CN102232952A - Photoaging inhibitor and skin thinning inhibitor - Google Patents
Photoaging inhibitor and skin thinning inhibitor Download PDFInfo
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- CN102232952A CN102232952A CN2011100931404A CN201110093140A CN102232952A CN 102232952 A CN102232952 A CN 102232952A CN 2011100931404 A CN2011100931404 A CN 2011100931404A CN 201110093140 A CN201110093140 A CN 201110093140A CN 102232952 A CN102232952 A CN 102232952A
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Abstract
The invention provides a new agent which is effective in inhibiting photoaging, especially inhibiting wrinkles generated by ultraviolet rays or skin thinning. The application of pyrro-quinoline quinine and/or salt allowed by the pharmacology of the pyrro-quinoline quinine in the preparation of the photoaging inhibitor is provided.
Description
Technical field
The present invention relates to photoaging inhibitor and skin thinning inhibitor.More particularly, The present invention be more particularly directed to can be used as the inhibitor that produces wrinkle is brought out in inhibition because of ultraviolet photoaging inhibitor and skin thinning inhibitor.
Background technology
Pyrro-quinoline quinone (PQQ) (following slightly be designated as sometimes " PQQ ") be from methanol utilize the type bacterium the metabolite isolation identification and material, confirm also to be present in Eukaryotic fungus, enzyme and mammal.
Biological activity about this PQQ has carried out a large amount of research all the time, confirms that up to the present the PQQ or derivatives thereof has antioxidation, mitochondrion activation, ultra-violet absorption effect, the effect that prevents skin aging, the active oxygen effect of removing, photoaging and prevents that effect (this effect is confirmed to the derivant of PQQ), anti-allergic effects, reverse transcriptase inhibitory action, melanocyte from synthesizing inhibitory action etc.
The various active ingredients and the active compound of the effect of these PQQ or derivatives thereofs have been proposed to utilize.
For example, in patent documentation 1, proposed to contain the mitochondrion activator of pyrro-quinoline quinone (PQQ) or derivatives thereof.UV absorbent by pyrro-quinoline quinone (PQQ) ester and/or its salt formation has been proposed in patent documentation 2.In patent documentation 3, proposed to contain PPQ or its salt, be used to improve that skin is coarse, the skin preparations for extenal use of the skin of giving no wrinkle.The active oxygen that has proposed to contain imidazo pyrroloquinoline chemical compound in patent documentation 4 goes out remover.In patent documentation 5, proposed Han You oxazole and pyrroloquinoline class and/or its salt to preventing that generating light adds the effective skin preparations for extenal use of photoaging such as rheological properties wrinkle.In patent documentation 6, disclosed with pyrroloquinoline quinone derivative and/or salt that its pharmacology was allowed be effective ingredient to prevention so that improve the inflammation effective I L-6 that brings out by uv light exposure and produce inhibitor.
Also have, in patent documentation 2, disclosed UV absorbent as previously mentioned, also put down in writing ultraviolet for forming the reason of little wrinkle and senile plaque, freckle etc. by pyrro-quinoline quinone (PQQ) ester and/or its salt formation.Also have, the skin preparations for extenal use that has disclosed Han You oxazole and pyrroloquinoline class in the embodiment of patent documentation 5 is effectively actual to the formation that prevents the photoaging wrinkle.
But, do not see as yet whether PQQ suppressed the document that practical study has been carried out in photoaging.
In addition, among the embodiment of each patent documentation that more than exemplifies, from the dissolubility solvent such as the angle of the effect of performance PQQ or derivatives thereof etc. and PQQ and the angle of preparation stability etc., the content of actual compositions that makes and the PQQ in the preparation etc. is (particularly the content of PQQ or its salt is about 0.1～10 weight %) about 0.01～10 weight %.
In recent years, the thinning of skin also begins to be paid close attention to as the problem of skin aging.The thinning of skin is meant that ability drop, epidermis attenuation, result that the amount of the collagen of the skin corium of skin with advancing age and elastoidin reduces, makes the myocyte of organism cause the phenomenon of thinning of skin.About the thinning of this skin, do not see relevant PQQ has the research document of what kind of association yet.
Patent documentation 1:WO2006/025247 text
Patent documentation 2: Japanese patent laid-open 8-20585 communique
Patent documentation 3: the Japan Patent spy opens clear 63-152309 communique
Patent documentation 4: Japanese patent laid-open 10-45594 communique
Patent documentation 5: Japanese patent laid-open 6-100428 communique
Patent documentation 6: the Japan Patent spy opens the 2009-221154 communique
Summary of the invention
The purpose of this invention is to provide suppressing photoaging, particularly suppressing to produce wrinkle or suppress the effective novel formulation of skin thinning because of ultraviolet brings out.
The present invention also aims to be provided at the inhibition photoaging, particularly suppress to bring out the novel formulation that contains effective ingredient in the preparation that produces wrinkle with specially suitable content because of ultraviolet.
The present inventor finds that the salt that PQQ or its pharmacology allow can solve above-mentioned problem, also find suppressing to bring out in the purposes of the preparation that produces wrinkle because of ultraviolet, the specially suitable content of PQQ etc. is for to have certain low concentration region of a great difference with the concentration of present employing, thereby finished the present invention.
That is, technology contents of the present invention is as follows.
1. pyrro-quinoline quinone (PQQ) and/or the application of salt in the preparation of photoaging inhibitor that its pharmacology allowed.
2. as [1] described purposes, it is characterized in that described photoaging inhibitor uses because of ultraviolet brings out the inhibitor that produces wrinkle as suppressing.
3. pyrro-quinoline quinone (PQQ) and/or the application of salt in the preparation of skin thinning inhibitor that its pharmacology allowed.
4. as [1] or [2] described purposes, it is characterized in that the pyrro-quinoline quinone (PQQ) in the described photoaging inhibitor and/or the content of the salt that its pharmacology allowed are 0.008～0.03 weight %.
5. as [3] described purposes, it is characterized in that the pyrro-quinoline quinone (PQQ) in the described skin thinning inhibitor and/or the content of the salt that its pharmacology allowed are 0.001～1 weight %.
6. as [2] described purposes, it is characterized in that the pyrro-quinoline quinone (PQQ) in the photoaging inhibitor that the inhibitor that produces wrinkle because of ultraviolet brings out as inhibition uses and/or the content of the salt that its pharmacology allowed are 0.01～0.03 weight %.
7. as each described purposes in [1], [2], [4] and [6], it is characterized in that the salt that the pharmacology allowed of described pyrro-quinoline quinone (PQQ) is the sodium salt or the potassium salt of pyrro-quinoline quinone (PQQ).
8. as [3] or [5] described purposes, it is characterized in that the salt that the pharmacology allowed of described pyrro-quinoline quinone (PQQ) is the sodium salt or the potassium salt of pyrro-quinoline quinone (PQQ).
The invention provides suppressing photoaging, particularly suppressing to produce wrinkle or suppress the effective novel formulation of skin thinning because of ultraviolet brings out.
In addition, the present invention also provides with specially suitable content and contains the inhibition photoaging of PQQ etc., particularly suppresses to bring out the novel formulation that produces wrinkle because of ultraviolet.
Description of drawings
Fig. 1 shows wrinkle area occupation ratio (test example 1) for expression forms the figure that suppresses the result that effect analyzes by the three-dimensional skin analysis software of reflection-type with bringing out property of the ultraviolet wrinkle of the photoaging inhibitor of embodiment 1～3 and comparative example 1 and tester.
Fig. 2 shows wrinkle volume fraction (test example 1) for expression forms the figure that suppresses the result that effect analyzes by the three-dimensional skin analysis software of reflection-type with the wrinkle of the bringing out property of ultraviolet of the photoaging inhibitor of embodiment 1～3 and comparative example 1 and tester.
Fig. 3 represents to test the embodiment 2 and 3 and the inhibiting measurement result of skin thinning of the skin thinning inhibitor of comparative example 1 (and tester) in the example 2.
Fig. 4 shows wrinkle area occupation ratio (test example 3) for expression forms the figure that suppresses the result that effect analyzes by the three-dimensional skin analysis software of reflection-type with bringing out property of the ultraviolet wrinkle of the photoaging inhibitor of embodiment 4～7 and comparative example 2 and tester.
Fig. 5 shows wrinkle volume fraction (test example 3) for expression forms the figure that suppresses the result that effect analyzes by the three-dimensional skin analysis software of reflection-type with the wrinkle of the bringing out property of ultraviolet of the photoaging inhibitor of embodiment 4～7 and comparative example 2 and tester.
Fig. 6 represents photoaging inhibitor and the glue protogene of tester and the measurement result (test example 4) of elastoidin expression of gene facilitation effect of embodiment 5 and comparative example 2.
The specific embodiment
Below, the present invention will be described in detail according to the order of photoaging inhibitor of making by application of the present invention and skin thinning inhibitor.
[photoaging inhibitor]
Conduct must contain at least one that is selected from pyrro-quinoline quinone (PQQ) and the salt that the pharmacology allowed thereof by composition in the photoaging inhibitor of the present invention.Light inhibitor of the present invention can contain other one-tenth described later as required and grade.Below described each composition is described.
The salt that＜PQQ and pharmacology thereof allowed 〉
PQQ is the chemical compound of being represented by following structural formula.
Alkali as the salt correspondence that the pharmacology allowed of this PQQ can exemplify alkali metal such as potassium and sodium, alkaline-earth metal such as calcium and magnesium, organic amines such as ammonium, triethanolamine and triethylamine, basic amino acids such as lysine and arginine.Wherein, from the inhibiting angle of photoaging, corresponding preferred sodium of alkali and potassium.
Described in " background technology ", PQQ is the chemical compound that always is being widely studied, and comprises that the salt that its pharmacology allows can both easily obtain.In addition, the salt that PQQ and pharmacology thereof allowed also has commercially available product.
In the present invention, the salt that above-described PQQ and pharmacology thereof allowed can a kind uses separately, also can be used in combination more than 2 kinds.
In the photoaging inhibitor of the present invention, the content of the salt that PQQ and/or its pharmacology allowed is generally 0.0001～1 weight % in photoaging inhibitor total amount 100 weight %, preferred 0.005～0.1 weight %, 0.001～0.03 weight % more preferably, 0.008～0.03 weight % more preferably is preferably 0.01～0.03 weight % again.
The present inventor has carried out various researchs to the effect of the salt that PQQ and pharmacology thereof allowed, and is shown by embodiment described later, and they have the effect of the expression of gene that promotes participation formation collagen and elastoidin.
Above-mentioned two kinds of protein for example constitute blood vessel wall and skin in organism, born important effect giving these organs aspect elastic force, play very large effect at aspects such as elastic force that keeps skin and tension force.
Think that such effect helps the photoaging inhibitory action and the skin thinning inhibitory action described later of the salt that PQQ and pharmacology thereof allow.
Owing to have foregoing gene expression facilitation, so the salt that PQQ and pharmacology thereof allowed can be used as collagen gene expression promoter and elastoidin gene expression promoter.
Described glue protogene can exemplify Col4a1 (its sequence can be consulted " Test No. (Assay ID): Mm00802372_ml; accession number (Accession number): Bru; Col4a-1; Del (8) 44H; Raw; Svc " .), Col1a1 (its sequence can be consulted " Test No.: Mm00801666_g1 accession number: Mov13; RP23-112C19.9; Col1a-1; Cola1; Mov-13 "), Col3a1 (its sequence can be consulted " Test No.: Mm01254476_ml accession number: AW550625; Col3a-1, KIAA4231, MMS10-W; Ms10w, mKIAA4231 ") and Col7a1 (its sequence can be consulted " Test No.: Mm00483818_ml accession number: AW209154 ").
Described elastoidin gene can exemplify ELN.This sequence can be consulted " Test No.: Mm00514670_ml, accession number: AI385707, AI480567 ".
Described collagen gene expression promoter and elastoidin gene expression promoter are except the purposes as the photoaging inhibitor, because collagen and elastoidin are important for the intensity and the elasticity that keep blood vessel wall, therefore can be used for purposes such as blood vessel wall reinforcing agent and blood vessel elastic force retention agent.In addition, also be applicable to the purposes of the gene expression promotion usefulness reagent in the laboratory.
Therefore photoaging inhibitor of the present invention has good photoaging inhibitory action owing to contain the salt that above-described PQQ and/or its pharmacology allows.Photoaging inhibitor of the present invention can be taked various dosage forms and forms such as skin preparations for extenal use, cosmetics, Oral preparation and diet product as described later, can contain other following one-tenth as required and grade.
Photoaging inhibitor of the present invention can contain oils and fats, thickening agent, sweet taste material, organic acid, on-steroidal anti-inflammatory agent, vitamins, analgesic agent, antifungal, steroid dose, weight reducing agent, antibacterial, antiviral agent, keratolytic, astringent or other active component etc. as required.
But the following composition of concrete example illustration of described each composition.
Oils and fats: Oleum Arachidis hypogaeae semen, cupu oil, rice embryo oil, perilla oil and core of Caulis et Folium Lini wet goods crude vegetal etc.; Glyceride of their solidified oil, fatty acid (comprising medium-chain fatty acid) (glyceride, two glyceride, triglyceride etc.) and Cera Flava etc.
Thickening agent: algaroba glue, guar gum, xanthan gum, tamarind gum, pectin and antler glue etc.
Sweet taste material: sucrose, fructose, maltose, erithritol, trehalose, maltose alcohol, Radix Glycyrrhizae extract, Flos Chrysanthemi processing sweet taste material, aspartame, acesulfame potassium, Sorbitol and xylitol etc.
Organic acid: citric acid, succinic acid, tartaric acid, ascorbic acid, lactic acid, malic acid, malonic acid, fumaric acid and maleic acid etc.
On-steroidal anti-inflammatory agent: glycyrrhizin derivatives such as Radix Glycyrrhizae extract, glycyrrhizic acid, glycyrrhizic acid dipotassium and glycyrrhizic acid one ammonium; The enoxolone or derivatives thereof; The allantoin or derivatives thereof; Indomethacin; Ibuprofen; Ibuprofen pyrrole methyl ester; Bufexamac; Butyl flufenamate; Bendazac; Piroxicam; Ketoprofen; Felbinac; Salicyclic acid derivatives such as methyl salicylate and glycol salicylate; Menthol; Camphora etc.
Vitamins: nicotinic acid classes such as vitamin methyl nicotinate, nicotinic acid and nicotinamide such as riboflavin, flavin-nucleotide, flavin adenine dinucleotide (FAD), Riboflavine Tertrabutyrate, Riboflavin Tetrabutyrate, riboflavin 5 '-phosphate ester sodium and riboflavin four nicotinates; Vitamin D classes such as hesperidin methyl, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol and dihydrotachysterol;
Vitamin K such as vitamin K1 and Menaquinone K6 class;
The Y-Hi-Z, thiamine disulfide, thiamine disulfide, DBT, benfotiamine, prosulthiamine, fursultiamine, bisbentiamine, cycotiamine, neuvitan, allithiamin, thiamine propyl disulfide, fursultiamine (thiamine tetrahydrofurfuryl disulfide), ground plug thiamine (Dicethiamine), sulbutiamine, curing one monophosphothiamine, ethyl thiamine disulfide element, thiamine propyl disulfide DBT hydrochlorate, thiamine hydrochloride, thiamine cetyl hydrochlorate, the vitamin B1 rhodanate, vitamin B1 spermaceti hydrochlorate, thiamine mononitrate, thiamine monophosphate, lysine thiamine, thiamine triphosphate, the thiamine phosphoric acid Monophosphate, the thiamine Monophosphate, the thiamine di-sulfate, the thiamine hydrochloride bisphosphate, the thiamine triguaiacyl phosphate, vitamin B 1 classes such as thiamine monophosphate triguaiacyl phosphate and thiamine cerul sulfuric ester;
Vitamin B6 classes such as Pyridoxin hydrochloride, acetic acid pyridoxin, pyridoxal hydrochloride, 5 '-pyridoxal 5-phosphate and hydrochloric acid pyridoxamine;
Vitamin B12 classes such as cyanocobalamin, hydroxocobalamin and desoxyadenosine cobalamine;
Folic acid classes such as folic acid, tetrahydrofolic acid, dihydrofoilic acid and pteroylglutamic acid;
Pantothenic acid classes such as pantothenic acid, calcium pantothenate, pantothenic acid alcohol, D-lactobacillus bulgaricus factor, D-pantethin, coenzyme A and pantoyl ether;
Biotin such as biotin and biotin complex of yeast. class;
The vitaminoid action factors such as carnitine, ferulic acid, alpha-lipoic acid and orotic acid etc.
Analgesic agent: indometacin, felbinac, methyl salicylate, glycol salicylate, allantoin or derivatives thereof, ibuprofen, ibuprofen pyrrole methyl ester, bufexamac, butyl flufenamate, bendazac, piroxicam and ketoprofen etc.
Antifungal: the special pyrene naphthols of hydrochloric acid, sulconazole nitrate, clotrimazole, Fazol (Schering), econazole nitrate, miconazole nitrate, econazole nitrate, Oxiconazole Nitrate, bifonazole, tioconazole, ketoconazole, tolnaftate, tolciclate, liranaftate, ciclopirox olamine, gram tinea peace, siccanin, 9-undecylenic acid, Zinc Undecenoate, pyrrolnitrin, butenafine hydrochloride, hydrochloric acid A Moluofen and hydrochloric acid is ticonazole etc. how.
Steroid dose: valeric acid dexamethasone acetate, dexamethasone, the propanoic acid dexamethasone, dexamethasone acetate, the valeric acid dexamethasone, prednisolone valerate acetate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone, pandel, cortisone acetate, prednisolone acetate, prednisolone, betamethasone, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, clobetasol propionate, acetic acid diflorasone, pentane acid double fluoro dragon-a/ible, beclometasone, the neopentanoic acid flumetasone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, amcinonide, halcinonide and difluprednate etc.
Weight reducing agent: xanthines such as caffeine, aminophylline, theophylline, Oxtriphylline, diprophylline, diisobutyl aminobenzoic acyl-oxygen base propyl group theophylline, theobromine, diprophylline, proxyphylline and hexanone theobromine; Capsaicin etc.
Antibacterial: isopropyl methyl phenol, gluconic acid chlorhexidine, Chlorhexidine hydrochloride, benzalkonium chloride, benzethonium chloride, cetab, dequalinium chloride, triclosan and triclocarban etc.
Antiviral agent: acyclovir and penciclovir etc.
Keratolytic: ethanol, isopropyl alcohol, propanol, butanols, Polyethylene Glycol, benzylalcohol, phenethanol, propylene carbonate, hexyl dodecanol, dimethyl sulfoxine, dimethyl acetylamide, dimethyl formamide, triethanolamine, diisopropyl adipate, ethyl laurate, agnolin, fatty acid dialkyl group alkylolamides, carbamide, sulfur, resorcinol, phytic acid, lactic acid, lactate, sodium hydroxide and potassium hydroxide etc.
Astringent: citric acid, tartaric acid, lactic acid, aluminum chloride, aluminum sulfate, allantoin aluminium chlorhydroxide, dihydroxy aldioxa, aluminium phenolsulfonate, p-phenolsulfonic acid's zinc, zinc sulfate, zinc lactate and aluminium chlorhydroxide etc.
In the photoaging inhibitor of the present invention, can use the described composition more than a kind separately or be used in combination more than 2 kinds.In addition, the content of these other compositions in the photoaging inhibitor of the present invention is generally 0.0001～99 weight %, preferred 0.001～70 weight %.
The dosage form of＜photoaging inhibitor 〉
Photoaging inhibitor of the present invention can adopt various dosage forms such as skin preparations for extenal use, cosmetics, Oral preparation and diet product.In these dosage forms, from manifesting the inhibiting angle of photoaging well, the form of preferred skin preparations for extenal use and cosmetics.
As the form more specifically of described skin preparations for extenal use, can exemplify various forms such as for example aqueous, emulsion form, paste, lotion shape, pulp-like, mousse shape, gel, lamellar (base material load), aerosol shape and spray form.
Form more specifically as described cosmetics, can exemplify for example basic cosmetics and cosmetics such as vanishing cream, kermes and lipstick such as astringent, emulsion, cream, oil and skin lotion, and cleansing milk, wash various forms such as abluents such as skin agent and bath gel and bathing agent.
There is no particular limitation as the form more specifically of described Oral preparation, can exemplify by PQQ directly or therein mix excipient or additive and various forms such as tablet, pill, granule, powder, powder, capsule (comprising soft capsule), drop, wettable powder, Emulsion, liquor, extractum and elixir.Wherein, this class preparation of preferred tablet, powder agent, granule, capsule and drop.
There is no particular limitation as the form more specifically of described diet product, can exemplify by PQQ directly or therein mix excipient commonly used in the food or additive and various forms such as tablet, pill, granule, powder, powder, capsule (comprising soft capsule), drop, wettable powder, Emulsion, liquor, extractum and gel.Wherein, the angle preferred drink from easily taking and carrying; Powder drink; And gel, tablet, powder, granule, capsule and this class preparation of drop.
The manufacture method of＜photoaging inhibitor 〉
Photoaging inhibitor of the present invention can make according to known method according to its dosage form.
For example, when the photoaging inhibitor is skin preparations for extenal use or cosmetics, the salt that can be allowed by fusion PQQ and/or its pharmacology, as other compositions of above-mentioned any composition and mixing of in scope amount and matter of harmless effect of the present invention, using as required at pharmaceuticals, non-pharmaceuticals or cosmetic field various compositions commonly used and with known method, obtain photoaging inhibitor of the present invention.
Described when carrying out fusion, to there is no particular limitation with each composition fusion in what order.
Described mixing was carried out 1～300 minute under 10～100 ℃ usually usually, stirred to surpass the above time sometimes according to the dissolubility of fusion composition.During mixing, can mix the composition that contains of photoaging inhibitor of the present invention simultaneously, also can be pre-mixed and add remaining composition more therein behind certain composition and mix.
Described mixing can be undertaken by various commercially available blenders.Can exemplify micro-granulating devices such as ultrasonic emulsification device, high-pressure uniform dispersal device, ultra micro granulation machine (nanomizer), homomixer, homogenizer, colloid mill, homogenizer as its example.In addition, there is no particular limitation to condition of physical agitation etc., can carry out according to conventional method.
In addition, when the form of described photoaging inhibitor adopts emulsion form and paste etc., mix the emulsifying agents such as surfactant as raw material, the composition that contains that mixes described photoaging inhibitor according to known method carries out emulsifying.
As at above-mentioned pharmaceuticals, non-pharmaceuticals or cosmetic field composition commonly used, can exemplify for example base, preservative agent, pH regulator agent, stabilization agent, stimulation palliative, antiseptic, coloring agent, dispersant, spice etc.; And the surfactant of low irritant.
These compositions can mix to combination in any more than a kind or 2 kinds separately.In addition, as long as the incorporation of these compositions can obtain effect of the present invention, there is no particular limitation, suitably selects but preferably exceed with the upper limit proportional quantity that pharmacy was allowed.
Can exemplify hydrocarbon such as paraffin, ceresine, ceresin, tristearin, microwax, three decanes (synthetic vegetalitas), alpha-olefin low polymers, liquid paraffin, Ultralube W 389 (plastibase etc.), liquid paraffin,light, light isoparaffins, liquid isoparaffin and polyethylene powders as described base;
Fatty acids such as lauric acid, myristic acid, Palmic acid, stearic acid, behenic acid, isostearic acid, oleic acid and linoleic acid;
Glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol one propyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol one propyl ether, diethylene glycol-butyl ether, propylene glycol monoethyl ether, propylene glycol one propyl ether, dipropylene glycol monoethyl ether and dipropylene glycol one propyl ether;
Ether compounds such as 2,2 '-[1,4-phenylene dioxy] diethanol, dioxane and butanediol adipate polyester etc.
Described preservative agent can exemplify benzoic acid, sodium benzoate, dehydroactic acid, dehydro sodium acetate, p-Hydroxybenzoic acid isobutyl ester, p-Hydroxybenzoic acid isopropyl ester, butyl p-hydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzyl p-hydroxybenzoate, methyl parahydroxybenzoate, phenyl phenol, sorbic acid and sodium sorbate etc.
＜suppress to bring out the inhibitor that produces wrinkle because of ultraviolet
Ultraviolet radiation is during to skin, and the collagen of the part that it shines and the internal layer of skin is destroyed or promote melanocyte to form, and therefore promotes the formation of the wrinkle of described part.
Photoaging inhibitor of the present invention is suitable for this purposes of bringing out the inhibitor that produces wrinkle because of ultraviolet.In addition, as described in " background technology ", in existing example, contain in the preparation or compositions of PQQ or derivatives thereof, the content of described PQQ etc. will be more than a certain amount of from the angle of the effect of performance PQQ etc., and will be below a certain amount of from the dissolubility and the angle of preparation stability solvent such as PQQ.Consequently, described content adopts the amount of (PQQ or its salt are about 0.1～10 weight %) about 0.01～10 weight %.
But, the present inventor finds now: bring out because of ultraviolet in the inhibitor purposes that produces wrinkle described, the content of the good especially salt that the PQQ of being and/or its pharmacology allowed in described inhibitor 100 weight % is generally 0.0001～1 weight %, preferred 0.001～0.1 weight %, 0.008～0.03 weight % more preferably, the particularly preferably amount that is lower than existing consumption of 0.01～0.03 weight %.
That is, among the present invention because the amount of needed PQQ etc. is less than standing crop in the preparation, therefore described inhibitor not only effect be better than existing preparation, and on manufacturing cost, also be dominant.Also have, the preparation that contains 10 weight %PQQ etc. as the conventional example PQQ etc. might occur and separate out the problem that is separated with bulk, but the present invention is because the content of the salt that PQQ and/or its pharmacology allowed in the preparation is low, therefore do not have above-mentioned situation about worrying, preparation stability is good.
Also have, described content range mainly is to be applicable to that the form of described wrinkle generation inhibitor is the scope of the situation of skin preparations for extenal use or cosmetics.It also can be diet product or Oral preparation that wrinkle produces inhibitor, in this case, the intake that the content of the salt that PQQ or its pharmacology allowed in wrinkle generation inhibitor can be set at them reaches common 0.01～100mg/ days, and preferred 0.1～60mg/ days, special 1～30mg/ days amount.
By using described inhibitor,, generally the generation of wrinkle can be controlled at 10～70% when not using inhibitor by bring out area or the volume reference that produces wrinkle because of ultraviolet.
[skin thinning inhibitor]
As described in " background technology ", the thinning of skin for example is meant that ability drop, epidermis attenuation, result that the amount of the collagen of the skin corium of skin with advancing age and elastoidin reduces, makes the myocyte of organism cause the phenomenon of thinning of skin.
The salt that the present inventor finds PQQ and pharmacology thereof now and allowed can suppress this phenomenon.Be as must composition containing at least one that is selected from the salt that PQQ and/or its pharmacology allow in the skin thinning inhibitor of the present invention.
As the salt that described pharmacology allowed, can exemplify with [photoaging inhibitor]＜salt that PQQ and pharmacology thereof allowed same salt, the i.e. alkali metal salt of PQQ (potassium salt and sodium salt etc.), alkali earth metal salt (calcium salt and magnesium salt etc.), organic amine salt (ammonium salt, triethanolamine salt and triethylamine salt etc.) and alkaline amino acid salt (lysine and arginine salt etc.) described in one.Wherein, from the inhibiting angle of skin thinning, sodium salt and the potassium salt of preferred PQQ.
In skin thinning inhibitor of the present invention, the salt that PQQ and pharmacology thereof allowed can use a kind separately, also can be used in combination more than 2 kinds.
Skin thinning inhibitor of the present invention can contain as required with [photoaging inhibitor]＜other compositions same other described in become to grade, i.e. oil preparation, thickening agent, sweet taste material, organic acid, on-steroidal anti-inflammatory agent, vitamins, analgesic agent, antifungal, steroid dose, weight reducing agent, antibacterial, antiviral agent, keratolytic, astringent or other active component etc.
Skin thinning inhibitor of the present invention can use a kind of described other composition separately or be used in combination more than 2 kinds, and its content is generally 0.0001～99 weight % in skin thinning inhibitor 100 weight %, preferred 0.001～70 weight %.
Skin thinning inhibitor of the present invention and photoaging inhibitor of the present invention are same, can adopt various forms such as skin preparations for extenal use, cosmetics, Oral preparation and diet product.The concrete form of these skin preparations for extenal use, cosmetics, Oral preparation and diet product is as the dosage form of＜photoaging inhibitor〉described in one.
In these forms, from manifesting the inhibiting angle of skin thinning well, the form of preferred skin preparations for extenal use and cosmetics.
This skin thinning inhibitor of the present invention and photoaging inhibitor of the present invention are same, can be according to its form by the known method manufacturing.
For example, when skin thinning inhibitor is skin preparations for extenal use or cosmetics, the salt that can be allowed by fusion PQQ and/or its pharmacology, as other compositions of above-mentioned any composition and the base that in scope amount and matter of harmless effect of the present invention, uses as required, preservative agent, the pH regulator agent, stabilization agent, stimulate palliative, antiseptic, coloring agent, dispersant, spice, pharmaceuticals such as low irritant surfactant, the various compositions that non-pharmaceuticals or cosmetic field are commonly used also mix with known method, obtain skin thinning inhibitor of the present invention.
The example of described fusion and blended method and their condition is as the manufacture method of＜photoaging inhibitor〉described in one.
The composition commonly used at above-mentioned pharmaceuticals, non-pharmaceuticals or cosmetic field can use a kind separately, perhaps at random is used in combination more than 2 kinds, better is that the upper limit blended amount that allowed with pharmacy is exceeded and carried out fusion.
The content of the salt that PQQ and/or its pharmacology allowed in the skin thinning inhibitor of the present invention (100 weight %) is generally 0.001～1 weight % from the inhibiting angle of skin thinning, preferred 0.01～0.1 weight %.
Described content range mainly is the form that the is applicable to skin thinning inhibitor scope when being skin preparations for extenal use or cosmetics.Skin thinning inhibitor also can be diet product or Oral preparation, at this moment, the content of the salt that PQQ or its pharmacology allowed in the skin thinning inhibitor intake that can be set at them reaches common 0.01～100mg/ days, preferred 0.1～60mg/ days, preferred especially 1～30mg/ days amount.
Embodiment
Below, the present invention will be described in more detail by embodiment, but the present invention is not limited to this.
[embodiment 1～3 and comparative example 1]
According to the composition of following table 1 record, at room temperature PQQ is dissolved in Purified Water after, in the solution of gained, add ethoxydiglycol, mixed 5 minutes, obtain each photoaging inhibitor.Comparative example 1 is not for containing the tester that photoaging suppresses composition.In addition, numeric representation weight % in table 1.
[table 1]
[test example 1]
Using Hos:HR-1 is female SPF mice (8 age in week), carries out the photoaging inhibitor of embodiment 1～3 and comparative example 1 and the evaluation of tester with n=10.
With 3 times/week frequency anesthesia under to mice body (10cm
2About) shine UVB 3 times altogether.Each exposure rate is 90mJ/cm
2
In addition, in duration of test, body is coated with photoaging inhibitor or tester with the each 100 μ l of 2 times/day frequency.Carry out collection of specimens in off-test day, the specimen of gathering utilized the three-dimensional skin analysis software of reflection-type (Korean and Japanese Bioisystech Co., Ltd (limited the ァ サ ヒ バ ィ ォ メ ッ of commercial firm De society) system) analyze, calculate wrinkle area occupation ratio and wrinkle volume fraction.Wrinkle area occupation ratio and wrinkle volume fraction are shown in Fig. 1 and Fig. 2.
Confirm that by Fig. 1 and 2 the tester group is brought out by ultraviolet radiation and produced tangible wrinkle.Can confirm on the other hand, used in the group of photoaging inhibitor of the present invention, whichever PQQ organizes the generation of bringing out that (0.005%PQQ, 0.01%PQQ and 0.1%PQQ) all suppresses wrinkle, can confirm that 0.01%PQQ organizes with respect to tester (comparative example 1), have to suppress effect (critical coefficient: 1%) especially significantly.Also have, in Fig. 1 and Fig. 2, Normal represents to shine wrinkle area occupation ratio and the wrinkle volume fraction of the preceding mice of UVB.
By this result of the test as can be known, the inhibitory action that produces wrinkle of bringing out of PQQ does not also rely on consumption, and PQQ excessive concentration or mistake are hanged down and all can not shown enough effects.
[test example 2]
Body to the Klotho mice of senilism model mice, with the preparation of 2 times/day frequencies coating embodiment 2, embodiment 3 or comparative example 1 (below be also referred to as checking matter), continued for 2 weeks, after the coating beginning, per 1 week is measured the skin thickness at the checking matter coating position of mice with micrometer (three rich (ミ ッ ト ョ) Co., Ltd.'s system).Each test is carried out with n=2～4.
Measurement result is shown in Fig. 3.Measure the skin thickness value of checking matter coating preceding (before on-test) in advance, each that demonstrates based on the gained measured value tested the initial coating 1 all backs of thing and the variable quantity (μ m) of the skin thickness after 2 weeks.
Can be confirmed by Fig. 3: the thinning of skin appears in tester group (being coated with the group of the preparation of comparative example 1) passing in time; And the thinning of PQQ group concentration dependent ground inhibition skin (keep or increase skin thickness).
[embodiment 4～7 and comparative example 2]
According to the composition of following table 2 record, at room temperature PQQ is dissolved in Purified Water after, in the solution of gained, add ethoxydiglycol, mixed 5 minutes, obtain each photoaging inhibitor.Comparative example 2 is not for containing the tester that photoaging suppresses composition.In addition, numeric representation weight % in table 2.
[table 2]
[test example 3]
With with the same method of test example 1, using Hos:HR-1 is female SPF mice (8 age in week), carries out the evaluation (calculating of wrinkle area occupation ratio and wrinkle volume fraction) of the photoaging inhibitor and the tester of embodiment 4～7 and comparative example 2 with n=7～8.The results are shown in Fig. 4 and Fig. 5.
By these results as can be known, when the content of the use salt that PQQ and/or its pharmacology allowed is the photoaging inhibitor of 0.01～0.03 weight %, can access the optimal inhibition effect that produces wrinkle to bringing out because of ultraviolet.
[test example 4]
＜experimental technique 〉
Using Hos:HR-1 is female SPF mice (7 age in week), implements following test with n=4～7.
This mice is divided into (i) UVB does not shine preparation (tester of comparative example 2) coating group, (ii) UVB does not shine preparation (the photoaging inhibitor of embodiment 5) coating group, (iii) UVB irradiation preparation (tester of comparative example 2) coating group, (iv) four experimental grouies of UVB irradiation preparation (the photoaging inhibitor of embodiment 5) coating group.
To described group of mice body (10cm that (iii) reaches (iv)
2About) under anesthesia, shine three UVB with the frequency in 3 times/week.Exposure rate each time is 90mJ/cm
2
In addition, in duration of test, to the mice body with the each 100 μ L painting preparations of 2 times/day frequency.At the skin of gathering body off-test day, in RNAlater (Ai Biweng (Ambion) corporate system), to preserve, the extraction of carrying out the RNA sample is refining.
Thereafter, use reverse transcriptase synthetic be present in glue protogene Col4a1 in the described sample and the complementary DNA of mRNA of elastoidin gene ELN, with the two strands of gained template as the PCR method.Use described template to implement the PCR in real time method, the amount of each mRNA sample is quantitative.In this method, the following substrate that uses u.s.a. applied biosystem company (Applied Biosystems) to produce.
(substrate of use)
ELN (Test No.: Mm00514670_ml)
Col4a1 (Test No.: Mm00802372_ml)
＜result 〉
Above measurement result is shown in Fig. 6.In Fig. 6, vehicle represents to have used tester (comparative example 2), and PQQ has represented to use the photoaging inhibitor of embodiment 5.
As shown in Figure 6, because of irradiation ultraviolet radiation, glue protogene and the expression of elastoidin gene in mouse skin all descend, but contain the preparation of PQQ by coating in advance, and to no matter which kind of gene all can suppress the decline of its expression significantly.By this, the photoaging inhibitor of the application of the invention can suppress or improve the photoaging that causes because of ultraviolet radiation.
Utilize probability on the industry
Photoaging inhibitor of the present invention is particularly useful because of ultraviolet brings out the inhibitor that produces wrinkle as inhibition, in addition, utilizes skin thinning inhibitor of the present invention can suppress the skin thinning, and their all are fit to use with form of skin preparations for extenal use and cosmetics.
Also have, the present invention can provide than existing preparation inexpensive and effect and preparation stability good bring out the inhibitor of generation wrinkle because of ultraviolet.
Claims (8)
1. pyrro-quinoline quinone (PQQ) and/or the application of salt in the preparation of photoaging inhibitor that its pharmacology allowed.
2. purposes as claimed in claim 1 is characterized in that, described photoaging inhibitor uses because of ultraviolet brings out the inhibitor that produces wrinkle as suppressing.
3. pyrro-quinoline quinone (PQQ) and/or the application of salt in the preparation of skin thinning inhibitor that its pharmacology allowed.
4. purposes as claimed in claim 1 or 2 is characterized in that, the pyrro-quinoline quinone (PQQ) in the described photoaging inhibitor and/or the content of the salt that its pharmacology allowed are 0.008～0.03 weight %.
5. purposes as claimed in claim 3 is characterized in that, the pyrro-quinoline quinone (PQQ) in the described skin thinning inhibitor and/or the content of the salt that its pharmacology allowed are 0.001～1 weight %.
6. purposes as claimed in claim 2 is characterized in that, the pyrro-quinoline quinone (PQQ) in the photoaging inhibitor that the inhibitor that produces wrinkle because of ultraviolet brings out as inhibition uses and/or the content of the salt that its pharmacology allowed are 0.01～0.03 weight %.
7. as each described purposes in the claim 1,2,4 and 6, it is characterized in that the salt that the pharmacology allowed of described pyrro-quinoline quinone (PQQ) is the sodium salt or the potassium salt of pyrro-quinoline quinone (PQQ).
8. as claim 3 or 5 described purposes, it is characterized in that the salt that the pharmacology allowed of described pyrro-quinoline quinone (PQQ) is the sodium salt or the potassium salt of pyrro-quinoline quinone (PQQ).
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| PL2722331T3 (en) | 2011-06-16 | 2018-02-28 | Mitsubishi Gas Chemical Company, Inc. | Crystal of pyrroloquinolinequinone disodium salt, and method for producing same |
| JP6329757B2 (en) * | 2012-12-04 | 2018-05-23 | ロート製薬株式会社 | Composition for external use |
| JP6284730B2 (en) * | 2013-09-25 | 2018-02-28 | ロート製薬株式会社 | Composition for external use |
| JP2015107946A (en) * | 2013-12-06 | 2015-06-11 | ロート製薬株式会社 | External composition |
| CN107106554A (en) * | 2014-09-22 | 2017-08-29 | 国立大学法人名古屋大学 | New life extender, the life method using the life extender, new dual oxide enzyme activator, the activation method of dual oxide enzyme activator, the manufacture of life extender and the manufacture of dual oxide enzyme activator |
| WO2017050171A1 (en) | 2015-09-25 | 2017-03-30 | 浙江海正药业股份有限公司 | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof |
| CN107007606B (en) * | 2016-02-04 | 2021-10-26 | 南京舒鹏生物科技有限公司 | Medicine for preventing and treating sjogren syndrome and combination thereof |
| JP7281156B2 (en) * | 2018-05-16 | 2023-05-25 | 共栄化学工業株式会社 | Skin topical agent |
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| US6203805B1 (en) * | 1998-11-10 | 2001-03-20 | Color Access, Inc. | Topical compositions containing whey proteins |
| FR2921259B1 (en) * | 2007-09-26 | 2015-02-13 | Lvmh Rech | COSMETIC USE OF TOCOPHEROL PHOSPHATE AS AN ANTI-AGING SKIN AGENT |
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