JP6370094B2 - Composition for suppressing yellowing of skin - Google Patents

Description

  The present invention relates to a composition that suppresses yellowing and dullness of the skin. More specifically, the present invention relates to a composition that suppresses skin browning and skin transparency reduction caused by accumulation of AGEs (Advanced Glycation End Products) generated by Maillard reaction.

  Reducing sugars, such as glucose, have been well-known as a browning phenomenon in foods and the like since the Maillard reaction (saccharification reaction) between proteins and the production of saccharified products has long been known in vivo, Especially when diabetes or other hyperglycemic conditions continue or the degradation reaction is difficult to progress due to aging, protein saccharification occurs and the production of saccharification products tends to occur, so protein functions are impaired or glycation products accumulate. Sometimes. The saccharification product by this Maillard reaction finally becomes a terminal saccharification product (Advanced Glycation End Products; hereinafter abbreviated as AGEs). The generation of AGEs is an irreversible reaction, but the generated AGEs are excreted from the body by metabolism. However, when the metabolic rate is slowed down due to aging or the like, it is more likely to be accumulated in each tissue in the living body (see, for example, Patent Documents 1 and 2).

AGEs in the skin are present in the dermis and have been reported to cause skin elasticity and yellowing. In recent years, it has been reported that AGEs are also present in the stratum corneum. Relevance to the state has been pointed out. (For example, see Non-Patent Document 1)
From these, it can be said that it is extremely important to prevent or suppress the generation of AGEs.

  So far, it has been reported that plant extracts have been tested for the purpose of searching for AGEs production inhibitory components in the skin (see, for example, Patent Document 3).

  On the other hand, tranexamic acid, which is an antiplasmin agent, is a drug known to have 1) hemostatic action, 2) antiallergic action, and 3) anti-inflammatory action (see, for example, Non-Patent Document 2). Tranexamic acid is blended in cosmetics as an anti-inflammatory agent (see, for example, Patent Document 4), and the internal tranexamic acid-containing composition is provided as an over-the-counter drug having an effect on stains (limited to melasma). (For example, see Non-Patent Document 3).

  Further, it is also known about the effect of tranexamic acid on the Maillard reaction, and thus on the prevention or suppression of skin browning, skin transparency reduction, diabetic cataract, diabetic vascular disorder or diabetic renal dysfunction (for example, patent document) 5).

  Vanillin is known as a main component of the scent of vanilla and is used as a flavoring agent and a fragrance. Vanillin is known to have an effect of whitening the skin (see Patent Document 6). However, there are no reports on vanillin's Maillard reaction inhibitory action or AGEs inhibitory action.

  Moreover, the composition which combined tranexamic acid and vanillin is not known.

JP 2010-248148 A JP 2004-035424 A JP 2003-212749 A Japanese Unexamined Patent Publication No. 04-036215 JP 2012-193174 A JP 2000-551110 A

Fragrance Journal Vol.40 No.9 pp.57-62 2012 2009 Edition Prescription Drug Collection JAPIC 2008 Japan Pharmaceutical Collection General Medicine 2010-11 Jiho 2009

  An object of the present invention is to provide a composition that suppresses in vivo Maillard reaction that is effective and safe for internal use and external use, and to find a composition that suppresses yellowing and dullness of the skin.

  As a result of repeated researches over many years in order to solve the above problems, the present inventor has found that the Maillard reaction is remarkably suppressed by combining tranexamic acid or a salt thereof and vanillin.

  Based on the above findings, the present invention has been found to be an effective preventive or ameliorating agent for skin browning change and skin transparency reduction, such as yellowing and dullness, caused by in vivo Maillard reaction containing tranexamic acid and vanillin as active ingredients. Was completed.

That is, the present invention provides the following (1) to (4).
(1) A composition comprising tranexamic acid or a salt thereof and vanillin.
(2) A composition for inhibiting AGE production, comprising tranexamic acid or a salt thereof and vanillin.
(3) A composition for suppressing skin browning or skin transparency reduction, comprising tranexamic acid or a salt thereof and vanillin.
(4) The composition according to any one of (1) to (3), wherein the preparation is for external use or oral administration.

  The composition of the present invention suppresses Maillard reaction in vivo, can prevent or improve skin browning and skin transparency reduction, and is safe. Furthermore, since it is effective for both oral administration and external use, it is extremely useful.

It is the figure which showed the inhibitory action of the AGEs production | generation by each of a tranexamic acid and vanillin individually and combined use of tranexamic acid and vanillin.

Tranexamic acid in the present invention means [trans-4- (aminomethyl) cyclohexane-1-carboxylic acid] and is listed in the 16th revised Japanese Pharmacopoeia. As tranexamic acid, a free form or a salt of tranexamic acid may be used. Examples of “salts” of tranexamic acid include acid addition salts, alkali metal salts, alkaline earth metal salts, amine salts, and salts with amino acids.
Specific examples of the salt of tranexamic acid in the present invention include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, Inorganic acid salts such as sulfate and phosphate; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate;
Alkali metal salts such as sodium salt and potassium salt; Alkaline earth metal salts such as calcium salt and magnesium salt; N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt Organic amine salts such as pyridine salt, 4-pyrrolidinopyridine salt, picoline salt; and
And salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate. In the present invention, tranexamic acid or a salt thereof is preferably tranexamic acid.

  The vanillin in the present invention is described in the Pharmaceutical Additives Encyclopedia 2005, and it is possible to use a commercially available product, or extract it from a natural product such as vanilla beans or chemically synthesize it by a known method. It can be easily obtained.

  The composition of the present invention is used as a pharmaceutical, a quasi drug or a cosmetic. The administration route of the present invention may be either oral or transdermal.

  The dosage form of the present invention is not particularly limited, but in the case of an external preparation to be applied to the skin or the like, for example, a liquid preparation such as lotion or emulsion, a semi-solid preparation such as cream, gel or ointment, or a tape, patch, Examples include patches such as pups. In the case of an orally administered preparation, examples include tablets, capsules, granules, powders, and liquids.

When the composition of the present invention is an external preparation, the amount of tranexamic acid or a salt thereof is preferably 0.01 to 10%, more preferably 0.1 to 3%, based on the total amount of the whole preparation, 0 More preferably, it is 5 to 2%. Moreover, as a compounding quantity of vanillin, 0.001 to 10% is preferable on the basis of the total amount of the whole preparation, and 0.01 to 2% is more preferable.
When the composition of the present invention is a preparation for oral administration, the amount of tranexamic acid or a salt thereof is preferably 50 to 3000 mg, more preferably 400 to 2000 mg, and further preferably 750 to 1500 mg as the daily dose. . Moreover, as a compounding quantity of vanillin, 0.01-300 mg is preferable and 0.1-100 mg is more preferable.

  The in vivo Maillard reaction inhibitor of the present invention contains, in addition to tranexamic acid or a salt thereof and vanillin, other whitening agents, anti-inflammatory agents, antioxidants, etc., as long as the effects of the present invention are not impaired. can do. In addition, bases, fragrances, preservatives, preservatives, moisturizers, surfactants, lubricants, excipients, binders, disintegrants, pH regulators, flavoring agents, fragrances, etc. are generally acceptable as ingredients for preparations. The pharmaceutical or cosmetic additive components that have been used can be blended together.

  Preparations for using the present invention as pharmaceuticals, quasi-drugs or cosmetics are manufactured according to the methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations or commonly used methods for manufacturing cosmetics. be able to.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Formulation Example 1 (Lotion)
(A) POE (30) POP (6) Decyl tetradecyl ether (0.6 g), vanillin (0.1 g), preservative (appropriate amount), and ethanol (10.0 g) were mixed.
(B) Tranexamic acid (2.0 g), sodium citrate (0.1 g), pyrrolidone carboxylic acid (1.0 g), 1,3-butylene glycol (5.0 g) are mixed, and purified water is mixed with A. The total amount with B was 100 g.
A and B were each dissolved by heating at 50 ° C., and B was added to A with stirring. The mixture was cooled with stirring, the stirring was stopped at 30 ° C., and the mixture was allowed to stand.

Formulation Example 2 (Emulsion)
(C) Vanillin (1.0 g), Nikomulus (registered trademark) (manufactured by Nikko Chemicals Co., Ltd.) (41 2.0 g), squalane (10.0 g), and preservative (appropriate amount) were mixed.
(D) Carboxyvinyl polymer (0.1 g), xanthan gum (0.2 g), and purified water (10.0 g) were mixed.
(E) Tranexamic acid (15.0 g), triethanolamine (0.1 g), 1,3-butylene glycol (5.0 g), and purified water (4.9 g) were mixed.
(F) Sodium hyaluronate (2.0 g) and purified water (3.0 g) were mixed, and the total amount of C to F was adjusted to 100 g with purified water.
C to F were each heated at 80 ° C. and mixed uniformly. While stirring C, D and E were added. The mixture was cooled with stirring, F was added at 50 ° C. or lower, stirring was stopped at 35-30 ° C., and the mixture was allowed to stand.

Formulation Example 3 (Liquid)
Tranexamic acid (15 g), vanillin (1.0 g), fructose-glucose liquid sugar (100 g), and a pH adjuster (appropriate amount) were mixed to prepare a liquid agent having a total amount of 1000 g with purified water.

Formulation Example 4 (tablet)
Tranexamic acid (15 g), vanillin (5.0 g), lactose (350 g) and crystalline cellulose (100 g) were added and mixed, and an aqueous hydroxypropylcellulose solution was sprayed as a binder to prepare granulated granules. A granulated granule (49.5 g) was mixed with magnesium stearate (0.5 g) and tableted to prepare a plain tablet.

Formulation Example 5 (Powder)
Tranexamic acid (15 g), vanillin (0.25 g), lactose (350 g), and crystalline cellulose (100 g) were added and mixed, and a hydroxypropylcellulose aqueous solution was sprayed as a binder to prepare a powder.

Test Example 1 (Fluorescent AGEs production inhibitory activity)
(Preparation of sample solution)
Tranexamic acid (Daiichi Fine Chemical Co., Ltd.) and vanillin (Wako Pure Chemical Industries, Ltd.) were diluted with 1/15 M phosphate buffer (pH 7.2), and each sample was 0.1 mg / mL (final concentration). It was set as the solution.

(Preparation of albumin solution)
Human serum albumin (manufactured by Sigma-Aldrich) was dissolved in 1/15 M phosphate buffer (pH 7.2) to prepare a 24 mg / mL albumin solution.

(Preparation of glucose solution)
Glucose (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 1/15 M phosphate buffer (pH 7.2) to prepare a 0.6 M glucose solution.

(Preparation of test solution, excitation light irradiation and fluorescence measurement)
In a 1.5 mL tube, a sample solution group of 150 μL, a glucose solution of 150 μL, and an albumin solution of 150 μL were mixed and held at 60 ° C. for 40 hours to prepare a test solution.
The test solution was irradiated with 370 nm excitation light, and the resulting fluorescence at 440 nm was measured. The result obtained by this measurement is defined as a measurement value A.

(Blank preparation, excitation light irradiation and fluorescence measurement)
The test solution blank was prepared as follows. In a 1.5 mL tube, a sample solution group of 150 μL and a glucose solution of 150 μL were mixed and held at 60 ° C. for 40 hours, and then an albumin solution of 150 μL was mixed. Then, the test solution was irradiated with excitation light of 370 nm, and the resulting fluorescence of 440 nm was measured. The result obtained by this measurement is defined as a measurement value B.
The amount of fluorescent AGEs produced was calculated as the amount of fluorescence obtained by the following formula (1).

(Test results)
The test results are shown as a ratio with the amount of AGEs produced when the concentration of tranexamic acid and vanillin is 0 being 100 (control).
(Fig. 1) shows that the combined use of tranexamic acid and vanillin suppresses the amount of AGEs produced and, consequently, suppresses the Maillard reaction of the living body as compared with the case where each drug is used alone. It was. From the above results, it was found that a composition using both tranexamic acid and vanillin is suitable as an in vivo Maillard reaction inhibitor.

  The composition of the present invention is extremely useful because it can prevent or improve skin browning and skin transparency reduction, and is safe and effective for oral administration and external use. Furthermore, it may be a preparation for oral administration or an external preparation, and can be used as a pharmaceutical, a quasi-drug or a cosmetic.

Claims (4)

A composition applied to the skin, comprising tranexamic acid or a salt thereof and vanillin.   The composition for AGEs production | generation suppression containing a tranexamic acid or its salt, and vanillin.   A composition for suppressing skin browning or skin transparency reduction, comprising tranexamic acid or a salt thereof and vanillin. The composition according to any one of claims 2 to 3, wherein the preparation is for external use or oral administration.