JP2009221153A - Complexion improving agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a nitrogen monoxide production inhibitor for preventing or improving complexion deterioration caused by nitrogen monoxide production and a skin care preparation that contains the nitrogen monoxide production inhibitor and is suitable for improving complexion. <P>SOLUTION: The nitrogen monoxide production inhibitor comprises a pyrroloquinoline quinone derivative represented by general formula (1) [wherein R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each independently a short-chain-length alkyl group, alkenyl group, aralkyl group, alaryl group, phenyl group or a hydrogen atom] and/or its pharmacologically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a nitric oxide production inhibitor and a topical skin preparation containing the same, and more specifically, a nitric oxide production inhibitor comprising a pyrroloquinoline quinone derivative and a pharmacologically acceptable salt thereof, and the like. The present invention relates to a skin external preparation suitable for improving the face color.

Due to changes in lifestyle habits in recent years, the number of people with skin troubles such as rough skin, poor complexion, and lack of glossy skin, which are thought to be caused by irregular lifestyles, unbalanced diets, stress, etc., tends to increase. It is expected that more effective solutions for these skin problems will be needed.

As a conventional main skin trouble solving method, it is possible to use cosmetics containing various components having a beautifying skin effect. These active ingredients exert their effects by directly acting on skin cells to promote metabolism and preventing aging by moisturizing action and the like.

In particular, as a method for resolving a bad complexion, there is an attempt to realize a healthy complexion without dullness by promoting blood circulation to skin cells. In other words, blood cells are promoted to sufficiently supply nutrient components and water to the skin cell layer, thereby activating metabolism and maintaining blood circulation well at the periphery of the skin. It is based on the idea that a beautiful and healthy skin color can be created without being dull on the face. However, the mere promotion of blood circulation induces the production of nitric oxide by reperfusion of blood flow, and there is a case where the tissue is damaged by the generated nitric oxide and its form is reversibly or irreversibly changed. It is said that if the damage caused by nitric oxide is small, the shape change becomes reversible, and if the damage is too large, it becomes irreversible. Such changes, whether reversible or irreversible, are recognized as facial color deterioration. At present, no useful means for improving the complexion of such a mechanism is known.

On the other hand, pyrroloquinoline quinone derivatives, especially pyrroloquinoline quinone (PQQ), are substances isolated and identified from metabolites of methanol-utilizing bacteria, and are found in eukaryotic molds, yeasts, and mammals. Has also been confirmed to exist. As its biological activity, cell growth promoting action (Patent Document 1), anti-cataract action (Patent Document 2), liver disease prevention and treatment action (Patent Document 3), wound healing action (Patent Document 4), anti-allergic action (Patent Document 5), reverse transcriptase inhibitory action (Patent Document 6) and glyoxalase I inhibitory action-anticancer action (Patent Document 7), melanin production inhibitory action (Patent Document 8) It has become.

However, it is not known that the pyrroloquinoline quinone derivative and / or a pharmacologically acceptable salt thereof has a nitric oxide production inhibitory action, and this is contained in the skin to have a facial color improving effect. No reports have been made yet.

JP-A 61-58584 JP 63-41421 A JP-A-63-192717 JP 63-152309 A JP-A-63-17493 JP-A 63-156724 JP 63-215628 A JP-A-8-20512

  An object of the present invention is to prevent or ameliorate facial color deterioration induced by the production of nitric oxide.

In view of such circumstances, the present inventors have made extensive efforts to search for compounds having an inhibitory effect on nitric oxide production in order to prevent or improve facial color deterioration induced by nitric oxide production. The present inventors have found a pyrroloquinoline quinone derivative having a remarkable inhibitory effect on nitric oxide production and have completed the invention.
That is, according to the present invention, the nitric oxide production inhibitor comprising as an active ingredient a pyrroloquinoline quinone derivative represented by the following general formula (1) and / or a pharmaceutically acceptable salt thereof: The problem can be solved. That is, the present invention is as follows.
<1> A nitric oxide production inhibitor comprising as an active ingredient a pyrroloquinoline quinone derivative represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof.

（１）
［式中、Ｒ１、Ｒ２、Ｒ３はそれぞれ独立して、短鎖長のアルキル基、アルケニル基、アラルキル基、アラアリ−ル基又はフェニル基、水素原子を表す。］

(1)
[Wherein R 1, R 2 and R 3 each independently represents a short-chain alkyl group, alkenyl group, aralkyl group, araryl group or phenyl group, or a hydrogen atom. ]

<2> The nitric oxide production inhibitor according to claim 1, wherein the compound represented by the general formula (1) is pyrroloquinoline quinone.

ピロロキノリンキノン（化合物２）

Pyrroloquinoline quinone (compound 2)

<3> For use in improving the face color, the person who is the subject of the face color improvement has a production amount of nitric oxide when measuring the amount of nitric oxide using a human nitric oxide measurement kit. The nitric oxide production inhibitor according to any one of <1> or <2>, which is a person having a value of xxx.

<4> It contains 0.0001% by mass to 10% by mass of the nitric oxide production inhibitor according to any one of <1> to <3> with respect to the total amount of the external preparation for skin. 3> The external preparation for skin according to 3>.

<5> The external preparation for skin according to <3> or <4>, which is intended to improve facial color.

<6> The facial color improving agent according to any one of <3> to <5>, wherein the facial color improving agent is outside the cosmetics or pharmacy.

  ADVANTAGE OF THE INVENTION According to this invention, the deterioration of the face color induced by the production of nitric oxide can be prevented or improved.

  The nitric oxide production inhibitor of the present invention comprises the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof as an active ingredient. In the general formula (1), R 1, R 2, and R 3 are each independently an alkyl group having a short chain length, more specifically, a linear, branched or cyclic structure having 1 to 4 carbon atoms, An alkenyl group, an aralkyl group, an araaryl group, an aromatic group in which one ring or two rings are independently bonded or condensed, or a hydrogen atom is preferred, and pyrroloquinoline quinone in which R1, R2, and R3 are all hydrogen atoms is preferred. It can be particularly preferably exemplified.

  Of the compounds represented by the general formula (1), pyrroloquinoline quinone (compound 2) can be preferably exemplified by preferable examples. The pyrroloquinoline quinone derivative represented by the general formula (1) can be used as it is as the nitric oxide production inhibitor of the present invention, but can also be used using an alkali metal. For example, alkali metals such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and organic amine salts such as triethylamine salts and piperidine salts can be preferably exemplified.

  The compound represented by the general formula (1) can be purified by culturing methanol-assimilating bacteria, or synthesized by the method described in Patent Document 8 (Japanese Patent Laid-Open No. Hei 8-205512). You can also get it. In addition, pyrroloquinoline quinone is commercially available from Mitsubishi Gas Chemical Co., Inc. and Dojin Chemical Co., Ltd., and such a commercial product can be purchased and used. The compounds represented by the general formula (1) thus obtained and / or their salts that are acceptable in an orderly manner cause excessive generation of nitric oxide in the living body and induce irreversible skin tissue changes. It has an action to prevent this. In order to obtain such an action, the compound represented by the general formula (1) and / or the pharmacologically acceptable salt thereof may be used in an amount of 0.1 mg to 10 g per day per adult. It is preferable to administer orally or transdermally in several divided portions.

In the external preparation for skin of the present invention, any component used in normal external preparation for skin can be contained in addition to the nitric oxide production inhibitor. Such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin , Hardened coconut oil, hardened oil, molasses, hardened castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, oils, waxes; , Hydrocarbons such as ceresin, petrolatum, microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol Le, isostear Higher alcohols such as alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol and cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, sebacic acid Di-2-ethylhexyl, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, tri-2-ethylhexane Synthetic ester oils such as glyceryl acid, tri-2-ethylhexanoic acid trimethylolpropane, triisostearic acid trimethylolpropane, tetra-2-ethylhexanoic acid pentane erythritol; dimethylpolysiloxane, methylphenyl Linear polysiloxanes such as siloxane and diphenylpolysiloxane; cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, Oil agents such as silicone oils such as modified polysiloxanes such as fluorine-modified polysiloxanes; Anionic surfactants such as fatty acid soaps (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether alkyl sulfates; Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride and laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imi Amphoteric surfactants such as dacolinium hydroxide-1-carboxyethyloxy disodium salt), betaine surfactants (alkylbetaine, amidebetaine, sulfobetaine, etc.), acylmethyltaurine; sorbitan fatty acid esters ( Sorbitan monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (such as glyceryl monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ether, POE sorbitan fatty acid ester (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid Steals (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / cured Nonionic surfactants such as castor oil derivatives (POE castor oil, POE hydrogenated castor oil, etc.), sucrose fatty acid esters, alkylglucosides; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol -L, Xylitol, Multi-Tole, Propile Glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol, etc. Moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate; surface treated mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic anhydride (Silica), powders such as aluminum oxide and barium sulfate; inorganic pigments such as bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide, which may be treated on the surface PAR agents such as titanium mica, fish phosphorus foil, bismuth oxychloride, etc. whose surface may be treated; red 202, which may be laked, Red 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 No., green 201, purple 201, red 204, etc .; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; paraaminobenzoic acid UV absorbers; Anthranilic acid UV absorbers; salicylic acid UV absorbers; cinnamic acid UV absorbers; benzophenone UV absorbers; sugar UV absorbers; 2- (2′-hydroxy-5′-t-octylphenyl) UV absorbers such as benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane; low such as ethanol and isopropanol Class B alcohols such as vitamin A or derivatives thereof, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or derivatives thereof, vitamin B12, vitamin B15 or derivatives thereof, etc. -Vitamin E such as tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate, vitamin D, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone, etc .; phenoxyethanol An antibacterial agent such as

  The skin external preparation of this invention can be manufactured by processing these essential components and arbitrary components according to a conventional method and processing them into lotions, emulsions, essences, creams, pack cosmetics, cleansing agents and the like. The skin external preparation of the present invention can be applied without particular limitation as long as it is applied externally to the skin, for example, cosmetics including quasi-drugs, skin external medicines, skin external goods and the like are preferable examples it can.

  Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

<Pyrroquinoline quinone which is a nitric oxide production inhibitor of the present invention>
The pyrroloquinoline quinone used for evaluating the inhibitory effect on nitric oxide production in the present invention was purchased from Dojin Chemical Co., Ltd.

<Nitric oxide production inhibitory action of the present invention>
RAW264.7 (10 ⁶ / ml), a macrophage-like cell derived from a mouse, was seeded in a 96-well plate, cultured overnight, then interferon γ (IFNγ) (10 ng / ml) (R & D Systems, Inc.) and lipopolysaccharide. (LPS) (10 μg / ml) (List Biological Laboratories, Inc) and PQQ were added, and cultured in an incubator at 37 ° C. for 24 hours. Griess reagent (100 μl) (Jounal of Leukocyte Biology Volume 54, August 1993, 199-124) is added to the culture solution (100 μl), and the amount of NO ₂ produced is measured by the change in absorbance at 550 nm. Synthetic enzyme inhibitory activity.

The nitric oxide production inhibitory action of the present nitric oxide production inhibitor evaluated in this manner is shown in FIG. This figure shows that the nitric oxide production inhibitor of the present invention has an excellent nitric oxide production inhibitory action.

  A cosmetic (lotion) which is an external preparation for skin of the present invention was prepared according to the formulation shown below. That is, the ingredients were heated to 80 ° C., stirred, dissolved, stirred and cooled to obtain Lotion 1.

<Evaluation>
The lotion of Example 2 was examined for the effect of improving the face color. For comparison, Comparative Example 1 in which pyrroloquinoline quinone was replaced with water was also produced in the same manner. Randomly collected 20 panelists with poor facial color and consciousness were divided into 2 groups. One group was given lotion 1 and the other group was given comparative example 1, which was used twice a day in the morning and evening for 30 days. received. 48 hours after the end of use, the questionnaire shows the degree of improvement in facial color, score 0: no improvement, score 1: almost no improvement, score 2: slight improvement, score 3: clear improvement The color was measured with a Konica Minolta color difference meter CR-400 before use and 48 hours after use to obtain ΔL. The results are shown in Tables 2 and 3. From this, it can be seen that the lotion 1 which is an external preparation for skin of the present invention improves the face color.

  The present invention can be applied to skin external preparations such as cosmetics.

It is a figure which shows the nitric oxide production inhibitory effect of the nitric oxide acidic inhibitor of this invention.

Claims (6)

A nitric oxide production inhibitor comprising a pyrroloquinoline quinone derivative represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof as an active ingredient.

(1)
[Wherein R 1, R 2 and R 3 each independently represents a short-chain alkyl group, alkenyl group, aralkyl group, araryl group or phenyl group, or a hydrogen atom. ] 2. The nitric oxide production inhibitor according to claim 1, wherein the compound represented by the general formula (1) is pyrroloquinoline quinone.

Pyrroloquinoline quinone (compound 2) A human skin color improvement target for use in facial color improvement, wherein the amount of nitric oxide produced is 150 ppb when the amount of nitric oxide is measured using a human nitric oxide measurement kit. The nitric oxide production inhibitor according to claim 1, wherein the nitric oxide production inhibitor is a person who exhibits It contains 0.0001 mass%-10 mass% of nitric oxide production inhibitors as described in any one of Claims 1-3 with respect to the skin external preparation whole quantity, It is characterized by the above-mentioned. Topical skin preparation. The external preparation for skin according to claim 3 or 4, characterized in that it aims to improve facial color. The facial color improving agent according to any one of claims 3 to 5, wherein the facial color improving agent is outside of cosmetics or medicine.

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