JP2008239545A - Elastase deactivator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel elastase deactivator which is good in safety. <P>SOLUTION: This elastase deactivator contains at least a kind of matter selected from the group consisting of coffeic acid and its pharmaceutically acceptable salt as an effective component. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a novel elastase activity inhibitor.

Overexpression of elastase due to aging or ultraviolet rays promotes the degradation of elastin, which is involved in skin flexibility and elasticity, reduces skin elasticity, and causes sensation such as sagging and wrinkles Yes. In recent years, it has been suggested that elastase is involved not only in the aging phenomenon as described above, but also in immune cell migration, hair follicle formation and growth in an inflammatory reaction. Therefore, an agent that can suppress the activity of elastase has attracted attention.
In addition, due to the growing interest in safety, elastase activity inhibitors derived from natural materials such as plants have been required. Several types of agents are known as elastase activity inhibitors derived from natural materials (patents) Literatures 1-3).
JP-A-11-246386 JP 2000-53578 A Japanese Patent No. 2969451

  An object of the present invention is to provide a novel elastase activity inhibitor having good safety.

As a result of intensive investigations on various components contained in plant extracts, the present inventors have found that caffeic acid, which is a component of extracts such as cacao, has a high elastase activity inhibitory effect. Based on this, the present invention has been completed.
That is, the present invention provides an elastase activity inhibitor containing, as an active ingredient, at least one selected from caffeic acid and pharmaceutically acceptable salts thereof in order to solve the above problems.
In another aspect, the present invention provides a method for inhibiting the activity of elastase by supplying at least one selected from caffeic acid and a pharmaceutically acceptable salt thereof (except for a human therapeutic method). A method for producing an elastase activity inhibitor comprising adding at least one selected from caffeic acid and a pharmaceutically acceptable salt thereof; and a plant extract containing at least caffeic acid and caffeine and / or theophylline. And a method for producing an elastase activity inhibitor comprising a treatment for increasing the content of caffeic acid.

  According to the present invention, a novel elastase activity inhibitor with good safety can be provided.

Hereinafter, the present invention will be described in detail. In the present specification, “to” means a range including numerical values before and after.
The present invention relates to an elastase activity inhibitor containing as an active ingredient at least one selected from caffeic acid and pharmaceutically acceptable salts thereof. Caffeic acid is another name for 3,4-dihydroxycinnamic acid represented by the following formula.

  In the present invention, a salt of caffeic acid may be used. By making it into a salt, water solubility can be improved, blending can be facilitated, and the effect can be increased. The salt of caffeic acid used in the present invention is a pharmacologically acceptable salt. Examples of counter cations that form such a salt include cations of alkali metals such as lithium, sodium, and potassium; magnesium, And alkaline earth metal cations such as calcium; ammonium; cations of amino acids such as arginine, lysine, histidine, and ornithine; and cations of organic bases such as mono, di, and triethanolamine.

  The caffeic acid used in the present invention may be a component derived from a natural product such as a plant, that is, obtained by extraction, or may be obtained entirely or partially by chemical synthesis. Moreover, you may use what is marketed as a reagent. In applications where safety is important, such as being supplied to humans and animals, it is preferable to use caffeic acid derived from natural products. Caffeic acid is known to be contained as a component of various plants such as cassava, coffea, somato tomato, carrot, ginger turmeric, lily onion, garlic, lame chamomile, lacquer ginseng. Yes.

  The extraction can be carried out by immersing all or part of the plant in a solvent at a low temperature or under heating for a predetermined time. The extraction solvent is not particularly limited, but water or lower monohydric alcohols such as methyl alcohol and ethyl alcohol; liquid polyhydric alcohols such as glycerin, propylene glycol and 1,3-butylene glycol; ketones such as acetone; ethyl ether and the like 1 type or 2 types or more of organic solvents, such as these ethers; or esters, such as ethyl acetate; and the mixed solvent of these and water can be used. Of these, ethyl alcohol is preferred. Moreover, you may give the extraction process etc., after giving the appropriate processes, such as drying, shredding, pressing, or fermentation, if desired to the whole or one part of the said plant.

  The elastase activity inhibitor of the present invention may contain components other than caffeic acid as long as the effects of the present invention are not impaired. Since the plant extract is generally a mixture of various components, it may contain other components extracted together with caffeic acid. For example, a cocoa extract or coffee bean extract containing caffeic acid contains caffeine and / or theophylline together with caffeic acid, and therefore may contain these other extraction components. However, it is preferable not to use the cacao extract and the coffee bean extract as they are, but to treat the caffeic acid content to increase or decrease the elastase activity-suppressing ability. For example, a plant extract is separated into various fractions having different adsorptivity to the solid phase by liquid chromatography, and a fraction having a high content of caffeic acid is used, or heat concentration, vacuum concentration, freeze concentration, etc. It is preferable to increase the content of caffeic acid by a concentration method.

The elastase activity inhibitor of the present invention can be used for various applications. Since the elastase activity inhibitor of the present invention has high safety and is excellent in stability at the time of blending, it is preferably used as an active ingredient of a skin external preparation such as cosmetics. The external preparation for skin containing the elastase activity inhibitor of the present invention suppresses the activity of elastase when applied to the skin. As a result, excessive degradation of elastin does not occur, skin flexibility and elasticity are maintained, and aging phenomena such as sagging and wrinkles are improved. That is, it has excellent effects as an anti-aging cosmetic and a wrinkle / sag improving cosmetic.
Moreover, since elastase may be involved in the migration of immune cells in an inflammatory reaction, the external preparation for skin containing the elastase activity inhibitor of the present invention is also useful as an external preparation for suppressing inflammation.
Furthermore, since elastase may be involved in hair follicle formation, the external preparation for skin containing the elastase activity inhibitor of the present invention is also useful as an external preparation for skin that controls hair growth and hair growth.

  The blending amount of the elastase activity inhibitor of the present invention in the external preparation for skin is not particularly limited, but in general, it is preferably 0.00005 to 1.5% by mass (hereinafter simply referred to as “ % ”), More preferably 0.0005 to 1%. Within this range, the elastase activity inhibitor of the present invention can be blended stably, and a high anti-aging effect and sagging / wrinkle improving effect can be exhibited.

  In addition, the above-mentioned external preparation for skin contains other active ingredients as long as they do not impair the effects of the present invention, for example, other active ingredients that exhibit a whitening effect, an anti-aging effect, or a wrinkle formation suppressing effect by exposure to ultraviolet rays. May be. More specifically, examples include, but are not limited to, UV protection agents, antibacterial agents, whitening agents, anti-inflammatory agents, cell activators, active oxygen scavengers, and moisturizers.

  Examples of the UV protection agent include paramethoxycinnamate-2-ethylhexyl, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5 sodium sulfate, 4-t-butyl-4′- Examples thereof include methoxydibenzoylmethane, 2-phenyl-benzimidazole-5-sulfuric acid, titanium oxide, and zinc oxide.

  Examples of the antibacterial agent include benzoic acid, sodium benzoate, p-hydroxybenzoate ester, benzalkonium chloride, phenoxyethanol, isopropylmethylphenol, and the like.

  Whitening agents have the effect of preventing the occurrence of darkening of the skin caused by sunburn, etc., stains caused by pigmentation, buckwheat, etc., such as arbutin, ellagic acid, linoleic acid, vitamin C and its derivatives, vitamin E And derivatives thereof, glycyrrhizic acid and derivatives thereof, tranexamic acid, placenta extract, chamomile extract, licorice extract, ages extract, seaweed extract, sea cucumber extract, cucumber extract, gokahi extract, rice bran extract Extract, Wheat germ extract, Saisin extract, Hawthorn extract, Sunpens extract, Shirayuri extract, Peonies extract, Sempukuka extract, Soy extract, Tea extract, Molasses extract, Byaclen extract, Grape extract Product, hop extract, micaika extract, mokka extract, yukinoshita extract and the like.

  Anti-inflammatory agents have the effect of suppressing inflammation such as hot flashes and erythema after sunburn. For example, sulfur and its derivatives, glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, Altea extract, Ashitaba extract , Arnica extract, Ginseng extract, nettle extract, Duckweed extract, Hypericum extract, Chamomile extract, Snapdragon extract, Watercress extract, Comfrey extract, Salvia extract, Bamboo extract, Perilla extract , Birch extract, gentian extract and the like.

  Cell activators are used for the purpose of improving rough skin, such as caffeine, chicken crown extract, shell extract, shell extract, royal jelly, silk protein and its degradation products or derivatives thereof, lactoferrin or degradation products thereof. , Mucopolysaccharides such as chondroitin sulfate and hyaluronic acid or their salts, collagen, yeast extract, lactic acid bacteria extract, bifidobacteria extract, fermentation metabolic extract, ginkgo biloba extract, barley extract, assembly extract, lysium extract Products, carrot extract, rosemary extract, glycolic acid, citric acid, lactic acid, malic acid, tartaric acid, succinic acid and the like.

  The active oxygen scavenger has an action such as suppression of lipid peroxide production. For example, superoxide dismutase, mannitol, quercetin, catechin and derivatives thereof, rutin and derivatives thereof, button pi extract, yashajitsu extract, melissa extract , Lanahan fruit extract, retinol and its derivatives, vitamin A such as carotenoid, thiamine and its derivative, riboflavin and its derivative, pyridoxine and its derivative, vitamin B such as nicotinic acid and its derivative, tocopherol and its derivative, etc. Vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, etc. are mentioned.

  Examples of the humectant include proteins such as elastin and keratin or derivatives thereof, hydrolysates and salts thereof, amino acids such as glycine, serine, aspartic acid, glutamic acid, arginine and theanine and derivatives thereof, sorbitol, erythritol, Trehalose, inositol, glucose, sucrose and derivatives thereof, dextrin and derivatives thereof, saccharides such as honey, D-panthenol and derivatives thereof, urea, phospholipid, ceramide, auren extract, ginger extract, diautum extract, sensyu extract Product, mallow extract, gypsophila extract, dokudami extract, hamamelis extract, bodaige extract, maronier extract, quince extract and the like.

  In addition, in the above-mentioned skin external preparation, components that are usually used in the production of cosmetics, quasi-drugs, skin external preparations and the like, for example, water (purified water, hot spring water, Deep water etc.), oil agent, surfactant, metal soap, gelling agent, powder, alcohol, water-soluble polymer, film forming agent, resin, inclusion compound, antibacterial agent, fragrance, deodorant, salt, pH adjuster, freshener, plant / animal / microbe extract, active oxygen remover, blood circulation promoter, astringent, antiseborrheic agent, moisturizer, chelating agent, keratolytic agent, enzyme, hormones, etc. Vitamins and the like can be added as necessary.

  The external preparation for skin includes powders such as powders and powder foundations; solids such as soaps and lipsticks; emulsions such as creams, emulsions and cream foundations; liquids such as skin lotions and cosmetic liquids; Preferably, the composition is a material composition. Further, it may be a shampoo, a treatment, or a skin external preparation for scalp, but is not limited thereto.

  Moreover, it is also preferable to mix | blend the elastase activity inhibitor of this invention with foodstuffs (a drink is included). Although it does not restrict | limit especially as said foodstuff, Specifically, a salmon, chewing gum, a drink etc. are mentioned, for example.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples.
[Example 1: Elastase activity inhibition test]
As a sample solution, a 1% solution of caffeic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) (ethyl alcohol / water = 1/1 (V / V)) was prepared.
The elastase activity inhibition test was performed using an elastase enzyme solution derived from porcine pancreas and N-Succinyl-Ala-Ala-Ala-p-nitroanilide as substrates. Specifically, it was performed as follows.
The enzyme solution was adjusted to a concentration of 0.05 units / mL.
The substrate solution was prepared by dissolving the substrate in dimethyl sulfoxide (DMSO) to obtain a 0.1 mol / L concentration solution, and then diluting with a 0.05 mol / L Tris-HCL (pH 8.8) buffer solution to obtain 1 mmol. / L concentration solution was prepared.
After mixing 100 μL of the substrate solution and 50 μL of the 1% sample solution, 50 μL of the enzyme solution was added and reacted at 37 ° C. for 30 minutes. Thereafter, the absorbance at a wavelength of 405 nm was measured with a spectrophotometer, the amount of produced nitroaniline was determined, and the elastase activity inhibition rate was calculated. The elastase activity inhibition rate was calculated by the following formula.
Elastase activity inhibition rate = {1- (AB) / (CD)} × 100
A: Absorbance at a wavelength of 405 nm of the mixed solution when the enzyme solution is added after mixing the substrate solution and the sample solution B: Absorbance at a wavelength of 405 nm of the mixed solution when the substrate solution and the sample solution are mixed C: Sample Instead of the solution, after the solvent of the solution is mixed with the substrate solution in the above ratio, the absorbance at a wavelength of 405 nm of the mixture solution when the enzyme solution is added. D: The sample solution and the enzyme solution are not added. Absorbance at a wavelength of 405 nm

In addition, dimethylsulfone (1% aqueous solution) and amla extract (1% solution (ethyl alcohol / water = 1/1 (V / V))), which are known to inhibit elastase activity, are the same tests as above. The elastase activity inhibition rate was calculated. The results are shown in FIG. 1 together with the results for caffeic acid.
From the results shown in the graph of FIG. 1, it can be understood that the elastase activity inhibitor of the present invention exhibited a higher effect than dimethylsulfone and amla extract, which are known elastase activity inhibitors. Therefore, by using the elastase activity inhibitor of the present invention, a higher elastase activity suppressing action can be obtained. In addition, since the same or higher effect can be obtained even when the blending amount is reduced than before, the selection range of the blending composition is widened, and the use of the elastase activity inhibitor of the present invention is advantageous in terms of preparation.

Further, caffeine and theophylline contained in the cacao extract and coffee bean extract together with caffeic acid were subjected to the same test as above to calculate the elastase activity inhibition rate. The results are shown in FIG. 2 together with the results for caffeic acid.
From the results shown in the graph of FIG. 2, it can be understood that caffeine and theophylline have no elastase activity inhibitory action. Therefore, for plant extracts containing caffeine and theophylline together with caffeic acid such as cacao extract and coffee bean extract, elastase activity suppression ability can be achieved by performing a treatment to increase the content of caffeic acid in the extract. Expression or improvement.

[Example 1: Face wash]
A face wash was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (7) are dissolved by heating.
B. The following components (8) to (11) are dissolved by heating.
C. Add B to A and mix.
D. After cooling C, the following components (12) to (14) are added and mixed to obtain a face wash.

(Ingredient) (mass%)
(1) Lauric acid 5.0
(2) Myristic acid 18.5
(3) Stearic acid 6.0
(4) Glycerin 12.0
(5) Polyethylene glycol 1500 5.0
(6) Potassium hydroxide 6.5
(7) Purified water remaining amount (8) Palm oil fatty acid diethanolamide 5.0
(9) Palm oil fatty acid methyl taurine sodium 1.8
(10) Polyoxyethylene (7.5E.O.) lauryl ether 2.0
(11) Ethylene glycol distearate 1.0
(12) Hydroxypropyl methylcellulose 1% aqueous solution 5.0
(13) Caffeic acid * 1 0.1
(14) Perfume appropriate amount * 1 Tokyo Chemical Industry Co., Ltd.

[Example 2: lotion]
A lotion was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (6) are mixed and dissolved.
B. The following components (7) to (12) are mixed and dissolved.
C. B was added to A and mixed to obtain a skin lotion.

(Ingredient) (mass%)
(1) Citric acid 0.05
(2) Sodium citrate 0.2
(3) Sodium pyrrolidonecarboxylate (50%) aqueous solution 0.5
(4) Dipotassium glycyrrhizinate 0.1
(5) Glycerin 3.0
(6) 1,3-butylene glycol 8.0
(7) Purified water remaining amount (8) Ethyl alcohol 10.0
(9) Caffeic acid * 1 0.1
(10) Perfume Appropriate amount (11) Preservative Appropriate amount (12) Polyoxyethylene monooleate (20E.O.)
Sorbitan 0.5
* 1: Tokyo Chemical Industry Co., Ltd.

[Example 3: Latex]
An emulsion was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (13) are dissolved by heating and maintained at 70 ° C.
B. The following components (14) to (18) are dissolved by heating and maintained at 70 ° C.
C. B is added to A to emulsify, and the following component (19) is further added and mixed.
D. C is cooled, the following component (20) is added and mixed to obtain an emulsion.

(Ingredient) (mass%)
(1) Stearic acid 1.0
(2) Cetanol 0.5
(3) Lipophilic glyceryl monostearate 0.5
(4) Liquid paraffin 2.0
(5) Squalane 3.0
(6) Jojoba oil 3.0
(7) Cetyl palmitate 0.2
(8) Retinol palmitate 0.2
(9) Tocopherol acetate 0.05
(10) Caffeic acid * 1 0.1
(11) Preservative appropriate amount (12) sorbitan monostearate 0.3
(13) Polyoxyethylene monooleate (20E.O.)
Sorbitan 0.5
(14) Triethanolamine 0.5
(15) 1,3-butylene glycol 15.0
(16) Glycerol 3.0
(17) Polyethylene glycol 6000 0.5
(18) Purified water remaining amount (19) 1% aqueous solution of carboxyvinyl polymer 8.0
(20) Fragrance appropriate amount * 1: Tokyo Chemical Industry Co., Ltd.

[Example 4: Cream]
A cream was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (14) are dissolved by heating and maintained at 70 ° C.
B. The following components (15) to (19) are dissolved by heating and maintained at 70 ° C.
C. B is added to A to emulsify, and the following component (20) is further added and mixed.
D. C is cooled, the following component (21) is added and mixed to obtain a cream.

(Ingredient) (mass%)
(1) Stearic acid 2.5
(2) Cetanol 2.5
(3) Lipophilic glyceryl monostearate 2.0
(4) Vaseline 2.0
(5) Dipentaerythritol fatty acid ester * 1 2.0
(6) Isotridecyl myristate 5.0
(7) Liquid paraffin 8.0
(8) Squalane 5.0
(9) Beeswax 1.0
(10) Caffeic acid * 2 0.1
(11) Cetyl palmitate 2.0
(12) Sorbitan sesquioleate 0.5
(13) Polyoxyethylene monooleate (20E.O.)
Sorbitan 1.5
(14) Preservative appropriate amount (15) Triethanolamine 1.2
(16) 1,3-butylene glycol 8.0
(17) Glycerin 2.0
(18) Polyethylene glycol 20000 0.5
(19) Purified water remaining amount (20) 1% aqueous solution of carboxyvinyl polymer 10.0
(21) Fragrance appropriate amount * 1: Cosmol 168AR (Nisshin Oillio Group)
* 2: Tokyo Chemical Industry Co., Ltd.

  Each of the various cosmetics prepared above is excellent in stability over time, and when applied to the skin, improves the wrinkle and sagging of the skin, and makes the skin beautiful and firm, with excellent anti-aging effects. there were.

  According to the present invention, a novel elastase activity inhibitor excellent in safety can be provided. This elastase activity inhibitor can be stably blended into an external preparation for skin and food. By using the elastase activity inhibitor of the present invention, it is possible to impart excellent anti-aging ability, sagging / wrinkle improving ability, inflammation suppressing ability, or hair growth / hair growth control ability by elastase activity inhibiting action to external preparations for skin etc. can do.

It is a graph which shows the result of the elastase activity suppression test performed in the Example. It is a graph which shows the result of the elastase activity suppression test performed in the Example.

Claims (1)

An elastase activity inhibitor comprising, as an active ingredient, at least one selected from caffeic acid and pharmaceutically acceptable salts thereof.

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