JP6283054B2 - In vivo Maillard reaction inhibitor or AGEs production inhibitor - Google Patents

Description

  The present invention relates to a composition that suppresses the Maillard reaction that occurs in a living body, or a composition that suppresses the generation and accumulation of Advanced Glycation End Products (AGEs). In particular, the present invention relates to an internal preparation or an external preparation composition for suppressing or improving skin browning, skin transparency reduction, diabetic cataract, vascular disorder or renal dysfunction.

  Reducing sugars such as glucose undergo a saccharification reaction (Maillard reaction) with proteins or amino acids, and the production of saccharified products has long been well known as a browning phenomenon in foods and the like. Even in the living body, especially when hyperglycemia continues due to diabetes, etc., or when the degradation reaction is difficult to progress due to aging, the glycation reaction of protein or amino acid occurs, and the production of glycation products tends to occur. Saccharification products may accumulate.

  The saccharification product by this Maillard reaction finally becomes an advanced glycation end product (hereinafter sometimes 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 accumulate in each tissue in the living body (see, for example, Patent Documents 1 and 2).

  When AGEs accumulate in each tissue in the living body or bind to its receptor, various symptoms are caused. For example, skin contributes to browning of the skin and skin dullness, and in a hyperglycemic state, cataracts, vascular disorders, and renal dysfunction are the cause. Therefore, it is extremely important to prevent or suppress the generation of AGEs (see, for example, Patent Documents 1 and 2).

  So far, various natural ingredients have been searched for as safe substances that suppress the Maillard reaction of food (see, for example, “Prior Art” in Patent Document 2). In addition, various plant extract components have been searched for as components for inhibiting the generation of AGEs in the skin (see, for example, Patent Document 3).

  On the other hand, diisopropylamine dichloroacetate (hereinafter sometimes abbreviated as DADA) is an anti-skin aging effect by a skin tissue activating action (see Patent Document 4) and a liver function improving action (for example, Non-Patent Document 1). And an anti-fatigue action (see Patent Document 5). Furthermore, DADA is blended in commercially available cosmetics as a skin blood circulation promoter or cell activator (see, for example, Patent Document 6), and has been provided as a pharmaceutical product having the effect of improving liver function in chronic liver disease ( For example, refer nonpatent literature 2).

  In addition, tranexamic acid, which is an antiplasmin agent, is a pharmaceutical known to have 1) anti-bleeding action, 2) anti-allergic action, 3) anti-inflammatory action, and the like (see, for example, Non-Patent Document 2). Furthermore, tranexamic acid is also incorporated into cosmetics as an anti-inflammatory agent (see, for example, Patent Document 7), and the internal tranexamic acid-containing composition is provided as an over-the-counter medicine having an effect on stains (limited to melasma). (See, for example, Non-Patent Document 3).

  However, neither DADA nor tranexamic acid has known or suggested the Maillard reaction inhibitory action, and therefore the prevention or suppression action of skin browning, skin transparency reduction, diabetic cataract, diabetic vascular disorder or diabetic renal dysfunction Absent. In addition, there is no literature reported on the combination of DADA and tranexamic acid.

JP2010-248148 JP 2004-035424 A JP2003-212749 JP 53-136528 A JP 2010-138170 A JP 61-56114 A JP 04-36215 A

Chisato Hirayama et al .: Hepatobiliary pancreas Vol.6 No.4 1983 p.637-645 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 an in-vivo Maillard reaction inhibitor composition or an AGEs production inhibitor that is safe whether it is used internally or externally.

  As a result of repeated researches over many years in order to solve the above-mentioned problems, the present inventors combined the use of DADA and tranexamic acid to suppress the in vivo Maillard reaction and, as a result, the generation of AGEs. I found out.

  Based on the above findings, the composition containing DADA and tranexamic acid is diabetic cataract, which is a skin browning change, skin transparency reduction, and hyperglycemia caused by in vivo Maillard reaction or AGEs generation and accumulation, The present invention has been completed by finding that it is an effective preventive or ameliorating agent for vascular disorders or renal dysfunction.

That is, the present invention
(1) A pharmaceutical or cosmetic composition characterized by containing tranexamic acid and dichloroacetic acid diisopropylamine,
(2) An in-vivo Maillard reaction inhibitor composition comprising tranexamic acid and dichloroacetic acid diisopropylamine,
(3) A composition for inhibiting the formation of advanced glycation end products, comprising tranexamic acid and diisopropylamine dichloroacetate,
(4) A skin browning change or skin transparency lowering inhibitor composition comprising tranexamic acid and dichloroacetic acid diisopropylamine,
(5) A composition for preventing or treating a disorder caused by hyperglycemia, comprising tranexamic acid and diisopropylamine dichloroacetate,
(6) The preventive or therapeutic agent composition according to claim 5, wherein the disorder due to hyperglycemia is diabetic cataract, vascular disorder or renal dysfunction, or
(7) The composition according to any one of (1) to (5), wherein the route of administration is external or internal use.

  In vivo Maillard reaction or advanced glycation end products (AGEs) inhibitors of the present invention prevent or improve skin browning, skin transparency, diabetic cataract, diabetic vascular disorder or renal dysfunction It is useful because it is extremely safe and effective for oral administration and external use.

It shows the AGEs production inhibitory effect in tranexamic acid, DADA, and combinations thereof.

  Diisopropylamine dichloroacetate (DADA) in the present invention is listed in the Japanese Pharmacopoeia Standard 2002, and tranexamic acid is listed in the 15th revised Japanese Pharmacopoeia, so both are readily available.

  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 administration form.

  The dosage form of the present invention is not particularly limited. In the case of an external preparation applied to the skin, for example, a liquid preparation such as lotion and emulsion, a semi-solid preparation such as cream, gel or ointment, or a tape, patch or patch. And the like. Moreover, in the case of oral administration, a tablet, a capsule, a liquid agent etc. are mentioned, for example.

  When the composition of the present invention is an internal preparation, the dose of DADA and tranexamic acid is preferably 0.1 to 2000 mg, more preferably 1 to 1000 mg per day, Take in divided doses.

  Moreover, when the composition of this invention is an external preparation, as compounding quantity of DADA and tranexamic acid, all are suitably 0.01-50 w / v% on the basis of the total amount of the whole preparation, More preferably, it is 0.8. 1 to 20 w / v%, and apply them in 1 to 3 times.

  In vivo Maillard reaction inhibitor or advanced glycation end products (AGEs) production inhibitor of the present invention is not limited to DADA and tranexamic acid, as long as the effects of the present invention are not impaired. Whitening agents, anti-inflammatory agents, antioxidants, and various antidiabetic agents can be added. In addition, bases, fragrances, preservatives, preservatives, moisturizers, surfactants, lubricants, excipients, pH regulators, flavoring agents, fragrances, etc., which are generally accepted as pharmaceutical ingredients, are used as pharmaceutical ingredients. Additive components 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 15th revised Japanese Pharmacopoeia General Rules for Preparations and 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) DADA 10 g, tranexamic acid 15 g, sodium citrate 0.1 g, pyrrolidone carboxylic acid 1 g, 1,3-butylene glycol 5 g were mixed, and the total amount was adjusted to 100 g with purified water.
(B) POE (30) POP (6) Decyltetradecyl 0.6 g, an appropriate amount of preservative, and 10 g of ethanol were mixed.
(A) and (B) were dissolved by heating at 50 ° C., and (B) was solubilized with stirring in (A). The mixture was cooled with stirring, the stirring was stopped at 30 ° C., and the mixture was left standing.

<Formulation example 2> Emulsion (A) DADA 10 g, tranexamic acid 15 g, Nicolulus 41 2 g, squalane 10 g, and preservative appropriate amount were mixed, and the total amount was adjusted to 100 g with purified water.
(B) 0.1 g of carboxyvinyl polymer, 0.2 g of xanthan gum and 10 g of purified water were mixed.
(C) Triethanolamine 0.1 g, 1,3-butylene glycol 5 g, and purified water 4.9 g were mixed.
(D) 2 g of sodium hyaluronate and 3 g of purified water were mixed.
(A) was heated at 80 ° C. and mixed uniformly. (B) to (D) were dissolved at room temperature. (B) and (C) were added while stirring (A). The mixture was cooled with stirring, (D) was added at 50 ° C. or lower, and stirring was stopped at 35 to 30 ° C. and left standing.

<Formulation Example 3> Liquid agent DDA 25 g, tranexamic acid 15 g, fructose glucose liquid sugar 100 g, and a pH adjuster appropriate amount were mixed, and a total amount of 1000 g liquid was prepared with purified water.

<Formulation Example 4> Tablets DADA 25 g, tranexamic acid 15 g, lactose 350 g, and appropriate amounts of crystalline cellulose were added and mixed, and hydroxypropylcellulose was sprayed as a binder to prepare granulated granules. A granulated granule (49.5 g) was mixed with 0.5 g of magnesium stearate and tableted to prepare a bare tablet.

<Formulation Example 5> Powder A 25 mg DADA, 15 g tranexamic acid, 350 g lactose, and appropriate amounts of crystalline cellulose were added and mixed, and hydroxypropylcellulose was sprayed as a binder to prepare a powder.

<Test Example 1> Fluorescence AGEs production inhibitory activity test (test drug)
Both DADA and tranexamic acid were manufactured by Daiichi Sankyo.

(Preparation of sample solution)
A mixture of DADA and tranexamic acid was diluted with a 1/15 M phosphate buffer (pH 7.2) so that each component had a predetermined concentration to obtain a sample solution.

(Preparation of albumin solution)
Human serum albumin (manufactured by Sigma-Aldrich) was prepared to be 24 mg / mL using 1/15 M phosphate buffer (pH 7.2).

(Preparation of glucose solution)
Glucose (manufactured by Wako Pure Chemical Industries, Ltd.) was prepared using a 1/15 M phosphate buffer (pH 7.2) so as to have a concentration of 0.6M.

(Preparation of test solution)
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 obtain a test solution. Next, 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.

(Preparation of blank)
The test solution blank was prepared as follows. A sample solution group of 150 μL and a glucose solution of 150 μL were mixed in a 1.5 mL tube and held at 60 ° C. for 40 hours. 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 B.
The amount of fluorescent ADEs produced was calculated as the amount of fluorescence obtained by the following formula.
AGE generation amount (fluorescence amount) = measured value A−measured value B

(Test results)
FIG. 1 shows the results of AGEs in the combination of DADA (10 mg / mL) and tranexamic acid (0.1 mg / mL) versus AGEs in the test drug-free (control). Each value is an average value of N = 6. In both cases, it was found that when DADA and tranexamic acid, which are not known to inhibit AGEs production, are used in combination, a remarkable AGEs production inhibitory effect appears as shown in FIG.

  The composition of the present invention can prevent or ameliorate skin browning, decreased skin transparency, diabetic cataract, diabetic vascular disorder or renal dysfunction, and is safe and effective for oral administration and external use. Therefore, it is extremely useful. Furthermore, it may be orally administered or applied externally, and can be used as a pharmaceutical, a quasi-drug or a cosmetic.

Claims (3)

An in-vivo Maillard reaction inhibitor composition comprising tranexamic acid and dichloroacetic acid diisopropylamine. A composition for inhibiting formation of advanced glycation end products, comprising tranexamic acid and diisopropylamine dichloroacetate. The composition according to any one of claims 1 to 2, wherein the administration route is external or internal use.