CN106852725A - Composition for improving skin - Google Patents

Composition for improving skin Download PDF

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Publication number
CN106852725A
CN106852725A CN201611106057.5A CN201611106057A CN106852725A CN 106852725 A CN106852725 A CN 106852725A CN 201611106057 A CN201611106057 A CN 201611106057A CN 106852725 A CN106852725 A CN 106852725A
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Prior art keywords
skin
fisetin
mentioned
composition
wrinkle
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Inventor
李惠珍
金美善
李相和
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LG H&H Co Ltd
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LG Household and Health Care Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Molecular Biology (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medicinal Preparation (AREA)

Abstract

Composition the present invention relates to contain fisetin as active ingredient, the effect that composition of the invention has to be improved or prevention skin aging, wrinkle, flexibility decrease, moisture decline, specifically, by the synthesis for promoting collagen (type I) and sulfated glycosaminoglycans in skin, improve and prevent wrinkle, the effect of the decline such as aging, elastic of skin with essence, and, due to from natural materials, therefore, Side effect is low, can effectively be used as the active ingredient of cosmetics, pharmaceuticals or food etc..

Description

Composition for improving skin
Technical field
The present invention relates to a kind of cosmetic for improving skin, health functional food and pharmaceutical composition.
Background technology
Skin is to undertake the vitals that bodily fuctions are protected from external environment condition.For example, carry the water for preventing inside Point and barrier function from active ingredient to outside outflow and body heat regulation function, the different physiological roles such as excretory function.With individual Body it is aging, skin also can lose critical function because aging.The reason for skin aging, can be roughly divided into:It is construed as the age The internal cause sexual factor of growth;And, because of the external cause sexual factor of sun light injury etc..Due to this inside and outside factor, skin occurs old Change, cause to generate wrinkle on skin and the phenomenon that elasticity is reduced occur, and this phenomenon is mainly the damage because of skin corium Produced with change.
The structure of skin is broadly dassified into epidermis, skin corium, subcutaneous layer of fat.Skin corium is the reality for occupying skin 90% The skin of matter, is made up of the matrix between connective tissue and tytosis and connective tissue such as collagenous fibres, elastomer.Glue Fibrillation is generated by fibroblast, it is known that its main function is to assign the robustness of skin machinery, assigns connective tissue and supports Drag and tissue adhesion, and worked in terms of the adhesion of support cell.This collagen its amount with age Gradually decrease, and structural damage, and this phenomenon is considered as endogenous skin aging, is the main cause for producing wrinkle.Also, The reason for exogen skin aging, generation wrinkle being can be regarded as because of the collagenous fibres damage of ultraviolet.Elastomer is used as guarantor The important substance of skin elasticity is held, when it occurs modified because of a variety of causes, the decline of skin elasticity can be caused.Matrix is to fill out The binding fiber and intercellular material of corium are filled, is existed with unbodied gel state.It is many as the hydrophily for constituting matrix The glycosaminoglycan of sugar, it exists when being dissolved in water with viscous liquid state, therefore also referred to as mucopolysaccharide (mucopolysaccharide).
Glycosaminoglycan (Glycosaminoglycan;GAG) be disaccharides the structure that connects repeatedly of sugar, for example, having transparent Matter acid (Hyaluronic acid), chondroitin sulfate (chondroitin sulfate), Heparan sulfate (heparan Sulfate), heparin (heparin), keratan sulfate (keratan sulfate), dermatan sulfate (dermatan sulfate).GAG can substantially be divided into two kinds, the i.e. GAG not comprising sulfate radical, such as hyaluronic acid (Hyaluronic acid); And the GAG comprising sulfate radical, as described above in remaining five kinds.
GAG is primarily present in extracellular matrix (Extracellular matrix in skin;ECM), filling is played to account for According to ECM most collagenous fibres, elastomer between space effect, and perceive change or the cell of peripheral protein matter Change, so as to transmit signal to cell.Thus, growth, differentiation and the normal function of cell are influenceed.Also, due to GAG with The adhesion of hydrone is outstanding, therefore to keeping moisture of skin to also function to important effect.When due to internal cause, outer thus generation skin When skin is aging, the GAG amounts being present in corium are reduced, and recombine the ability decline of GAG, so as to increase the sky of skin corium Gap, the problems such as cause the generation of wrinkle, the reduction of skin elasticity and moisture to reduce.
At present, the prevention as the wrinkle used for improving this skin aging and wrinkle and improvement cosmetic In, it is representative containing vitamin A (view alcohol) or the product of retinyl palmitate.However, the product containing these raw materials Product process over time, not only the change to composition in product is fragile, also, when being impregnated with concentration more than valid density or Decompose in skin, there is a problem that obvious skin irritatin and redness etc. can be caused, therefore, for safety, its usage amount is received Limit, so that the prevention of wrinkle and improvement and moistening effect are substantially faint.
Therefore, to exploitation can neither trigger safety issue, additionally it is possible to improve the aging and moisturizing of skin material and The demand of the cosmetic comprising the material exists always.
As described above, exist can either improve to essence skin aging and wrinkle, moisturizing energy to exploitation all the time Power etc., and do not have the demand of virose age resister, in order to solve above-mentioned problem, the present inventor is old to that can suppress skin always Change and material that wrinkle is produced studied, confirm fisetin to the synthesis of the sulfated glycosaminoglycans of Skin Cell and The facilitation effect of the synthesis of collagen types I is outstanding, so as to complete the present invention.
The content of the invention
Therefore, it is an object of the present invention to provide cosmetic composition, pharmaceutical composition with skin improvement effects And food compositions.
In order to reach above-mentioned problem, the present invention provides a kind of cosmetic composition, and it is yellow comprising paint as active ingredient Plain (fisetin) or derivatives thereof.
Above-mentioned composition, can be for promoting sulfated glycosaminoglycans (sulfated Glycosaminoglycan) to close Into composition.
Above-mentioned composition, can be the composition for promoting collagen synthesis.
Above-mentioned composition, can be for improving or preventing skin aging, wrinkle of skin, skin elasticity decline, skin water Content is divided to decline or aging composition.
The content of the fisetin being included in above-mentioned composition can be 1 × 10 relative to total composition-5~10 weights Amount %.
Above-mentioned cosmetic composition can have be selected from by solution, suspension, emulsion, paste, gel, creme, Skin lotion, pulvis, soap agent, the cleaning agent containing surfactant, oil, vanishing cream, toner class, cosmetic ointment, spray, face Formulation in the group that film, suncream, sun screen, makeup removing agent and cleaning agent are constituted.
In addition, the present invention provides a kind of cosmetics, it makees active ingredient, comprising fisetin (fisetin) or derivatives thereof.
In addition, the present invention provides a kind of pharmaceutical composition for preventing and treating skin injury disease, it is used as effective Composition, comprising fisetin (fisetin) or derivatives thereof.
Above-mentioned skin injury disease, can be selected from by erythema (erythema), skin aging, wrinkle of skin, skin capillary Blood vessel dilatation disease, skin elasticity decline and skin moisture content decline in constituted group.
Can be that aforementioned pharmaceutical compositions have selected from by ointment, creme, tablet, pill, pulvis, granule, glue The use of the formulation in the group that wafer, oral solution, syrup, the aqueous solution, non-aqueous solvent, suspending agent and emulsion are constituted In the composition of prevention and treatment skin injury disease.
In addition, the present invention provides a kind of health functional food composition, it includes fisetin as active ingredient (fisetin) or derivatives thereof, and for improving or preventing skin aging, wrinkle of skin, skin elasticity to decline or moisture of skin Content declines.
It is of the invention as active ingredient comprising fisetin composition, with improve or prevention the aging of skin, wrinkle, The effect that flexibility decrease, moisture decline, specifically, by promoting collagen in skin (I types) and sulphation The synthesis of glycosaminoglycan, it is possible to increase the mechanical robustness of skin, so as to have the essence ground to improve and prevention wrinkle of skin, old The effect of the declines such as change, elasticity, also, because from natural materials, Side effect is few, therefore in cosmetic, medicine It is highly useful in composition and food compositions.
Specific embodiment
The present invention relates to a kind of cosmetic composition, its as active ingredient, comprising fisetin or derivatives thereof.
Above-mentioned fisetin can be represented by following chemical formula 1.
Chemical formula 1:
The compound name of above-mentioned chemical formula 1 is 2- (3,4- dihydroxy phenyl) -3,7- dihydroxy chromone (2- (3,4- Dihydroxyphenyl) -3,7-dihydroxychromen-4-one), general entitled fisetin (fisetin).
Above-mentioned fisetin is the one kind in flavonoids species, is that molecular formula is C15H10O6, molecular weight is 286 compound. Above-mentioned fisetin is generally the crystallization of yellow needles, and fusing point is more than 360 DEG C, and the fisetin recrystallized in spirit of vinegar can contain 6 molecular crystalline water.
Above-mentioned fisetin, can be by chemical syntheses such as various organic chemistry procedures as known in the art.Furthermore it is possible to from Extracted in plant extracts and refined, so as to be readily available.Fisetin of the invention, is from Sigma-Aldrich (Sigma Aldrich, the U.S.) purchase use.
The derivative of above-mentioned fisetin, including fisetin part-structure is substituted or the compound that changes in, show All compounds of the effect similar to the effect of fisetin of the present invention.Fisetin of the invention, can be used as active ingredient, should For suppress, treat and improve with during collagen is reduced and the relevant wrinkle of flexibility decrease is produced, and, can be used as effective Composition, is applied to suppress, treat and improve other constituents i.e. conjunction of sulfated glycosaminoglycans because of dermal extracellular matrix It is during wrinkle is produced caused by declining and decomposing acceleration into amount also, also outstanding in the curative effect of the wound of skin etc. to occurring, And hence it is also possible to be used as the active ingredient of treat wound.And then, even comprising a small amount of fisetin, it is also possible to keep Outstanding effect, therefore in pharmaceuticals or cosmetics, it is old as improvement or prevention wrinkle of skin, skin elasticity decline or skin The active ingredient of change, can be utilized with various formulations, so as to have the advantages that have a wide range of application.
Confirming above-mentioned fisetin can promote the biosynthesis of sulfated glycosaminoglycans and collagen types I, from And can play makes the composition of collagen types I and dermis of skin extracellular matrix keep fine and close effect.
In a specific embodiment, in order to understand fisetin to HF and the effect of keratinocyte, And when HF processes fisetin, the generation for having confirmed sulfated glycosaminoglycans and collagen types I increases (Tables 1 and 2).Above-mentioned fisetin can promote the expression of HAS-2, HAS-3, in an embodiment of the present invention, in order to understand paint The enhancing effect that flavine is expressed HAS-2, HAS-3, and Human keratinocytes process fisetin when, confirm HAS-2, The expression of HAS-3 increases (table 3).
Therefore, cosmetic composition of the invention, can be for promoting sulfated glycosaminoglycans (sulfated Glycosaminoglycan) the cosmetic composition of synthesis and/or collagen synthesis.
In addition, cosmetic composition of the invention can be the cosmetic composition of skin moisture-keeping.
Cosmetic composition comprising above-mentioned fisetin, plays the generation for improving sulfated glycosaminoglycans in skin, And promote I collagen types albumen generation, enhancing HAS expression effect such that it is able to improve skin, it is therefore preferable that be for Improve or prevention skin aging, wrinkle of skin, the cosmetic composition that skin elasticity declines or skin moisture content declines.
By experiment, confirm during using composition of the invention, skin moisture content increases and water holding capacity Increase (table 4), also, by experiment, confirm the effect of improvement, pre- anti-aging, prevention or the improvement wrinkle of skin of skin elasticity Really outstanding (table 5).
Above-mentioned term " skin aging ", refers to occur elasticity reduction, gloss reduction, wrinkle generation, power of regeneration on skin Decrease or the seriously symptom such as dry, can induce, when same with collagen, elastin laminin because of the passage of time or external environment condition etc. When the extracellular matrix such as sulfated glycosaminoglycans constituent when reducing, can produce that skin elasticity declines or wrinkle of skin is generated Phenomenon, it is possible to induced because of the reduction of mentioned component.
Term " wrinkle of skin " of the invention, refers to the microgroove or fold (fold) being formed on skin.Above-mentioned skin wrinkle Line can induce because of gene, the reduction of the collagen being present in dermis of skin, external environment condition etc., when contributing to elastin laminin When sulfated glycosaminoglycans with the structural support in the cell such as collagen are reduced, wrinkle of skin can be produced.
Above-mentioned term " skin elasticity ", is the bullet being made up of the elastin laminin (elastin) by being present in skin corium Property fiber produce, due to this elastomer as rubber with low-down coefficient of elasticity, therefore by small strength Can easily deform, and can be resiled easily when above-mentioned strength is removed.Due to above-mentioned sulfated glycosaminoglycans Reduction, can not only bring the reduction of collagen and elastin laminin, and be difficult to holding structure, therefore skin elasticity occurs The situation of decline.
Above-mentioned term " moisturizing ", refers to suitably regulation moisture loss (moisture evaporation) etc., so as to keep the perseverance of organism Perseverance.When with the sulfated glycosaminoglycans reduction simultaneously of hyaluronic acid in skin, moisture loss can be caused.
Above-mentioned term " prevention ", no matter referring to the reason for causing aging, suppresses or postpones skin using composition of the invention The situation that skin is aging or wrinkle is generated, elasticity or moisture decline, preferably refers to be formed by fibroblast and cutin Promote the effect of the biosynthesis of sulfated glycosaminoglycans and collagen types I in cell, reach the situation for suppressing or postponing.
Above-mentioned term " improvement ", refers to keep or reinforcing and wrinkle of skin, aging and elastic related ability, so that skin Skin state takes a turn for the better or benefited all behaviors, specifically referring to the synthesis for promoting sulfated glycosaminoglycans, not only suppresses elastic egg The reduction of white and collagen, also keeps their structure, so that wrinkle of skin, aging, elastic or moisture are obtained Turn.
Fisetin can be included in above-mentioned composition with effective dose.
Above-mentioned term " effective dose ", is the phenomenon for referring to suppress or postpone skin aging or wrinkle generation, or can The amount of the fisetin of the wrinkle that alleviation has been generated.
The effective dose of the above-mentioned fisetin being included in wrinkle improvement composition of the invention, can improve according to wrinkle With the form of composite preparation, and the above-mentioned fisetin method for being used in skin and time for resting on skin etc. without Together.For example, when above-mentioned wrinkle improvement composition is produced in the pharmaceuticals form of the wrinkle of skin generated in dermatological treatment During product, compared with the form of the daily cosmetics suitable for skin by the situation of commercialization, the paint of higher concentration can be included Flavine.Also, in the case of in the form of the cosmetics by commercialization, the makeup removing of skin is stayed in when the active ingredient short time In the case that agent, cleaning agent etc. rinse the cosmetics of (wash-off) type, the fisetin of higher concentration can be included.Conversely, When the cosmetic for staying in disposable (leave-on) type such as toner, emulsion, frost, the essence of skin for a long time for active ingredient In the case of product, the fisetin of low concentration can be included compared with the cosmetics of type of flush.
Specifically, the content of the fisetin being included in above-mentioned composition, relative to total composition can for 1 × 10-5~10 weight %, or 1 × 10-4~8 weight %, or 1 × 10-3~6 weight %, or 1 × 10-2~5 weight %, or 0.05~ 4 weight %, or 0.01~2 weight %.When the content of mentioned component is less than 0.00001 weight %, it is difficult to obtain its effect, and When more than 10 weight %, then as solvent the composition such as dissolubility overall processing reduction, accordingly, as described laterization The use of the various uses such as cosmetic formulation may be limited.
In addition, the concentration of the fisetin in being included in above-mentioned composition, preferably 0.1 μ g/mL~100 μ g/mL, more preferably It is 1 μ g/mL~50 μ g/mL, more preferably 5 μ g/mL~25 μ g/mL.
Above-mentioned cosmetic composition can be used with any formulation suitable for epidermis.For example, can have be selected from by Solution, suspension, emulsion, paste, gel, creme, skin lotion, pulvis, soap agent, the cleaning agent containing surfactant, oil, powder In the group that cream base, toner class, cosmetic ointment, spray, facial mask, suncream, sun screen, makeup removing agent and cleaning agent are constituted Formulation, but it is not limited to above-mentioned concrete example.
In addition, above-mentioned cosmetic composition can be as strengthening skin elasticity, preventing skin aging, improvement skin The skin preparations for extenal use of wrinkle etc. and use.
In one embodiment of this invention, fisetin is manufactured into externally-applied ointment or essence formulation, and is applied to During the skin of people, confirm that there is outstanding wrinkle of skin improvement.Especially, confirm in the present invention, even if with low dense Degree is i.e. a small amount of using in the case of fisetin, it is also possible to show outstanding effect improving wrinkles.
For the ease of using and processing, the cosmetic composition containing fisetin of the invention can also be comprising cosmetic Acceptable carrier on, diluent, auxiliary agent, colouring agent, stabilizer, fragrant agent, surfactant, oil, NMF, alcohol, Thickener, antioxidant, pH adjusting agent, sun-screening agent etc., when being used as composition for external application, additionally it is possible to liquid, breast Any formulation that shape, white shape, ointment, bar-shaped, facial mask, paste, pulvis etc. can be applied to epidermis is used.
For the ease of using and processing, above-mentioned cosmetic composition can also learn upper acceptable figuration comprising making up Agent.As the upper acceptable excipient of above-mentioned cosmetic, can enumerate surfactant, emulsifying agent, soap acid, solvent, adhesive, Diluent, lubricant, stabilizer, spices, water, lower alcohol, thickener, chelating agent, pigment, preservative, colouring agent, preservative agent, It is antibiotic, antioxidant, defoamer, antiseptic, anti-reprecipitation agent, enzyme, plant or mineral oil, fat, fluorescent material, antifungal It is agent, hydrotropism's inducing substance, NMF, aromatic, aroma carrier, protein, organosilicon, solubilizer, sugar derivatives, sun-proof Agent, vitamin, plant extracts or wax etc., and can comprising it is therein one or more.
When above-mentioned cosmetic combination dosage form is turned into cosmetics, the carrier function for playing active component can be included The acceptable known excipient of skin, specifically may be referred to International cosmetic ingredient Dictionary, 6th ed., The cosmetic, Toiletry and Fragrance Association, Inc., Washington, the content disclosed in 1995.By above-mentioned document as part of this specification.
Moreover, it relates to a kind of cosmetics, its as active ingredient, comprising fisetin or derivatives thereof.
Above-mentioned cosmetics can have selected from by toner class, essence class, surfactant class, skin lotion class, white class, face Any one formulation in the group that film class is constituted.
For example, above-mentioned cosmetics can be surfactant, smoothing toner, toner, astringent lotion, skin lotion, emulsion, skin-moisturizing, skin Liquid, nutrition skin lotion, massage cream, nourishing cream, moisturiser, hand lotion, vanishing cream, essence, nutrition essence, facial mask, soap, Mildy wash, clean skin dew, makeup removing frost, body lotion and shower cream etc., but it is not limited to this.
Moreover, it relates to a kind of pharmaceutical composition for preventing or treating skin injury disease, it is used as effective Composition, comprising fisetin or derivatives thereof.
Moreover, it relates to a kind of pharmaceuticals comprising aforementioned pharmaceutical compositions or medical auxiliary product (sanitary aid)。
Aforementioned pharmaceutical compositions, refer to for the purpose of diagnosing, treat, mitigate, dispose or prevention includes the Animal diseases of people And the medicinal material for using.
Above-mentioned skin injury disease, refers to the disease occurred by skin damage, specifically, be can be selected from by erythema (erythema), skin aging, wrinkle of skin, skin capillary vascular expansion disease, skin elasticity decline, skin moisture content decline And in aging constituted group.
The preferred dosage of pharmaceutical composition of the invention, age, sex according to administration object, body weight, symptom, disease Without same during degree, drug form, method of administration and the administration of disease, those skilled in the art can properly select.In order to Outstanding effect is obtained, preferably pharmaceutical composition of the invention was administered with the amount of 0.01~1000mg/ days.Administration can be daily Once, it is also possible to carry out several times.In addition, dosage can be entered according to age, sex, body weight, the degree of disease, method of administration etc. Row increase and decrease.Therefore, above-mentioned dosage does not limit the scope of the present invention in any way.
Above-mentioned composition can be delivered medicine to by the lactations such as rat, mouse, domestic animal, people by the number of ways such as parenteral, oral Animal, all modes of administration can be it is contemplated that for example, can be by oral, rectum or vein, muscle, subcutaneous, intrauterine (intracerebroventricular) injection is administered in film or telocoele.
Pharmaceutical composition for preventing or treating skin injury disease of the invention, can individually comprising as effectively into The above-mentioned fisetin for dividing, in addition, according to formulation, application method and application target, can also include pharmaceutically acceptable Carrier, excipient, diluent and/or auxiliary element.
More specifically, in addition to above-mentioned active ingredient, can also comprising nutritional agents, vitamin, electrolyte, flavouring agent, Colouring agent, hardening agent (enhancer), pectic acid and its salt, alginic acid and its salt, organic acid, protective colloid thickener, pH are adjusted Section agent, stabilizer, preservative, glycerine, alcohol, the carbonating agent etc. for soda.
Above-mentioned " pharmaceutically acceptable ", refers to acceptable in a physiologically, and when being administered to animal, preferred pair people, generally The allergic reactions such as gastrointestinal dysfunction, dizziness or reaction similarly will not be caused.Above-mentioned pharmaceutically effective amount, can basis Suitably change during disease and its order of severity, patient age, body weight, health status, sex, method of administration and treatment etc..
As the example of above-mentioned pharmaceutically acceptable carrier, excipient or diluent, can enumerate selected from by lactose, Glucose, sucrose, D-sorbite, mannitol, xylitol, antierythrite, maltitol, starch, gum arabic, alginates, Gelatin, calcium phosphate, calcium silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxy benzene Formates, the third hydroxy benzoate, talcum, magnesium stearate and mineral oil, dextrin, calcium carbonate, propane diols, atoleine and physiology One or more of group that salt solution is constituted, but this is not limited to, common carrier, excipient or diluent can make With.
Mentioned component can be added in the above-mentioned fisetin as active ingredient afterwards alone or in combination.
The formulation of aforementioned pharmaceutical compositions can be different according to application method, it is possible to use known in art of the present invention Method carry out formulation, with after being administered to mammal, using the teaching of the invention it is possible to provide active component it is rapid, continue or postpone release Put.As the example of above-mentioned formulation, can enumerate selected from by ointment, creme, tablet, pill, pulvis, granule, capsule, Formulation in the group that oral solution, syrup, the aqueous solution, non-aqueous solvent, suspending agent and emulsion are constituted.
For above-mentioned formulation, excipient can also be included, for example, comprising conventional filler, increment drug, adhesive, collapsing Solution agent, surfactant, anti-coagulants, lubricant, wetting agent, spices, emulsifying agent, preservative, sweetener, aromatic or preservative agent Deng.
The solid pharmaceutical preparation being administered orally is commonly used for, comprising tablet (TABLETS), soft or hard rubber wafer (CAPSULES), pill (PILLS), pulvis (POWDERS) and granule (GRANULES) etc., this preparation can mix one kind More than excipient and modulate, for example, mixing starch, calcium carbonate (calcium carbonate), sucrose (sucrose) or breast Sugared (lactose), gelatin etc..In addition, in addition to simple excipient, the lubricants such as magnesium stearate, talcum can also be used.
In addition, for the liquid preparation being administered orally, there is suspending agent (SUSTESIONS), oral solution, emulsion (EMULSIONS) and syrup (SYRUPS) etc., in addition to water or atoleine as usually used simple diluent, also Various excipient can be included, for example, wetting agent, sweetener, aromatic, preservative agent etc..
In the example of cutaneous penetration, have and be adapted to generation talcum powder, emulsion, suspension, oil, spray, ointment, soft containing fat Cream (greasy ointment), cream ointment, gel, foaming agent or solution, and suitable for transdermal drug delivery system (TTS: Transdermal therapeuticsystem) carrier and/or excipient.Topical pharmaceutical formulations of the invention, Ke Yishi Semi-solid formulation, particularly, there is ointment (solution ointment, suspension ointment), creme, gel or paste.It is main in emulsus What is used has:Fatty alcohol, for example, laruyl alcohol, cetanol, stearyl alcohol;Aliphatic acid, for example, palmitic acid or stearic acid;Liquid is solid Body paraffin or ceresine, liquid to solid-like wax, for example, isopropyl myristate;Natural fat or partially synthetic fat, for example, The ester of coconut fatty acid three;Fixed oil, for example, hydrogenated groundnut or castor oil;Or, the part esterification of glycerine fatty acid Material, for example, glycerin monostearate or distearin.As preferred emulsifying agent, there is surfactant, can lift Go out nonionic surfactant:The fatty acid ester of polyalcohol or its ethylene oxide adduct, for example, aliphatic acid polyglycerol esters or poly- Ethylene oxide sorbitan fatty acid ester;Sorbitan fatty acid ester, for example, sorbitan monooleate and/or dehydration Sorbierite isostearate etc., isostearate, sterol, polyoxyethylene aliphatic alcohol ether or fatty acid ester, anionic surface are lived Property agent:The alkali metal salt of fatty alcohol sulfonates, for example, NaLS, cetanol sodium sulfovinate or sodium stearyl sulfate, These are typically in the presence of above-mentioned fatty alcohol, for example, being used in the presence of cetanol or stearyl alcohol.Wherein, particularly, To can be used to prevent the dry preparation of creme, for example, being that glycerine, D-sorbite, propane diols and/or polyethylene glycol add by polyalcohol It is added in water phase, or, in preservative agent, spices etc. being made an addition into water phase.
Pharmaceutical preparation of the invention can be the ointment of anhydrous state.In addition, said medicine preparation can be local comprising being adapted to Purposes and under body temperature for liquid paraffin, particularly, low viscosity paraffin can be included.Or, said medicine preparation can be wrapped Containing natural fat or partially synthetic fat (for example, the ester of coconut fatty acid three), fixed oil is (for example, hydrogenated groundnut or castor Sesame oil), the material (for example, glycerin monostearate and distearin) of the fatty acid part esterification of glycerine, organosilicon (for example, polymethyl siloxane, such as HMDO or octamethyltrisiloxane).In addition, said medicine preparation, for example also Comprising relevant with aqueous creams, and the fatty alcohol of moisture absorption amount can be improved, and sterol, lanocerin (wool wax), Other emulsifying agents and/or other additives.
In the present invention, when aforementioned pharmaceutical compositions formulation is turned into pharmaceuticals, Remington ' s are referred to Content disclosed in Pharmaceutical Science, Mack Publishing Company, Easton PA, and will be above-mentioned Document as part of this specification.
In addition, for improvement, mitigation, treatment or the prevention of skin injury disease, can be used alone medicine group of the invention Compound, or can be by pharmaceutical composition of the invention and operation, hormone therapy, drug therapy and use BRM Method is used in combination.
More than, unless illustrated in this manual, the numerical value described in this specification includes the scope impartial with it.
Moreover, it relates to health functional food composition, it contains fisetin or derivatives thereof as active ingredient, And skin aging, wrinkle of skin, skin elasticity decline or skin moisture content declines for improving or preventing.
Above-mentioned food, refers to the natural materials containing more than one nutrients or processing material, preferably refers to by certain The direct-edible state of the operation of degree, including common health functional food, functional food, beverage, food additives, And beverage additive.
Above-mentioned food, for example, can be various foodstuffs, beverage, chewing gum class, tea, B B-complex, healthcare function food Product etc..And, in the present invention, food is also including food of special nutrients (for example, the newborn class of modulation, infant food etc.), meat Processed goods, processed fish meat products, Tofu, bean jelly class, noodles (for example, hand-pulled noodles class, such as noodles etc.), health care accesary foods, seasoning food Product (for example, soy sauce, salty sauce, thick chilli sauce, mixing sauce etc.), sauce class, Biscuits (for example, snack categories), newborn processed goods (for example, Acidified milk, cheese etc.), other processed foods, pickles, cure foods (various pickles classes, sauced class etc.), beverage is (for example, fruit With greengrocery beverage, soya-bean milk class, fermented beverage class etc.), natural flavouring (for example, hand-pulled noodles soup etc.), but it is not limited to this.
Above-mentioned food, functional food, health functional food, beverage, food additives and beverage additive, can pass through Conventional manufacture method manufacture.
" health functional food " in the present invention, refers to by physics, biological, biological engineering method etc., to food Product impart added value, so as to the function of the food, the food group of specific purpose is expressed in, or, refer to by setting Meter processing, make that food composition has prevents with organism defence tempo adjustment, disease and the relevant body regulation such as recovers Function, gives full expression to the food in organism.
Above-mentioned health functional food, be able to can also include usual comprising acceptable food auxiliary additive in bromatology Suitable carrier, excipient and the diluent used in the manufacture of health functional food.
Beverage of the invention, refers to the general designation of the material drunk to quenching one's thirst or sample, including health functional beverage.
Above-mentioned beverage, except as must composition above-mentioned fisetin (fisetin) or its derivative are included with the ratio that specifies Beyond thing is as active ingredient, do not have special restriction to other compositions, also, identical with common beverage, may be used also Comprising the other compositions such as various flavouring agents or natural carbohydrate.
As above-mentioned natural carbohydrate, the disaccharides of the monose of glucose, fructose etc., maltose, sucrose etc. can be enumerated, The polysaccharide of dextrin, cyclodextrin etc., or xylitol, D-sorbite, antierythrite etc. sugar alcohol etc..Above-mentioned flavouring agent, can be as The natural flavours such as the qualities of stevia extract of Talin, rebaudioside A (Rebaudioside-A) or glycyrrhizic acid, or, can be with It is the synthesis flavouring agent of essence, Aspartame etc..
The addition of above-mentioned natural carbohydrate relative to food compositions 100mL of the invention ordinarily be about 1g~ 20g, preferably 5g~12g.In addition, composition of the invention can also be containing for manufacturing fruit juice, fruit drink, vegetables The pulp of beverage.
Apart from the above, food compositions of the invention can include various nutritional agents, vitamin, mineral matter (electrolyte), Synthesis flavouring agent and the natural flavour mountaineous dose of flavouring agent of grade, colouring agent and hardening agent (cheese, chocolate etc.), pectic acid and its salt, Alginic acid and its salt, organic acid, protective colloid thickener, pH adjusting agent, stabilizer, preservative, glycerine, alcohol, in soda Carbonating agent for using etc..
These compositions may be used alone or in combination and use.The ratio of above-mentioned additive is unimportant, can be relative to this hair Bright fisetin (fisetin) or derivatives thereof 100 weight portions are to be selected in the range of 0~2000 weight portion.
Above-mentioned " health functional beverage ", refers to, by physics, biological, biological engineering method etc., beverage to be assigned Added value, so as to the function of the beverage, be expressed in the beverage group of specific purpose, or, refer to be processed by designing, Make beverage constitute have the relevant body regulatory function such as prevent and recover with organism defence tempo adjustment, disease, fill Divide the beverage for being expressed in organism.
Above-mentioned health functional beverage, except as must composition with the ratio that specifies comprising fisetin of the invention as Beyond active ingredient, do not have special restriction to other compositions, identically with common beverage, can also include various fragrance The other compositions such as agent or natural carbohydrate
As above-mentioned natural carbohydrate, the disaccharides of the monose of glucose, fructose etc., maltose, sucrose etc. can be enumerated, The polysaccharide of dextrin, cyclodextrin etc., or xylitol, D-sorbite, antierythrite etc. sugar alcohol etc..Above-mentioned flavouring agent, can be as The natural flavours such as the qualities of stevia extract of Talin, rebaudioside A (RebaudiosideA) or glycyrrhizic acid, or, Ke Yishi The synthesis flavouring agent of essence, Aspartame etc..
The addition of above-mentioned natural carbohydrate relative to food compositions 100mL of the invention ordinarily be about 1g~ 20g, preferably 5g~12g.In addition, composition of the invention can also be containing for manufacturing fruit juice, fruit drink, vegetables The pulp of beverage.
Apart from the above, food compositions of the invention can include various nutritional agents, vitamin, mineral matter (electrolyte), Synthesis flavouring agent and the natural flavour mountaineous dose of flavouring agent of grade, colouring agent and hardening agent (cheese, chocolate etc.), pectic acid and its salt, Alginic acid and its salt, organic acid, protective colloid thickener, pH adjusting agent, stabilizer, preservative, glycerine, alcohol, in soda Carbonating agent for using etc..These compositions may be used alone or in combination and use.The ratio of above-mentioned additive is unimportant, can be in phase It is to be selected in the range of 0~20 weight portion for the weight portion of fisetin of the invention 100.
Above-mentioned health functional food can also include food additives, if suitable as food additives, without it In the case that he specifies, then according to the food additives code general provisions and ordinary test side ratified by food pharmaceuticals State Security Department Method etc., and specification and standard based on relevant classification judged.
During health functional food of the invention is manufactured, can as needed, suitably increase and decrease is including including beverage Food in the fisetin of the present invention (fisetin) that is added or derivatives thereof content, preferably its usage amount is relative to food The weight % of total amount 100 is 0.00001~10 weight %.
Moreover, it relates to use of the fisetin in above-mentioned cosmetic, pharmaceutical composition or food compositions are manufactured On the way, the method for further relating to improve skin, the method includes the step of fisetin of effective dose is applied to skin or is taken.
Below, for the ease of understanding the present invention, preferred embodiment is enumerated.But, following embodiments are merely to more hold Change places and understand the present invention and provide, present disclosure is not limited to following embodiments.
Embodiment 1:Confirm the synthetic effect of promotion collagen types I in HF
During fisetin made an addition into the nutrient solution of HF (Human fibroblast), on a cellular level really Accept and promote the synthetic effect of collagen.The fisetin for being used, is from Sigma-Aldrich (Sigma Aldrich, U.S. State) buy and use.It is using PICP EIA kits (Procollagen Type to the measure of synthesized collagen I C-Peptide Enzyme Immuno Assay KIT) quantified.
In an experiment, the ultimate density of fisetin is adjusted to 10 μ g/mL, 20 μ g/mL.By fisetin addition in people into fibre After tieing up in the culture medium (DMEM culture mediums) of cell culture 48 hours, take nutrient solution, by PICP EIA kits, and using point Light photometer, determines the collagen synthesis degree in each concentration respectively at 450 nm.
For comparative effectiveness, to fibroblastic culture medium (control group) and ultimate density without any material of addition The mode for reaching 10ng/mL adds the sample of TGF-beta, and the synthesis degree of collagen is determined by identical method.
The increment rate of collagen generation, is calculated relative to the relative ratios of control group with collagen growing amount, In showing the result in table 1 below.
Table 1
Embodiment 2:Confirm the effect for promoting sulfated glycosaminoglycans to synthesize in HF
During fisetin made an addition into the nutrient solution of HF (Human fibroblast), on a cellular level really Accept and promote sulfated glycosaminoglycans synthetic effect.To the measure of sulfated glycosaminoglycans, detected using aminopolysaccharide sulfate Kit (Blyscan glycosaminoglycan assay kit, Biocolor) is quantified.
In an experiment, the ultimate density of fisetin is adjusted to 1 μ g/mL, 10 μ g/mL, 20 μ g/mL.Fisetin is added After being cultivated 24 hours in the culture medium (DMEM culture mediums) of HF, nutrient solution is taken, examined by aminopolysaccharide sulfate Test agent box, and spectrophotometer is utilized, sulfated glycosaminoglycans total amount in determining each concentration respectively under 656nm.
The increment rate of sulfated glycosaminoglycans generation, is any relative to without addition with sulfated glycosaminoglycans growing amount The relative ratios of the fibroblast culture medium (control group) of material calculate, in showing the result in table 2 below.
Table 2
As above-mentioned table 2 is represented, compared with the control group of untreated fisetin, confirm in 10 μ g/mL and 20 μ g/mL, There is outstanding sulfated glycosaminoglycans synthetic effect respectively.
Embodiment 3:The increasing of hyaluronic acid synthetase (HAS) gene expression based on fisetin in Human keratinocytes Plus
By Human keratinocytes in the DMEM culture mediums comprising 10% cow's serum (fetal bovin serum) with 1 ×106Cell/mL is cultivated, and is injected separately into 6 orifice plates, is 3000 μ L per hole injection rate, has been cultivated 18 hours.Then, Washed 2 times with the DMEM culture mediums not comprising cow's serum, processed 24 hours with fisetin (1ppm or 10ppm).Cell is reclaimed, is led to After crossing RNeasy mini kits (Qiagen) extraction wholes RNA, quantified, the RNA of 1 μ g is utilized RNA PCR kits (Applied Biosystems) carry out reverse transcription (reverse transcription).Reverse transcription reaction It is to pass throughPCR instrument device (Biorad) is carried out.
Then, using the μ L of reverse transcription reaction solution 2 and HAS-2, HAS-3, GAPDH (glyceraldehyde 3-phosphate dehydro-genase, Glyceraldehyde-3-phosphate dehydrogenase)Probe (Invitrogen, the U.S., HS02511055_S1, HS03929097_g1), carry out real-time fluorescence quantitative PCR (quantitative real time PCR).Real-time fluorescence quantitative PCR, is using CFX 96touchTMReal-time fluorescent quantitative PCR detection system instrument (CFX96 TouchTMReal-Time PCR Detection System, Biorad) carry out.The experiment obtained by real-time fluorescence quantitative PCR As a result, be on the basis of GAPDH as special (housekeeping) gene, by Livak K.J. it is outer (Methods, 2001,25,402-408) method described in is calculated.
In addition, as positive controls, in the group processed instead of above-mentioned fisetin with glucosamine 100ppm, Confirm mrna expression amount.To the above results, on the basis of the mrna expression amount of negative control group for not carrying out any treatment (100%), the mrna expression amount that fisetin processes experimental group and positive controls is quantized, and is shown in Table 3.
Table 3
As described in above-mentioned table 3, processed by fisetin, the expression of hyaluronic acid synthetase increases in Human keratinocytes Plus, especially, the expression of HAS-2 and HAS-3 increases.In addition, it is thus identified that be less than 100 times than positive controls (glucosamine) It is a small amount of using the expression quantity in the case of fisetin, also showing the HAS-2 similar to positive controls and HAS-3, with When a small amount of less than 10 times uses, then confirm that the expression higher than positive controls can be induced.Thus, it is possible to confirm, even if Lead to too small amount of fisetin, it is also possible to there is outstanding moistening effect to the reduction of moisture of skin maintenance dose.
Production Example 1 and comparative example 1:The manufacture of external ointment for skin
According to the composition of table 4 below, manufactured fisetin as outside the skin that active ingredient is included by conventional method Use ointment.In addition, as comparative example 1, using the other compositions in addition to active ingredient, having manufactured external ointment for skin.
Table 4
Composition (weight %) Production Example 1 (weight %) Comparative example 1 (weight %)
Fisetin 0.2 0
Diethyl sebacate 8 8
Spermaceti 5 5
Polyoxyethylene oleyl ether phosphate 6 6
Sodium Benzoate 1 1
Vaseline To 100 To 100
Production Example 2 and comparative example 2:The manufacture of essence
Used as Production Example 2, manufactured prevents skin aging with improvement wrinkle using fisetin as what active ingredient was included Cosmetic essence formulation, in addition, as comparative example 2, using the other compositions in addition to active ingredient, with Production Example 2 Cosmetic essence has been manufactured in the same manner.Detailed composition is shown in table 5 below.
Table 5
Composition (weight %) Production Example 2 (weight %) Comparative example 2 (weight %)
Fisetin 0.5 0
Glycerine 10.0 10.0
Aqueous solution of sodium hyaluronate (1%) 5.0 5.0
Crodaret 1.0 1.0
Methyl p-hydroxybenzoate 0.1 0.1
Spices 0.05 0.05
Pure water To 100 To 100
Experimental example 1:Wrinkle of skin improvement is confirmed by panel test (panel test)
It is object with the healthy women of 35 years old~50 years old for above-mentioned Production Example 2 and the essence of comparative example 2, following institute Test wrinkle of skin improvement with stating.
The women 30 of 35 years old~50 years old is divided into two groups, every group 15, to one of which, is painted with comprising 0.5 weight % The essence of the Production Example 2 of flavine smears face once daily, and smears three months, and another group then with the essence of comparative example 2 Smear face once daily, and smear three months.After three months, by the survey to testee, skin wrinkle is have rated The improvement degree of line.In the survey of testee, compared with before use, wrinkle of skin is improved and elasticity raising is commented Valency be without improving, the slightly three phases that improve, greatly improve, and the results are shown in table 6 below.
As above-mentioned table 6 is represented, in the case of the essence of Production Example 2 of the use comprising 0.5% fisetin, with use not The situation of the essence of the comparative example 2 comprising fisetin is compared, and is able to confirm that the improvement of wrinkle of skin is more excellent.
Table 6
Distinguish (name) Without improvement Slightly improve Greatly improve
Production Example 2 1 7 7
Comparative example 2 9 4 2
Experimental example 2:The effect improving wrinkles experiment of the cosmetic essence carried out by graphical analysis
By graphical analysis, the effect improving wrinkles of the essence of above-mentioned Production Example 2 and comparative example 2 are have rated.
Specifically, before on-test, the copy of side skin under collection (Xantopren, Bayer) eyes (replica), after off-test, the same position below eyes gathers copy immediately, by graphical analysis, to wrinkle of skin Two-dimension analysis has been carried out, the density of wrinkle of skin has been determined.The slip of the wrinkle of skin density based on graphical analysis, is to use essence The wrinkle of skin density of Hua Suhou relative to the average value using the ratio between the wrinkle of skin density before essence, by said determination Result is shown in table 7 below.
Table 7
Wrinkle of skin density slip (%)
Comparative example 2 14
Production Example 2 56
Knowable to above-mentioned table 7, in the case of using the essence of the Production Example 2 comprising fisetin, and using being provided without The situation of the essence of the comparative example 2 of fisetin is compared, and wrinkle of skin improvement is more excellent.In addition, in above-mentioned process of the test In, do not find the stimulation or side effect of the essence to skin of Production Example 2.

Claims (11)

1. a kind of cosmetic composition, wherein, as active ingredient, comprising fisetin or derivatives thereof.
2. cosmetic composition according to claim 1, wherein, above-mentioned composition is for promoting sulphation osamine to gather The composition of sugar synthesis.
3. cosmetic composition according to claim 1, wherein, above-mentioned composition is for promoting collagen synthesis Composition.
4. cosmetic composition according to claim 1, wherein, above-mentioned composition is old for improving or preventing skin Change, wrinkle of skin, the composition that skin elasticity declines or skin moisture content declines.
5. cosmetic composition according to claim 1, wherein, the content of above-mentioned fisetin is relative to total composition It is 1 × 10-5~10 weight %.
6. the cosmetic composition according to any one of Claims 1 to 5, wherein, above-mentioned cosmetic composition tool Have selected from by solution, suspension, emulsion, paste, gel, creme, skin lotion, pulvis, soap agent, containing the clear of surfactant Lotion, oil, vanishing cream, toner class, cosmetic ointment, spray, facial mask, suncream, sun screen, makeup removing agent and cleaning agent institute Formulation in the group of composition.
7. a kind of cosmetics, wherein, as active ingredient, contain fisetin or derivatives thereof.
8. a kind of pharmaceutical composition for preventing and treating skin injury disease, wherein, as active ingredient, contain fisetin Or derivatives thereof.
9. pharmaceutical composition according to claim 8, wherein, above-mentioned skin injury disease is selected from old by erythema, skin Change, wrinkle of skin, skin capillary vascular expansion disease, skin elasticity decline and skin moisture content decline in constituted group.
10. pharmaceutical composition according to claim 8, wherein, aforementioned pharmaceutical compositions have and are selected from by ointment, frost Agent, tablet, pill, pulvis, granule, capsule, oral solution, syrup, the aqueous solution, non-aqueous solvent, suspending agent with And the formulation in the group that is constituted of emulsion.
A kind of 11. health functional food compositions, wherein, contain fisetin or derivatives thereof as active ingredient, and for changing Kind or prevention skin aging, wrinkle of skin, skin elasticity decline, skin moisture content declines or aging.
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