JP6027752B2 - AGEs production inhibitor - Google Patents

Description

  The present invention relates to a production and accumulation inhibitor of advanced glycation end products (AGEs). It is related with the internal use or external preparation composition which suppresses or improves especially the fall of the transparency of the skin by skin browning.

  Reducing sugars, such as glucose, have been well known as a browning phenomenon in foods for a long time, because a saccharification reaction (Maillard reaction) occurs between proteins and glycation products are produced. 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. This saccharification product finally becomes a terminal saccharification product (hereinafter also abbreviated as AGEs). The generation of AGEs is an irreversible reaction, but the generated AGEs are excreted out of 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).

  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 can be said that preventing or suppressing the generation of AGEs is extremely important (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 a skin aging preventive effect (see Patent Document 4) due to a skin tissue activating action, or a liver function improving action (for example, Non-Patent Document 1). And an anti-fatigue action (see Patent Document 5).

  So far, DADA has been blended in commercial cosmetics as a skin blood circulation promoter or cell activator (see, for example, Patent Document 6), and DADA is a drug having the effect of improving liver function in chronic liver disease. (See, for example, Non-Patent Document 2).

  However, the Maillard reaction inhibitory action, and hence the skin browning change, skin transparency reduction, diabetic cataract, diabetic vascular disorder or diabetic renal dysfunction is not known or suggested.

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

Chisato Hirayama et al .: Hepatobiliary pancreas Vol.6 No.4 1983 p.637-645 2009 Edition Prescription Drug Collection JAPIC 2008

  An object of the present invention is to provide an AGEs production inhibitor that is effective and safe for internal use and external use.

  As a result of many years of research to solve the above problems, the present inventor has found that the generation of AGEs is suppressed by DADA.

  Based on the above findings, skin browning caused by the generation and accumulation of AGEs containing DADA as an active ingredient, reduced skin transparency, and effective diabetic cataract, vascular disorder or renal dysfunction due to hyperglycemia It discovered that it became a prevention or improvement agent, and completed this invention.

That is, the present invention
(1) Advanced glycation end products production inhibitor composition comprising dichloroacetic acid diisopropylamine as an active ingredient,
(2) A skin browning change or skin transparency lowering inhibitor composition comprising dichloroacetic acid diisopropylamine as an active ingredient,
(3) A composition for preventing or treating hyperglycemia-related disorders, comprising diisopropylamine dichloroacetate as an active ingredient as an active ingredient,
(4) The preventive or therapeutic agent composition according to (3) above, wherein the disorder due to hyperglycemia is diabetic cataract, vascular disorder or renal dysfunction, or (5) It is a composition as described in 1)-(4).

  The inhibitor of production of advanced glycation end products (AGEs) of the present invention can prevent or ameliorate skin browning, decreased skin transparency, diabetic cataract, diabetic vascular disorder or renal dysfunction, In addition, it is very useful because it is safe and effective for oral administration and external use.

The AGE generation in Example 1 is shown by the amount of fluorescence. It is a graph which shows the dose-dependent AGEs production inhibitory effect by DADA.

  Diisopropylamine dichloroacetate (hereinafter, sometimes simply referred to as DADA) in the present invention is listed in the Japanese Pharmacopoeia Standard 2002 and 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 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 external preparation, the amount of DADA is preferably 0.01 to 1000 mg / ml, more preferably 0.01 to 100 mg / ml, based on the total amount of the whole preparation. When the composition of the present invention is an internal preparation, the amount of DADA is preferably 0.01 to 1000 mg / ml, more preferably 0.01 to 100 mg / ml, based on the total amount of the whole preparation.

  The inhibitor of advanced glycation end products production of the present invention is not limited to DADA, as long as it does not impair the effects of the present invention, whitening agents, anti-inflammatory agents, antioxidants, various diabetes A therapeutic agent can be formulated. 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 10.0 g sodium citrate 0.1 g, pyrrolidone carboxylic acid 1. 0 g and 5.0 g of 1,3-butylene glycol were mixed, and the total amount was adjusted to 100 g with purified water.

(B) POE (30) POP (6) decyltetradecyl 0.6g, preservative appropriate amount, ethanol 10.0g was mixed.
A and B were dissolved by heating at 50 ° C., and B was solubilized in A while 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) DADA 10.0g, Nicolulus 41 2.0g, squalane 10.0g, preservative appropriate quantity was mixed, and the whole quantity was made into 100g with purified water.

(D) Carboxyvinyl polymer 0.1 g, xanthan gum 0.2 g, purified water 10. 0 g was mixed.

(E) Triethanolamine 0.1 g, 1,3-butylene glycol 5.0 g, and purified water 4.9 were mixed.
(F) 2.0 g of sodium hyaluronate and 3.0 of purified water were mixed.
C was heated at 80 ° C. and mixed uniformly. D to F were dissolved at room temperature. 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 left standing.

(Formulation Example 3) Solution
25 g of DADA, 100 g of fructose-glucose liquid sugar, and an appropriate amount of a pH adjusting agent were mixed, and a total amount of 1000 g of liquid was prepared with purified water.

(Formulation Example 4) Tablet
25 g of DADA, 350 g of lactose 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
DADA 25g, lactose 350g, and a suitable amount of crystalline cellulose were added and mixed, and hydroxypropylcellulose was sprayed as a binder to prepare a powder.

Example 1 (Fluorescent AGEs production inhibitory activity)
(Preparation of sample solution)
DADA was diluted with 1 / 15M phosphate buffer (pH 7.2) so that the concentration of DADA would be 3 mg / mL, 30 mg / mL, and 300 mg / mL. .

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

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

(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. 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)
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. 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 designated as measurement value B.
The amount of fluorescent AGEs 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 that DADA suppresses the production of AGEs in a dose-dependent manner.

  From the above results, it was found that DADA is suitable as an AGEs production inhibitor.

  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 used orally or externally and can be used as a pharmaceutical, a quasi-drug or a cosmetic.

Claims (1)

An external or internal skin browning inhibitor that contains diisopropylamine dichloroacetate as an active ingredient (excluding a skin browning inhibitor related to melanin) .