JP2012211129A - External composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external composition having an excellent inhibitory action against elastase activity which includes pyrroloquinoline quinone or a physiologically acceptable salt thereof and EDTA or a physiologically acceptable salt thereof.SOLUTION: The external composition includes (a) pyrroloquinoline quinone or a physiologically acceptable salt thereof, (b) EDTA or a physiologically acceptable salt thereof, and (c) at least one hydroxy group-containing compound selected from the group consisting of 2-6C polyols having 2-4 hydroxy groups and glycol ether. The content of the (c) hydroxy group-containing compound is 5 pts.wt. or more based on 1 pt.wt. of (a) pyrroloquinoline quinone or a physiologically acceptable salt thereof.

Description

  The present invention includes pyrroloquinoline quinone (hereinafter sometimes abbreviated as “PQQ”) or a physiologically acceptable salt thereof, and EDTA or a physiologically acceptable salt thereof. Or relates to an external composition used as a medicine.

In the living body, elastin is widely distributed in organs that require stretchability, such as ligaments, blood vessel walls, lungs, skin dermis, and joints. Elastin plays a role of imparting elasticity to the tissues of these organs, and plays a major role in maintaining elasticity or elasticity in the skin.
It is known that the amount of elastin gradually decreases due to aging, ultraviolet rays, active oxygen, or stress. In the skin, elastin reduction has been shown to gradually lose skin elasticity, causing wrinkles or sagging, which is a major contributor to aging.
Among elastases that degrade and reduce elastin, elastases involved in the degradation of elastin present in the dermal matrix of the skin are known as elastase derived from neutrophils and elastase derived from fibroblasts. It is known that elastase derived from fibroblasts degrades elastin constituting elastic fibers involved in maintaining skin elasticity. Therefore, it is predicted that a high anti-wrinkle effect can be obtained by inhibiting the activity.

Here, if a metal is mixed in a composition such as cosmetics, pharmaceuticals, or foods, it is not only harmful depending on the type of metal, but also, for example, a lotion or emulsion prepared using a carboxyvinyl polymer or the like. Or the property of a gel-like composition cannot be maintained. For this reason, EDTA which is a chelating agent is often blended with these compositions.
EDTA is known to have an inhibitory effect on elastase activity (Patent Document 1) and may be added to these compositions as an anti-aging active ingredient.

PQQ exists in a wide range of organisms such as animals, plants, and microorganisms, and functions as a redox coenzyme essential for energy acquisition.
PQQ is known to have many physiological activities, and is expected to be used as an active ingredient of pharmaceuticals, cosmetics, or foods. Such physiological activities include removal of active oxygen and radicals, cell growth promotion action, ultraviolet absorption action, nerve growth factor production promotion action, brain function improvement action, hair growth action, facial color improvement action, melanin production suppression and whitening action, Mitochondrial activation action and anti-fatigue action are known.

JP 2006-298812 A

  The present invention includes pyrroloquinoline quinone, or a physiologically acceptable salt thereof (hereinafter sometimes abbreviated as “a salt thereof”), and EDTA or a salt thereof, and has an excellent elastase activity inhibitory effect. The issue is to provide goods.

The present inventor repeated researches to solve the above problems, and obtained the following knowledge.
(i) PQQ or a salt thereof has an elastase activity inhibitory action.
(ii) When PQQ or a salt thereof is added to a composition containing EDTA or a salt thereof, the elastase activity inhibitory effect as predicted from the elastase activity inhibitory action possessed by each component cannot be obtained. Rather, the elastase activity inhibitory action of EDTA or a salt thereof is attenuated.
(iii) A composition containing EDTA or a salt thereof and PQQ or a salt thereof, and at least one selected from the group consisting of polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and glycol ethers Each of EDTA or a salt thereof and PQQ or a salt thereof has a hydroxyl group-containing compound and the content of the hydroxyl group-containing compound is 5 parts by weight or more with respect to 1 part by weight of PQQ or a salt thereof. Elastase activity inhibitory action is effectively exhibited.

This invention is completed based on the said knowledge, and provides the following external compositions.
Item 1. (a) pyrroloquinoline quinone or a physiologically acceptable salt thereof; (b) EDTA or a physiologically acceptable salt thereof; and (c) a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups. And at least one hydroxyl group-containing compound selected from the group consisting of glycol ethers, wherein the content of the hydroxyl group-containing compound (c) is 1 weight of pyrroloquinoline quinone or a physiologically acceptable salt thereof (a) The external composition which is 5 weight part or more with respect to a part.
Item 2. Item 1 containing 0.00001 to 500 parts by weight of EDTA or a physiologically acceptable salt (b) thereof relative to 1 part by weight of pyrroloquinoline quinone or a physiologically acceptable salt (a) thereof. The external composition as described.
Item 3. Item 3. The topical composition according to Item 1 or 2, comprising 0.00001 to 10% by weight of pyrroloquinoline quinone or a physiologically acceptable salt thereof (a) based on the total amount of the composition.
Item 4. Item 4. The topical composition according to any one of Items 1 to 3, comprising 0.0001 to 3% by weight of EDTA or a physiologically acceptable salt (b) thereof based on the total amount of the composition.
Item 5. The hydroxyl group-containing compound (c) is at least one selected from the group consisting of propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, isoprene glycol, diglycerin, ethylene glycol monomethyl ether, and diethylene glycol monoethyl ether. Item 5. The composition for external use according to any one of Items 1 to 4.
Item 6. Item 6. The external composition according to any one of Items 1 to 5, comprising 0.01 to 97% by weight of the hydroxyl group-containing compound (c) based on the total amount of the composition.

Item 7. A composition comprising (a) pyrroloquinoline quinone or a physiologically acceptable salt thereof, and (b) EDTA or a physiologically acceptable salt thereof, (c) having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups Inhibition of elastase activity of component (a) by adding component (a) and component (b) by adding at least one hydroxyl group-containing compound selected from the group consisting of polyhydric alcohols and glycol ethers A method for suppressing a decrease in an action, or a decrease in an elastase activity inhibitory action of the component (b) by mixing the component (a) and the component (b).
Item 8. (c) The above composition after adding at least one hydroxyl group-containing compound selected from the group consisting of a C2-C6, C2-C4 polyhydric alcohol, and glycol ether is pyrroloquinoline quinone, or Item 8. The method according to Item 7, comprising 0.00001 to 500 parts by weight of EDTA or a physiologically acceptable salt (b) thereof relative to 1 part by weight of the physiologically acceptable salt (a).
Item 9. (c) The composition after addition of at least one hydroxyl group-containing compound selected from the group consisting of a C2-C6, C2-C4 polyhydric alcohol, and glycol ether is pyrroloquinoline quinone or physiological Item 9. The method according to Item 7 or 8, comprising 0.00001 to 10% by weight of the pharmaceutically acceptable salt (a) based on the total amount of the composition.
Item 10. (c) the composition after addition of at least one hydroxyl group-containing compound selected from the group consisting of a polyhydric alcohol having 2 to 6 carbon atoms, a polyhydric alcohol having 2 to 4 hydroxyl groups, and a glycol ether is EDTA or physiologically Item 10. The method according to any one of Items 7 to 9, wherein the acceptable salt (b) is contained in an amount of 0.0001 to 3% by weight based on the total amount of the composition.
Item 11. The hydroxyl group-containing compound (c) is at least one selected from the group consisting of propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, isoprene glycol, diglycerin, ethylene glycol monomethyl ether, and diethylene glycol monoethyl ether. Item 11. The method according to any one of Items 7 to 10.
Item 12. The above hydroxyl group-containing compound (c) is added with at least one hydroxyl group-containing compound selected from the group consisting of (c) a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and a glycol ether. Item 12. The method according to any one of Items 7 to 11, which is added to the composition so that the concentration relative to the total amount of the composition is 0.01 to 97% by weight.

Since PQQ or a salt thereof has various pharmacological activities, it is expected to be used as an active ingredient in cosmetics, pharmaceuticals, or quasi drugs. The present inventor has also found that PQQ or a salt thereof has an elastase activity inhibitory action and is a useful component for preventing or improving wrinkles or tarmi due to a decrease in elastin.
On the other hand, EDTA or a salt thereof may be desired to be blended as a chelating agent in cosmetics, pharmaceuticals, or quasi drugs. It is also known to have an elastase activity inhibitory action, and may be added for the prevention or improvement of wrinkles or tarmi.
Therefore, in some cases, PQQ or a salt thereof and EDTA or a salt thereof may be added to these external compositions, and in that case, an excellent effect of combining the elastase activity inhibiting action of both is expected. However, the present inventors have found that an additive effect predicted from the elastase activity inhibitory action of each component cannot be obtained with a composition containing PQQ or a salt thereof and EDTA or a salt thereof. Moreover, it discovered that the elastase activity inhibitory action became weak on the contrary compared with the case of EDTA or its salt alone.

In addition to PQQ or a salt thereof, and EDTA or a salt thereof, the composition of the present invention includes at least one selected from the group consisting of polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and glycol ethers. An elastase comprising a hydroxyl group-containing compound, and the content of the hydroxyl group-containing compound is 5 parts by weight or more relative to 1 part by weight of PQQ or a salt thereof, so that each of PQQ or a salt thereof and EDTA or a salt thereof has The activity inhibitory action is effectively exhibited. Especially, the elastase activity inhibitory action derived from a fibroblast is exhibited effectively.
Thereby, it is possible to effectively improve the elasticity of the skin, give firmness or gloss to the skin, and prevent or improve the skin's tarmi, wrinkles, rough skin, or dullness.

It is a figure which shows that elastase activity inhibitory action reduces by combined use with PQQ or its salt, and EDTA or its salt. It is a figure which shows that the elastase activity inhibitory action recovers by glycol ether addition. It is a figure which shows that the elastase activity inhibitory action recovers by polyhydric alcohol or glycol ether addition.

Hereinafter, the present invention will be described in detail.
The composition for external use of the present invention comprises (a) PQQ or a salt thereof, (b) EDTA or a salt thereof, and (c) a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and a glycol ether. It is a composition comprising at least one hydroxyl group-containing compound selected from above, wherein the content of the hydroxyl group-containing compound (c) is 5 parts by weight or more with respect to 1 part by weight of PQQ or a salt thereof (a).

Since PQQ or its salt PQQ exists in various organisms such as animals, plants, and microorganisms, it can be extracted from various organisms. Moreover, PQQ can purchase a commercial item.
Examples of the salt of PQQ include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. Among the salts, sodium salt, potassium salt, calcium salt, and magnesium salt are preferable.

The content of PQQ or a salt thereof in the composition is preferably 0.00001% by weight or more, more preferably 0.0001% by weight or more, and still more preferably 0.001% by weight or more with respect to the total amount of the composition. . Moreover, 10 weight% or less is preferable, 5 weight% or less is more preferable, and 1 weight% or less is still more preferable. If it is the said range, the physiological activity of PQQ or its salt is fully acquired by the normal usage-amount of cosmetics, a quasi-drug, or a pharmaceutical external preparation. Moreover, if it is the said range, the solubility in a formulation will be favorable and it will become the thing excellent as a formulation of an external composition.
Further, the content of PQQ or a salt thereof in the composition is, for example, preferably 0.00001 to 10% by weight, more preferably 0.0001 to 5% by weight, and more preferably 0.001 to 0.001% by weight with respect to the total amount of the composition. 1% by weight is even more preferred.

EDTA or its salt As a salt of EDTA, Na salt (2Na salt, 3Na salt, and 4Na salt) of EDTA, K salt (2K salt, 3K salt, and 4K salt), and Ca * Na salt (Ca * 2Na salt) ) And the like. These may be hydrates. Among them, EDTA salt is preferable because of its high chelating action, and Na salt and K salt of EDTA are more preferable.
EDTA or its salt can be used individually by 1 type or in combination of 2 or more types.

The content of EDTA or a salt thereof in the composition for external use of the present invention is preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, and more preferably 0.01% by weight or more based on the total amount of the composition. Is even more preferred. Moreover, 3 weight% or less is preferable, 1 weight% or less is more preferable, and 0.5 weight% or less is still more preferable.
The content of EDTA or a salt thereof in the composition for external use of the present invention is, for example, preferably 0.0001 to 3% by weight, more preferably 0.001 to 1% by weight, based on the total amount of the composition. Even more preferred is 01-0.5 wt%.
When the content of EDTA or a salt thereof is in the above range, a composition that can sufficiently provide an elastase activity inhibiting action and a chelating action and is less prone to irritation to the skin.

Further, the ratio of the content of EDTA or a salt thereof to the content of PQQ or a salt thereof is preferably 0.00001 part by weight or more and more preferably 0.0001 part by weight or more with respect to 1 part by weight of PQQ or a salt thereof. Preferably, 0.001 part by weight or more is even more preferable. Moreover, 500 weight part or less is preferable, 100 weight part or less is more preferable, and 10 weight part or less is still more preferable.
The ratio of the content of EDTA or a salt thereof to the content of PQQ or a salt thereof is preferably, for example, 0.00001 to 500 parts by weight, and 0.0001 to 100 parts by weight with respect to 1 part by weight of PQQ or a salt thereof. Is more preferable, and 0.001 to 10 parts by weight is even more preferable.
If the ratio of the content of EDTA or a salt thereof to the content of PQQ or a salt thereof is within the above range, a composition that can sufficiently provide an elastase activity inhibiting action and a chelating action and is less likely to cause irritation to the skin. It becomes.

Polyhydric alcohol When the composition of the present invention contains a polyhydric alcohol as a hydroxyl group-containing compound, a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups is used.
Specifically, ethylene glycol, propylene glycol, 1,3-propanediol (trimethylene glycol), 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, 1,4-butanediol (Tetramethylene glycol), 2-butene-1,4-diol, 1,5-pentanediol (pentamethylene glycol), 1,2-pentanediol, isoprene glycol (isopentyldiol), hexylene glycol, and dipropylene Examples include dihydric alcohols such as glycol; trihydric alcohols such as glycerin and trimethylolpropane; and tetrahydric alcohols such as diglycerin, pentaerythritol, and 1,2,6-hexanetriol.
Among these, propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, isoprene glycol, and diglycerin are preferable, and propylene glycol, 1,3-butylene glycol, glycerin, and diglycerin are more preferable.

Glycol ether When the composition of the present invention contains a glycol ether as the hydroxyl group-containing compound, the glycol ether is specifically an ethylene glycol type such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and ethylene glycol monopropyl ether. Glycol ethers of
Diethylene glycol-based glycol ethers such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and diethylene glycol monopropyl ether;
And propylene glycol-based glycol ethers such as propylene glycol monoethyl ether and propylene glycol monopropyl ether; and dipropylene glycol-based glycol ethers such as dipropylene glycol monoethyl ether and dipropylene glycol monopropyl ether It is done.
Among these, ethylene glycol and diethylene glycol glycol ethers are preferred, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether are more preferred, and diethylene glycol monoethyl ether is particularly preferred.

  A hydroxyl group-containing compound selected from the group consisting of a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups and a glycol ether can be used singly or in combination of two or more.

The content of the polyhydric alcohol / glycol ether in the composition of at least one hydroxyl group-containing compound selected from the group consisting of a polyhydric alcohol having 2 to 6 carbon atoms, a polyhydric alcohol having 2 to 4 hydroxyl groups, and a glycol ether, 0.01% by weight or more is preferable, 0.1% by weight or more is more preferable, and 0.5% by weight or more is even more preferable with respect to the total amount of the composition. If it is the said range, the elastase activity inhibitory action which PQQ or its salt and EDTA or its salt have will be exhibited effectively.
In addition, the content of the hydroxyl group-containing compound in the composition is preferably 97% by weight or less, more preferably 50% by weight or less, and still more preferably 30% by weight or less based on the total amount of the composition. If it is the said range, it will become a composition of favorable usability | use_condition.
In addition, the content of the hydroxyl group-containing compound in the composition is, for example, preferably 0.01 to 97% by weight, more preferably 0.1 to 50% by weight, with respect to the total amount of the composition, 0.5 to 30% by weight is even more preferred.

Ratio of polyhydric alcohol / glycol ether to PQQ or a salt thereof The total amount of at least one hydroxyl group-containing compound selected from the group consisting of polyhydric alcohol having 2 to 6 carbon atoms, polyhydric alcohol having 2 to 4 hydroxyl groups, and glycol ether, What is necessary is just to set it as 5 weight part or more with respect to 1 weight part of PQQ or its salt. Moreover, 10 weight part or more is preferable and 20 weight part or more is more preferable. If it is the said range, the elastase activity inhibitory action which PQQ or its salt and EDTA or its salt have will be exhibited effectively.
The total amount of the hydroxyl group-containing compound is not particularly limited, but is preferably 800 parts by weight or less, more preferably 500 parts by weight or less, and even more preferably 300 parts by weight or less with respect to 1 part by weight of PQQ or a salt thereof. preferable. If it is the said range, the elastase activity inhibitory action which PQQ or its salt and EDTA or its salt have will be exhibited effectively, and a favorable usability | use_condition will be obtained.
The total amount of at least one hydroxyl group-containing compound selected from the group consisting of polyhydric alcohols having 2 to 6 carbon atoms, 2 to 4 hydroxyl groups, and glycol ether is, for example, 1 part by weight of PQQ or a salt thereof. 5 parts by weight or more, preferably 800 parts by weight or less, more preferably 10 to 500 parts by weight, and even more preferably 20 to 300 parts by weight.

Formulation Form The composition for external use of the present invention comprises PQQ or a salt thereof, EDTA or a salt thereof, and the above polyhydric alcohol and / or glycol ether, It can be mixed with a carrier and, if necessary, an additive to make an external composition for skin for pharmaceuticals, quasi drugs, or cosmetics.

The form of the external composition for skin for pharmaceuticals is not particularly limited, and examples thereof include solutions, suspensions, emulsions, creams, ointments, gels, liniments, lotions, and aerosols. These preparations can be produced according to the method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations. Of these, liquids, suspensions, emulsions, creams, ointments, gels, lotions, and aerosols are preferable, and creams, emulsions, and gels are more preferable.
Also when it is set as the composition for external use on the skin for quasi drugs or cosmetics, it can be made into the same form as said pharmaceutical. In addition, a stick agent, a sheet agent obtained by impregnating a non-woven fabric with a chemical solution, and the like can be given. Among these, a liquid agent, a suspension agent, an emulsion, a cream agent, an ointment, a gel agent, a lotion agent, and a sheet agent are preferable, and a cream agent, an emulsion, and a gel agent are more preferable.
When an oily base and an aqueous base are included, such as creams and emulsions, they may be W / O type or O / W type, but O / W type is preferred.
In the case of a base that does not contain water, an ointment and a liquid that contains the above-described polyhydric alcohol and / or glycol ether as a base are preferable.

  Specifically, the use in the case of a quasi-drug or cosmetic composition for external use in skin includes, for example, lotion, emulsion, gel, cream, cosmetic liquid, sunscreen cosmetic, pack, mask, hand cream Basic cosmetics such as body lotions and body creams; cleansing cosmetics such as face wash, makeup remover, shaving agent, body shampoo, shampoo, rinse, and treatment; lip makeup such as lip balm and lipstick Cosmetics, foundations, makeup cosmetics such as mascara; hair removal agents; and bath preparations.

As a base or carrier base or carrier, for example, liquid paraffin, squalane, vaseline, hydrocarbon gel (such as Plastibase), ozokerite, alpha-olefin oligomers, and hydrocarbons such as light liquid paraffin; methylpolysiloxane, Cross-linked methylpolysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, cross-linked alkylpoly Ether-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified Silicone oils such as silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; sterols such as cholesterol, phytosterol, and phytosteryl hydroxystearate Vegetable oils such as jojoba oil, medofoam oil, sunflower oil, grape seed oil, grape oil, squalane, shea butter and rice germ oil; animal oils such as lanolin, orange raffie oil, squalane, and horse oil; ethyl cellulose, hydroxy Natural polymer derivatives such as propylcellulose, hydroxypropylmethylcellulose, cationized guar gum, and acetylated hyaluronic acid; polyvinylpyrrolidone, carboxy Synthetic polymers such as vinyl polymers and alkyl methacrylate copolymers; natural polymers such as carrageenan, alginic acid, cellulose, guar gum, quince seed, dextran, gellan gum, and hyaluronic acid; polyvinyl butyrate; polyethylene glycol Dioxane; butylene glycol adipic acid polyester; isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate, jojoba oil, and tri (caprylic / caprin) Acid) esters such as glyceryl; dextrins and polysaccharides such as maltodextrin; lower alcohols such as ethanol and isopropanol; Polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups as described above; glycol ethers as described above; organic acids such as succinic acid, glycolic acid, gluconic acid, and citric acid; and aqueous bases such as water Can be mentioned.

Among these, polyhydric alcohols, higher alcohols, hydrocarbons, esters, silicone oils, and organic acids are preferable, and polyhydric alcohols are more preferable.
Preferable examples of the composition of the present invention include solutions, lotions, creams, gels, and emulsions containing the above-described polyhydric alcohol as a base.
A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

Additives In the composition for external use of the present invention, known additives that are added to pharmaceuticals, quasi drugs, or cosmetics, for example, antioxidants, surfactants, enhancers, within the range that does not impair the effects of the present invention. A sticking agent, a preservative, a pH adjuster, a stabilizer, an irritation reducing agent, an antiseptic, a coloring agent, a fragrance, a pearl luster imparting agent, and the like can be added.

  Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, ascorbic acid derivative, tocopherol, tocopherol derivative, erythorbic acid, and L-cysteine hydrochloride.

  Examples of the surfactant include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate. Sorbitan fatty acid esters such as propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene Hardened castor oil 60 (HCO-60) and hardened castor oil derivatives such as polyoxyethylene hardened castor oil 80; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene stearate (20) sorbitan (polysorbate 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate; Polyoxyethylene mono coconut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; amines such as stearylamine and oleylamine; polyoxyethylene methylpolysiloxane copolymer Silicone based surface actives such as lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone Agents; natural surfactants such as phospholipids, surfactins, and saponins; fatty acid amide amines such as diethylaminoethylamide stearate and diethylaminopropylamide stearate; trilaurylamine, dimethylstearylamine, and di-2-ethylhexylamine Alkylamines of the following: betaine amphoteric surfactants such as dimethylaminopropylamide stearate and lauryl hydroxysulfobetaine.

  Examples of thickeners include guar gum, locust bean gum, carrageenan, hyaluronic acid, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, macrogol, Examples thereof include cellulose thickeners such as sodium chondroitin sulfate, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose.

  Examples of the preservatives or preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, Examples include benzyl paraoxybenzoate, methyl paraoxybenzoate, phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and its salts, chlorhexidine gluconate, alkanediol, and glycerin fatty acid ester.

  Examples of pH adjusters include inorganic acids (such as hydrochloric acid and sulfuric acid), organic acids (such as lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, and sodium succinate), inorganic bases (potassium hydroxide, And sodium hydroxide), and organic bases (such as triethanolamine, diisopropanolamine, and triisopropanolamine).

Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole.
Examples of the irritation reducing agent include licorice extract and sodium alginate.

  An additive can be used individually by 1 type or in combination of 2 or more types.

Other active ingredients The composition for external use of this invention can contain another active ingredient in the range which does not impair the effect of this invention. Specific examples of active ingredients include, for example, moisturizing ingredients, anti-inflammatory ingredients, antibacterial ingredients, vitamins, peptides or derivatives thereof, amino acids or derivatives thereof, cell activation ingredients, anti-aging ingredients, blood circulation promoting ingredients, keratin softening ingredients, Examples include whitening ingredients, astringent ingredients, and UV protection ingredients.

  Examples of moisturizing ingredients include polyhydric alcohols such as glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol, and diglycerin trehalose; sodium hyaluronate, heparin analog, chondroitin sulfate sodium, collagen, elastin, keratin , Chitin, and polymeric compounds such as chitosan; amino acids such as glycine, aspartic acid, and arginine; natural moisturizing factors such as sodium lactate, urea, and sodium pyrrolidonecarboxylate; such as ceramide, cholesterol, and phospholipids And lipids; plant extract extracts such as chamomile extract, chamelle extract, tea extract, and perilla extract.

  Examples of the anti-inflammatory component include a component derived from a plant (for example, Comfrey), allantoin, glycyrrhizic acid or a derivative thereof, zinc oxide, pyridoxine hydrochloride, tocopherol acetate, salicylic acid or a derivative thereof, and ε-aminocaproic acid. It is done.

  Antibacterial or bactericidal components include, for example, chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, sulfur, resorcin, ethanol, benzethonium chloride, adapalene, benzoyl peroxide, clindamycin, cresol, gluconic acid and its derivatives, popidone iodine, iodine Potassium iodide, iodine, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101, photosensitizer 201, paraben, phenoxyethanol, 1,2-pentanediol, alkanediol, glycerin fatty acid ester, azelaic acid, alkyldiaminoglycine hydrochloride, Examples include chlorhexidine gluconate and zinc paraphenolsulfonate.

  Examples of vitamins include retinol derivatives such as retinol, retinol acetate, and retinol palmitate, retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, d-δ-tocopheryl retinoate, α-tocopheryl. Vitamin A such as retinoate and β-tocopheryl retinoate; vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate Riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5'-phosphate, and riboflavin tetranicotinate Nicotinic acids such as dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, and 1- (4-methylphenyl) ethyl nicotinate; ascorbigen-A, Vitamin Cs such as ascorbyl stearate, ascorbyl palmitate, and L-ascorbyl dipalmitate; Vitamin D such as methyl hesperidin, ergocalciferol, and cholecalciferol; Vitamin K such as phylloquinone and farnoquinone Dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine Vitamin B1 such as mintriphosphate, thiamine monophosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, and thiamine triphosphate monophosphate; pyridoxine hydrochloride Vitamin B6s such as pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxamine phosphate, and pyridoxamine hydrochloride; vitamin B12s such as cyanocobalamin, hydroxocobalamin, and deoxyadenosylcobalamin; folic acids such as folic acid and pteroylglutamic acid; Nicotinic acids such as nicotinic acid and nicotinic acid amide; pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-panthecin, D-panthetin, coenzyme A And pantothenic acids such as pantothenyl ethyl ether; biotins such as biotin and biotisin; ascorbic acid derivatives such as ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, and magnesium ascorbate phosphate And vitamin-like agents such as γ-oryzanol, carnitine, ferulic acid, α-lipoic acid, and orotic acid.

  Peptides or derivatives thereof include, for example, keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, elastin Degraded peptide, conchiolin degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soy proteolytic peptide, hydrolyzed soy protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, casein Degraded peptides, acylated peptides (palmitoyl oligopeptides, palmitoyl pentapeptides, palmitoyl tetrapeptides, etc.) and the like can be mentioned.

  Examples of amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine. Methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine and the like.

Cell activation components include, for example, amino acids such as γ-aminobutyric acid and ε-aminoproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acids; α- such as glycolic acid and lactic acid Hydroxy acids; Tannins; Flavonoids; Saponins; Allantoins;
Examples of anti-aging components include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

  Examples of the blood circulation promoting component include plants (e.g., ginseng, ashitaba, arnica, ginkgo, fennel, enmelio, Dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, hawthorn, papaver, Senkyu, assembly, thyme, clove, chimpi, spruce, spruce, spruce, carrot, garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, chimpi, spruce, spruce, peach, apricot , Walnuts, or corn); and glucosyl hesperidin.

Examples of the keratin softening component include urea, salicylic acid, glycolic acid, fruit acid, phytic acid, and sulfur.
Examples of the whitening component include ascorbic acid and its derivatives, arbutin, tocopherol, and tranexamic acid.
Examples of the astringent component include zinc paraphenol sulfonate, zinc oxide, menthol, and ethanol.
Examples of the UV protection component include 2-methoxyhexyl paramethoxycinnamate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, 2,4,6-tris [4- (2-ethylhexyl) Oxycarbonyl) anilino] -1,3,5-triazine, t-butylmethoxydibenzoylmethane, dibenzylidenedioxoimidazolidinepropionate ethylhexyl, etorhexyltriazoline, paraaminobenzoic acid and its derivatives, paradimethylaminobenzoic acid Examples include octyl, ethylene glycol salicylate, dihydroxybenzophenone, titanium oxide, and zinc oxide.

  Other active ingredients can be used alone or in combination of two or more.

Method of Use The composition for external use of the present invention varies depending on the skin condition, age, sex or the like of the subject of use, but may be the following method, for example. That is, an appropriate amount (for example, 0.05 to 5 g) may be applied to the skin several times a day (for example, 1 to 5 times, preferably 1 to 3 times). Further, the composition is applied so that the daily use amount of PQQ or a salt thereof is, for example, 0.0005 to 0.05 g, preferably 0.001 to 0.02 g, more preferably 0.002 to 0.01 g. do it.
The application period may be, for example, 1 to 6 months, preferably 3 to 6 months.
The composition for external use of this invention can be used conveniently for the person who has a skin talmi, a wrinkle, rough skin, or a dullness. In addition, in view of the physiological activity of PQQ or a salt thereof, it can be suitably used for people with various skin diseases or skin problems. Moreover, the person who has normal skin also becomes a suitable use object for prevention of a skin trouble.

Others The present invention relates to a composition containing (a) PQQ or a salt thereof, and (b) EDTA or a salt thereof, from (c) a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and a glycol ether. Addition of at least one hydroxyl group-containing compound selected from the group consisting of (a) component and (b) component to reduce the elastase activity inhibitory action of component (a), or (a) component And a method of suppressing a decrease in the elastase activity inhibitory action of the component (b) by mixing the component (b).
Specific examples of component (a), component (b), and component (c) in this method, component (a), component (b), and preferred component (c), component (a), component (b) Component, and amount of component (c) used, ratio of component (a), component (b), and component (c), base or carrier that may be included in the composition, included in the composition Good additives, other active ingredients that may be contained in the composition, formulation form of the composition, and the like are as described for the external composition of the present invention.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.
(1) Test method of elastase activity inhibitory effect The elastase activity inhibition rate derived from human fibroblasts was tested as follows.
Normal human adult skin-derived fibroblasts; a (NHDF Kurabo), fetal bovine serum using Dulbecco minimal medium (DMEM) containing 10%, 2 × 10 ⁴ to 96-well microplate for cell culture (Corning) The cells were seeded at a density of cells / well and cultured in a 37 ° C., 5% CO ₂ incubator for 24 hours. After removing the culture supernatant, 50 μl of 0.5% Triton X-100 aqueous solution was added, and the mixture was allowed to stand at room temperature for 30 minutes and used as a crude enzyme solution.
In the crude enzyme solution (50 μl) in each well, add 50 μl of 0.1 M Tris-HCl buffer (pH 8.0) solution in which one or more components such as EDTA-2Na (Wako Pure Chemical Industries) and PQQ-2Na are dissolved. Added. Furthermore, 100 μl of 0.1 M Tris-HCl buffer (pH 8.0) solution containing 1.5 mM PMSF and 5 mM elastase synthesis substrate succinyl-alanyl-alanyl-alanyl-p-nitroanilide (Peptide Institute) was added to each well. After the addition, the total inside of the well was made 200 μl, and allowed to stand in the dark at 37 ° C. for 2 hours.
The absorbance at 405 nm of p-nitroaniline produced by hydrolysis with fibroblast-derived elastase was measured using an absorptiometer.

The elastase inhibition rate was calculated from the following equation, where C ′ was the absorbance value when no test drug was added (buffer only), and S ′ was the absorbance value when the test drug was added.

Fibroblast-derived elastase inhibition rate (%) = (1− (S ′ / C ′)) × 100

(2) Reduction of elastase activity inhibitory action by combined use of PQQ or a salt thereof and EDTA or a salt thereof A test solution having the composition shown in Table 1 below is prepared, and the elastase activity inhibition rate is calculated as described in (1). did. The relative values when the elastase activity inhibition rate of EDTA-2Na in Reference Example 1 is taken as 100 are shown in Table 1 and FIGS. 1 (A) and 1 (B).

As is clear from Table 1 and FIG. 1, EDTA-2Na and PQQ have elastase activity inhibitory action from the comparison between Reference Examples 1, 2, and 3 and the comparison between Reference Examples 1, 4, and 5, respectively. It can be seen that even if both are used in combination, the expected additive effect cannot be obtained.
In addition, it can be seen from the comparison of Reference Examples 1 and 3 and the comparison of Reference Examples 1 and 5 that the combined use of PQQ reduces the elastase activity inhibitory action of EDTA-2Na.

(3) Effect of addition of glycol ether A test solution having the composition shown in Table 2 below was prepared, and the elastase activity inhibition rate was calculated as described in (1). The elastase activity inhibition rate is shown in Table 2 and FIG.
As is clear from Table 2 and FIG. 2, the elastase activity inhibition rate was decreased by using PQQ-2Na in combination with EDTA-2Na, but ethoxydiglycol (diethylene glycol monoethyl ether), which is a glycol ether, was further added. As a result, the elastase activity inhibition rate was improved, and the elastase activity inhibition effects of EDTA-2Na and PQQ were sufficiently exhibited.

(4) Effect of addition of polyhydric alcohol and glycol ether A test solution having the composition shown in Table 3 below was prepared, and the elastase activity inhibition rate was calculated as described in (1). The elastase activity inhibition rate is shown in Table 3 and FIG.
As is apparent from Table 3 and FIG. 3, EDTA-2Na and PQQ-2Na are further mixed with dihydric glycol, which is a polyhydric alcohol, 1,3-butylene glycol, or ethoxydiglycol, which is a glycol ether. It can be seen that the activity inhibition rate was improved.

(5) Effect of ratio of hydroxyl group-containing compound to PQQ Test solutions having compositions shown in Tables 4 and 5 below were prepared, and the elastase activity inhibition rate was calculated as described in (1). Tables 4 and 5 show the relative values when the elastase activity inhibition rate in the case of EDTA-2Na and PQQ alone is taken as 100.

It can be seen that when the blending ratio of polyhydric alcohol to PQQ exceeds 2, the effect of improving the elastase activity inhibitory effect by the hydroxyl group-containing compound blending can be obtained.

  The composition for external use of the present invention contains PQQ or a salt thereof, and EDTA or a salt thereof, and has an excellent inhibitory action on elastase activity. Therefore, it is useful as a cosmetic, a quasi-drug, or a pharmaceutical external preparation.

Claims (5)

  (a) pyrroloquinoline quinone or a physiologically acceptable salt thereof; (b) EDTA or a physiologically acceptable salt thereof; and (c) a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups. And at least one hydroxyl group-containing compound selected from the group consisting of glycol ethers, wherein the content of the hydroxyl group-containing compound (c) is 1 weight of pyrroloquinoline quinone or a physiologically acceptable salt thereof (a) The external composition which is 5 weight part or more with respect to a part.   The pyrrole quinoline quinone or the physiologically acceptable salt (a) thereof is contained in an amount of 0.00001 to 500 parts by weight of EDTA or a physiologically acceptable salt (b) thereof per 1 part by weight of the physiologically acceptable salt (a) thereof. The composition for external use described in 1.   The external composition of Claim 1 or 2 which contains 0.00001-10 weight% of pyrroloquinoline quinone or its physiologically acceptable salt (a) with respect to the whole quantity of a composition.   The external composition in any one of Claims 1-3 which contains 0.0001-3 weight% of EDTA or its physiologically acceptable salt (b) with respect to the whole quantity of a composition.   The hydroxyl group-containing compound (c) is at least one selected from the group consisting of propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, isoprene glycol, diglycerin, ethylene glycol monomethyl ether, and diethylene glycol monoethyl ether. The composition for external use according to any one of claims 1 to 4.