of the present invention. As such components, for example, in addition to functional components such as whitening agents, anti-aging agents, moisturizing agents, preservatives, antibacterial agents, enzymes, plant extracts, etc., oil agents, surfactants, fragrances, pigments, pH regulators, purified water, etc. can also be cited. Each of them can be used alone in an appropriate amount or two or more of them can be used in an appropriate combination.

[0047] Among them, polyhydric alcohols are preferably formulated in the external preparation of the present invention. Polyhydric alcohols can be used alone or two or more of them can be used in an appropriate combination. As polyhydric alcohols, isopentylene glycol, 2-ethylhexanediol, octanediol, ethylene glycol, (C15-18) diol, (C20-30) diol, glycerol, diethylene glycol, diglycerol, dithiol octanediol, dipropylene glycol, thioglycerol, 1,10-decanediol, decanediol, triethylene glycol, trimethylhydroxymethylcyclohexanol, phytantriol, phenoxypropanediol, 1,2-butanediol, 2,3-butanediol, butylethylpropanediol, 1,3-butanediol, etc. such as BG, PG, 1,2-hexanediol, hexanediol, pentanediol, methylpropanediol, menthane diol, lauryl diol, etc. can be cited.

[0048] When polyhydric alcohols are formulated, their content is preferably 1.0 to 30.0% by mass, more preferably 2.0 to 30.0% by mass in the external preparation.

[0049] As the external preparation, there is no particular limitation, such as pharmaceuticals, quasi-drugs, cosmetics, etc. Among them, it is suitable for external preparations for skin and hair. The skin is the body such as the face, scalp, arms, etc., without particular limitation, but does not include the inside of the mouth. The form of the external preparation is not particularly limited and can be made into a liquid, suspension, emulsion, cream, ointment, gel, lotion, aerosol, etc. As the form expecting the effect of inhibiting tranexamic acid crystallization, liquid, lotion, etc. can be cited.

[0050] When used as an external preparation, particularly an external preparation for quasi-drugs or cosmetics, examples include: basic cosmetics such as lotion, emulsion, cream, gel, essence, sunscreen cosmetics, skin care products, facial masks, hand creams, body lotions, body creams, etc.; skin cleansers such as facial cleansers, makeup removers, body washes; scalp and hair cosmetics such as shampoos, hair conditioners, hair care products; and color cosmetics such as foundations, lip makeup, mascaras, etc.

[0051] The pH of the external preparation is not particularly limited, and is preferably 3 to 8, more preferably 5.0 to 7.0 at 25°C.

[0052] [Method for inhibiting crystallization of tranexamic acid]

[0053] The present invention provides a method for inhibiting the crystallization of tranexamic acid. In an external preparation containing one or more components selected from (A) tranexamic acid, tranexamic acid derivatives, and their salts, one or more components selected from (B) arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, their derivatives, and salts of them and their derivatives are formulated. In addition, a tranexamic acid crystallization inhibitor containing the above components (A) and (B) can also be prepared. Preferred components, formulation amounts, etc. are the same as above respectively.

[0054] Examples

[0055] Examples and comparative examples are given below to specifically illustrate the present invention, but the present invention is not limited by the following examples. It should be noted that in the following examples, unless otherwise specified, "%" of the composition represents mass %, the ratio represents mass ratio, and the amounts of each component in the table are amounts converted to pure components.

[0056] For the following components, a tranexamic acid crystallization inhibition test was carried out at the concentrations recorded in the table. The results are also recorded in the table.

[0057] [Test example: Inhibition of tranexamic acid crystallization]

[0058] (1) Test samples (pH 3 - 8)

[0059] Compositions with the following formulations were prepared.

[0060]

[0061]

[0062] (2) Test method

[0063] The above compositions were added to the following plates, 3.0 g / well, and stored at room temperature for 24 hours, and then image analysis was carried out by the method described in (3) below.

[0064] Plate

[0065] Manufactured by STEM Co., Ltd.

[0066] Material: PS (polystyrene)

[0067] Flat panel size: 128×86×20 mm

[0068] Model: 6 holes (flat bottom)

[0069] Aperture diameter × height (mm): φ33.5×16.7

[0070] (3) Image analysis

[0071] · Image analysis

[0072] Scanner: Docu Center-IV C5575 (manufactured by Fuji Xerox Co., Ltd.)

[0073] Image acquisition resolution: 300 dpi

[0074] Image analysis software: ImageJ (ver.1.50i)

[0075] Use the Oval tool to select the internal area of the circular image hole, and use Analyze / Measure to measure the Mean grayvalue (average gray value).

[0076] (4) Based on the results of the Mean gray value, the tranexamic acid crystallization inhibition effect is expressed according to the following criteria. The lower the value, the higher the tranexamic acid crystallization inhibition effect.

[0077] +++: Less than 20

[0078] ++: 20 or more and less than 40

[0079] +: 40 or more and less than 60

[0080] -: 60 or more

[0081] The following are abbreviations.

[0082] Ala: L-alanine

[0083] Arg: L-arginine

[0084] Asp: L-aspartic acid

[0085] Cys: DL-cysteine

[0086] Glu: L-glutamic acid

[0087] Gly: L-glycine

[0088] His: L-Histidine

[0089] Ile: L-Isoleucine

[0090] Pro: L-Proline

[0091] Ser: L-Serine

[0092] Thr: DL-Threonine

[0093] Tyr: L-Tyrosine

[0094] Poly-Lys: Poly-L-Lysine

[0095] Poly-PA: Sodium Polyphosphate

[0096] Theanine: L-Theanine

[0097] GABA: γ-Aminobutyric Acid

[0098] PCA: DL-Pyrrolidonecarboxylic Acid

[0099] [Table 1]

[0100]

[0101] Photos of the above tranexamic acid crystallization inhibition tests with 0.5%, 0.25%, 0.125% Asp, 0.16% phytic acid, and blank after storage at room temperature for 24 hours are shown in Figure 1 . It was confirmed that aspartic acid has a higher tranexamic acid crystallization inhibition effect than phytic acid.

[0102] [Table 2]

[0103] Sample concentration (%) Arg Asp Glu Gly Pro Ser Thr Theanine GABA PCA 2％ +++ + 1％ ++ +++ +++ + + ++ + 0.50％ + +++ +++ ++ ++ +++ 0.25％ +++ ++ + + + ++ 0.125％ ++ + + +

[0104] Based on 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 tranexamic acid crystallization inhibition effect.

[0105] [Table 3]

[0106] Sample concentration (%) Ala Cys His Ile Tyr Poly-Lys Poly-PA 1％ - - - - - - 0.5％ - - 0.25％ - -

[0107] Based on the above results, no tranexamic acid crystallization inhibition effect was confirmed in alanine, cysteine, histidine, isoleucine, tyrosine, polylysine, and sodium polyphosphate.

[0108] [Table 4]

[0109] Sample concentration (%) 0.125％ Glu (0.125%) + GABA (0.125%) + Glu (0.0625) + GABA (0.0625) +++

[0110] [Table 5]

[0111] Sample concentration (%) 0.125％ GABA (0.125%) + Theanine (0.125%) + GABA (0.0625) + Theanine (0.0625) ++

[0112] Based on the results of Table 3, by using Glu: L-glutamic acid and GABA: γ-aminobutyric acid in combination, a synergistic effect in the inhibition of tranexamic acid crystallization was confirmed.

[0113] Based on the results of Table 4, since the total amount was adjusted to 0.125%, GABA and Theanine should be "+", but are "++" in the case of additive effects. Therefore, by using GABA: γ-aminobutyric acid and Theanine: L-theanine in combination, a synergistic effect in the inhibition of tranexamic acid crystallization was confirmed.

[0114] [Examples, Comparative Examples]

[0115] The components other than purified water were mixed and dissolved in purified water for preparation to obtain a lotion having the composition shown in Table 4. It was described using the name of the cosmetic. The inhibitory effect of tranexamic acid crystallization was evaluated by the same method as above. The results were recorded in the table together.

[0116] [Table 6]

[0117]

Claims

1. Use of a component (B) for manufacturing a crystallization inhibitor of a component (A), wherein the component (A) is tranexamic acid, which is formulated in an external preparation, and the component (B) contains one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, theanine, and pyrrolidone carboxylic acid.

2. Use of a component (B) as a crystallization inhibitor of a component (A), wherein the component (A) is tranexamic acid, and the component (B) contains one or more selected from arginine, aspartic acid, glutamic acid, glycine, proline, serine, threonine, γ-aminobutyric acid, theanine, and pyrrolidone carboxylic acid.

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