CN105662903A - Skin whitening and brightening compound and application thereof - Google Patents
Skin whitening and brightening compound and application thereof Download PDFInfo
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- CN105662903A CN105662903A CN201410655197.2A CN201410655197A CN105662903A CN 105662903 A CN105662903 A CN 105662903A CN 201410655197 A CN201410655197 A CN 201410655197A CN 105662903 A CN105662903 A CN 105662903A
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Abstract
The invention discloses a skin whitening and brightening compound and application thereof. The compound disclosed by the invention can be used for preparing a cosmetic composition for whitening and brightening skin.
Description
Technical field
The present invention relates to biological technical field, particularly relate to a kind of skin whitening lightening compounds and application thereof.
Background technology
Cutaneous visual appearance, physical property or physiological function a lot of because have, such as old and feeble, be exposed to hostile environment factor (such as ultraviolet radiation), nutritional disorder etc. for a long time. Change the most significantly and include the loss of the development of microgroove and wrinkle, elastic reduction, the reduction of consolidation, color homogeneity or tone, coarse superficial makings and mottled painted. Also include cell along with skin aging or the change experiencing long-term environmental nuisance and occur and the generally reduction of tissue activity, the reduction of cell replication rates, the minimizing of SkBF, moisture reduce, the 26S Proteasome Structure and Function of accumulation is lost and the decline of skin remodeling and self repair ability.
On visual appearance, one of significant change is the change of skin color. The color of application on human skin is by being positioned at melanic amount and type decided produced by the specialized cell melanocyte of skin base layer. Melanin is to be distributed one of natural pigment the most widely, and its structure complexity is the homogenizing polyphenol sample biopolymer that a kind of color changes from brown to black (eumelanin) and redness to yellow (pheomelanin). In human skin, melanin is considered to serve as the protective agent of ultra-violet radiation resisting.
Melanic excessive generation can cause different types of abnormal skin color, hair color and other dermatological conditions, for instance chloasma, senile plaque and photic damage site. Melanin is by originating in a series of oxidation reactions of amino acid tyrosine and polymerization procedure generation. Tryrosinase (EC1.14.18.1) is the type III enzyme comprising copper, it is two primary responses of catalysis in melanin produces: 1) by the vicinal hydroxyl groups of the TYR of single phenolase effect, and 2) by the oxidation of the 3,4-dihydroxyphenyl-L-alanine (L-DOPA) of two phenolase effects → o-DOPA quinone. Than previous step more faster, therefore the hydroxylating of tyrosine is considered as the rate-determing step in melanin biosynthesis to a rear oxidation step. O-DOPA quinone is converted into melanin by a series of enzymatics and non-enzymatic polyreaction subsequently. Such as dopachrome tautomerase (tyrosinase related protein1; And dihydroxy indole carboxylic acid (DICHA) oxidase (tyrosinase-related protein 1 TRP-2); TRP-1) other enzymes are also included within melanic biosynthetic process. Owing to tryrosinase plays the effect of key in the process that melanin produces, so the inhibitor of this enzyme is typically used as skin whitener.
Prior art has been described with the multiple tyrosinase inhibitor naturally occurring and synthesizing. Most compounds comprises phenol structure. These compounds serve as metal-chelator. The medicine comprising hydroquinone (2-4%) is effective for appropriateness, but hydroquinone is considered melanocyte is had cytotoxicity, and mammalian cell has potential mutagenicity. Many tyrosinase inhibitors are resorcinol derivatives or the polyphenol derivatives of flavonoid or trans-stilbene, for instance resveratrol or derivatives thereof. The compound of these types known and metal ion form strong chelate.
Although it have been reported that multiple compounds is effective tyrosinase inhibitor, but the character showing skin whitener considerably less in them. Further, it is found that most of poisonous in these reagent, or show the adverse side effect to people. Therefore, the research for having effective tyrosinase inhibitory activity and the low new natural product of cytotoxicity or synthesis compound is still continuing.
Summary of the invention
First purpose of the present invention is to provide a kind of skin whitening lightening compounds and application thereof.
The preparation method that second purpose of the present invention is to provide a kind of above-mentioned composition.
A first aspect of the present invention provides the compound shown in a kind of Formulas I or its pharmaceutically acceptable salt, the purposes in preparation compositions or medicine,
Described compositions or medicine are used for:
(1) tyrosinase activity is suppressed; And/or
(2) melanin is suppressed to produce; And/or
(3) prevent or treat the disease relevant with melanic excessive generation or skewness or symptom; And/or
(4) the brightening of skin or tooth; And/or
(5) blast of skin or tooth; And/or
(6) skin injury is repaired.
In another preference, described disease or symptom are selected from: tanned, cutaneous pigmentation, chloasma, vitiligo, and melanoma.
In another preference, described skin is mammal skin, and described mammal is preferably people.
In another preference, described compositions is used for preparing medicine, emulsion, cream for skin care, cream, essence, facial film, sunscreen cream, foundation cream or lip pomade, but the scope of the present invention is not limited to this.
In another preference, the invention provides the compound shown in a kind of Formulas I or its pharmaceutically acceptable salt, the purposes in the compositions or medicine of preparation suppression tyrosinase activity.
In another preference, the invention provides the compound shown in a kind of Formulas I or its pharmaceutically acceptable salt, the purposes in the compositions or medicine of preparation suppression melanin generation.
In another preference, the invention provides the compound shown in a kind of Formulas I or its pharmaceutically acceptable salt, the purposes in the compositions or medicine of preparation prevention or the treatment disease relevant with melanic excessive generation or skewness or symptom.
In another preference, the invention provides the compound shown in a kind of Formulas I or its pharmaceutically acceptable salt, the purposes in preparing the compositions for skin or teeth whitening and/or blast or medicine.
In another preference, the invention provides the compound shown in a kind of Formulas I or its pharmaceutically acceptable salt, the purposes in the compositions or medicine of preparation reparation skin injury.
A second aspect of the present invention provides a kind of compositions, the compound shown in the contained I of described compositions or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, and described compositions is used for,
(1) tyrosinase activity is suppressed; And/or
(2) melanin is suppressed to produce; And/or
(3) prevent or treat the disease relevant with melanic excessive generation or skewness or symptom; And/or
(4) the brightening of skin or tooth; And/or
(5) blast of skin or tooth; And/or
(6) skin injury is repaired.
In another preference, described compositions includes pharmaceutical composition, cosmetic composition, dentifrice composition, food additive, Halth-care composition etc.
In another preference, described carrier includes water, organic solvent etc.
In another preference, described cosmetic composition includes: emulsion, cream for skin care, cream, essence, facial film, sunscreen cream, foundation cream or lip pomade, but the scope of the present invention is not limited to this.
A third aspect of the present invention provides a kind of method suppressing tyrosinase activity, and described method includes step: contacted with formula I by tryrosinase, thus suppressing tyrosinase activity.
In another preference, described method is for the purpose of non-treatment.
A fourth aspect of the present invention provides a kind of prevention and the method treating the disease relevant with tyrosinase activity and disease condition, including step: inside or administer locally to the compound of formula I of the present invention of individual treatment effective dose in need.
A fifth aspect of the present invention provides a kind of method suppressing B16 cell in individuality in need, and described method includes the compound of formula I giving the present invention that this individuality uses effective dose.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus constituting new or preferred technical scheme. As space is limited, tired no longer one by one state at this.
Accompanying drawing explanation
Fig. 1 shows that tryrosinase is had inhibitory activity significantly by the compound of the present invention;
Fig. 2 shows the inhibition that melanin is produced by the compound of the present invention.
Detailed description of the invention
This application provides tryrosinase is had excellence inhibitory activity and low-down Cytotoxic compound. The present invention includes the pharmaceutically acceptable salt of this tyrosinase inhibitor. Present invention additionally comprises the pharmaceutical composition of tyrosinase inhibitor and at least one pharmaceutically acceptable carrier comprised to the present invention. The compositions of the present invention can be prepared with any suitable pharmaceutically acceptable dosage form.
Present invention also offers the method suppressing tryrosinase in individuality in need, described method includes the compositions giving the tyrosinase inhibitor comprising the present invention of effective dose.
Present invention also offers prevention and the method treating the disease relevant with tyrosinase activity and disease condition. The prevention of the present invention and the method for the treatment of include inside or administer locally to the tyrosinase inhibitor of the present invention of individual treatment effective dose in need.
Present invention also offers the method suppressing B16 cell in individuality in need. Such method includes the compositions giving the compound comprising the present invention of effective dose.
Present invention also offers prevention and the method treating the disease relevant with melanic excessive generation or skewness and disease condition, described method includes inside or administers locally to the compound of the present invention of individual treatment effective dose in need. The disease relevant with melanic excessive generation or skewness and disease condition include but not limited to the pigmentation speckle, chloasma, hepatopathy, thermal burn and the local wound that are caused by skin aging, the cutaneous pigmentation that the inflammatory conditions caused by fungus, microorganism and viral infection causes, vitiligo, tumor, melanoma and other mammal skin disease conditions. The skin that described method can be also used for prevention and treatment causes by exposure to the sun, ultraviolet (UV) radiation, chemicals, heat, wind and dry environment is dark-coloured and damages. Finally, described method may be used for prevention and treatment wrinkle, lax skin, the wrinkle of around eyes and black eye, lax sensitive skin and the dermatosis situation that prevention is relevant with other anaphylaxiss with treatment dermatitis.
In particular embodiments, giving the dosage of the tyrosinase inhibitor of the present invention of individuality in need is effectively nontoxic amount, and it is generally selected from: based on the 0.001% to 100% of the gross weight of final preparation; And/or based on every kilogram of 0.01mg to 200mg of whose body weight. Those skilled in the art use routine clinical test to may determine that the optimal dose for the specified disease being treated. The compositions of the present invention can be given by any method known to those skilled in the art. Administering mode includes but not limited to intestinal (being administered orally) administration, parenteral (intravenous, subcutaneous and intramuscular) administration and topical application. The Therapeutic Method of the present invention includes the compound of the present invention that is internal to patient in need or that administer locally to therapeutically effective amount. In preferred embodiments, described compositions is administered locally to.
In another embodiment, it is possible to the compound of the present invention is used in food industry to suppress brown stain and the variable color of water fruits and vegetables, juice and other food.
Although the method similar or suitable with those described herein and material may be used for practice or the test of the present invention, suitable method and material are still described below. All publicly available publication referred to herein, patent application, patent and other lists of references are incorporated herein by reference to the overall.
The invention provides salvianolic acid A or its pharmaceutically acceptable salt, the purposes in preparation compositions or medicine, described compositions or medicine are used for:
(1) tyrosinase activity is suppressed; And/or
(2) melanin is suppressed to produce; And/or
(3) prevent or treat the disease relevant with melanic excessive generation or skewness or symptom; And/or
(4) the brightening of skin or tooth; And/or
(5) blast of skin or tooth; And/or
(6) skin injury is repaired.
The invention provides the compound of the effective inhibitor as tryrosinase. Specifically, the invention provides the tyrosinase inhibitor with structure described in below formula I or its pharmaceutically acceptable salt,
This compound shows as the tyrosinase inhibitory activity and low cytotoxicity with excellence. Embodiment demonstrates the compound of formula I inhibitory activity to Mushroom Tyrosinase, and to melanic suppression produced by Mus B16-F1 melanoma cells. And the skin whitening character of representative compound is evaluated by the application on human skin model rebuild. These compounds or their pharmaceutically acceptable salt show as the cosmetics for being detailed below and medical application.
The preparation method of the compound shown in Formulas I is referred to method described in document Chinese patent application CN201310192210.0.
Various term used herein relates to the many aspects of the present invention. In order to help to set forth the description of instant component, it is provided that defined below. Unless otherwise defined, all technology used herein and scientific terminology have the implication that those skilled in the art in the invention are generally understood that.
As used herein, term " tyrosinase inhibitor ", " shown in Formulas I compound ", " present invention () compound " each mean the compound with structure shown in Formulas I.
As used in this article, " about " can be readily appreciated by one skilled in the art, and can be changed to a certain degree in the linguistic context that it is used. If in the linguistic context used by this given term, there is those skilled in the art the purposes of this term unclear, then " about " represent that being equal to this particular term adds or deduct 10%.
" treatment " used herein includes prevention (prevention), treatment and/or prevention (prophylaxis). When deployed, treatment refers to the mankind and other animals.
" medicine or therapeutically effective dosage or amount " refers to the dosage level being enough to induce desired biological results. Described result can be sign, symptom or disease reason alleviate or desired living things system any other change. Accurate dosage can change according to various factors, and described factor includes but not limited to Individual Age and the effect of size, disease and treatment.
" host " or " patient " or " individuality " are the mammal alive of expectation treatment, the mankind or animal. " host ", " patient " or " individuality " typically refers to the method according to the invention and implements the receptor for the treatment of. It should be noted that, invention as herein described may be used for veterinary and people's application, and term " host " should do not explained in a limiting fashion. When veterinary applies, dosage range can be as described below, it is considered to the body weight of animal is determined.
Term used herein " pharmaceutically acceptable " represents to be checked and approved or is listed in state-promulgated pharmacopoeia list or other pharmacopeia generally approved by federal or national authority for animal, and more specifically to the mankind. Term " carrier " refers to the diluent, adjuvant, excipient or the vehicle that give together with treating, and includes but not limited to such as water and oil sterile liquid.
" the pharmaceutically acceptable salt " of tyrosinase inhibitor or the product that " salt " is the compounds as disclosed herein containing ionic bond, it is suitable for giving individuality, and usually by making disclosed compound prepare with acid or alkali reaction. Pharmaceutically acceptable salt can include but not limited to acid-addition salts, and it includes hydrochlorate, hydrobromate, phosphate, sulfate, disulfate, alkylsulfonate, arylsulphonate, alkylaryl sulfonate, acetate, benzoate, citrate, maleate, fumarate, succinate, lactate and tartrate; Alkali metal cation, for instance Li, Na, K; Alkali salt, for instance Mg or Ca; Or organic amine salt.
" pharmaceutical composition " is for being suitable for administration to the preparation comprising disclosed compound of the form of individuality. Preferably the pharmaceutical composition of the present invention is formulated as route of administration desired with it compatible. The example of route of administration includes but not limited to oral and parenteral, for instance intravenous, Intradermal, subcutaneous, suck, locally, transdermal, saturating mucosa and rectally.
The present invention includes the pharmaceutical composition comprising at least one tyrosinase inhibitor as herein described. The compositions of the present invention can be formulated as the pharmaceutical composition comprising other components, these other components acceptable excipient of such as pharmacy and/or cosmetics, adjuvant and/or carrier. For example, it is possible to the compositions of the present invention is formulated in the tolerable excipient of the host to treat. Excipient is the inert substance of diluent or the vehicle being used as therapeutic agent. The example of such excipient includes but not limited to water, buffer, saline, Ringer's mixture (Ringer ' ssolution), glucose solution, mannitol, hanks solution (Hank ' ssolution), preservative and other aqueous physiological balanced salt solutions. Non-aqueous vehicles can also be used, for instance fixed oil, Oleum sesami, ethyl oleate or triglyceride. Other useful preparations include the suspension containing viscosity intensifier, and described viscosity intensifier is sodium carboxymethyl cellulose, Sorbitol or glucosan such as. Excipient can also contain a small amount of additive, for instance strengthens the material of isotonicity and chemical stability. The example of buffer includes phosphate buffer, bicarbonate buffer, tris buffer, histidine, citrate and glycine or their mixture, and the example of preservative includes but not limited to EDTA, EDETATE SODIUM, BHA, BHT, vitamin C, vitamin E, sodium sulfite, SnCl2, thimerosal, m-or o-cresols, formalin and benzylalcohol. Standard preparation can be liquid or solid, and it can be absorbed by the suitable liquid form of the suspension for being administered or solution. Therefore, in non-liquid formulation, excipient can comprise glucose, human serum albumin, preservative etc., it is possible to is added to sterilized water or saline before administration.
In an embodiment of the present invention, compositions can also include adjuvant or carrier. Generally, adjuvant is generally strengthen host's material to the biological answer-reply of particular bioactive agent. Suitable adjuvant includes but not limited to Freund adjuvant; Other bacterial cell wall components; Salt based on aluminum, magnesium, copper, zinc, ferrum, calcium and other metal ions; Silicon dioxide; Polynucleotide; Toxoid; Serum albumin; Virus capsid protein; The prepared product (preparation) of other bacterial origins; IFN-γ; Block copolymer adjuvants, for instance Hunter ' sTitermax adjuvant (Vaxcel.TM., Inc.Norcross, Ga.); Ribi adjuvant (from RibiImmunoChemResearch, Inc., Hamilton, Mont.); And saponin and their derivant, for instance QuilA (from SuperfosBiosectorA/S, Denmark). Carrier is generally increases the compound of therapeutic combination half-life in the host treated. Suitable carrier includes but not limited to polymeric controlled release preparation, biodegradable implant, liposome, antibacterial, virus, oil, ester and glycol. Suitable carrier is described in LippincottWilliams&Wilkins " Remington:TheScienceandPractice, the TwentiethEdition " published, and it is hereby incorporated herein by.
In one embodiment, being controlled release preparation by compositions preparation, the compositions of the present invention is discharged to host by lentamente. As it is used herein, controlled release preparation comprises the compositions of the present invention in controlled release vehicles thing. Suitable controlled release vehicles thing is that those skilled in the art are known. Preferred controlled release preparation is biodegradable (getting final product bio-digestion).
The compositions of the present invention can be given by any method known to those skilled in the art. Administering mode includes but not limited to intestinal (being administered orally) administration, parenteral (intravenous, subcutaneous and intramuscular) administration and topical application. The Therapeutic Method of the present invention includes the compound of the present invention that is internal to patient in need or that administer locally to therapeutically effective amount.
In one embodiment, being given the therapeutic agent of the present invention partly by any appropriate method for administering locally to therapeutic combination well known by persons skilled in the art, described therapeutic agent includes but not limited to ointment, gel, lotion or emulsifiable paste matrix; Or as toothpaste, collutory or coating on flossing material or as Emulsion, the therapeutic agent giving the present invention as patch, dressing or facial film (mask), inadhesive gauze, binder, swab or cleaning wiping cloth partly.
According to medication, it is possible to give therapeutic combination with various unit dosage forms. For the ad hoc fashion delivered, it is possible to the therapeutic combination of the present invention is formulated in the excipient of the present invention. Any host can be given, it is preferable that mammal by the treatment reagent of the present invention, and more preferably people. The ad hoc fashion of administration depends on the disease condition to treat.
In one embodiment, suitable ointment packets is containing the compound of the present invention of expectation concentration, and it is effectively nontoxic amount, and this amount is generally selected from 0.001% to 100% based on topical formulations gross weight; The White soft paraffin of 65% to 100% (preferably 75% to 96%); The liquid paraffin of 0% to 15%; And the lanoline or derivatives thereof of 0% to 7% (preferably 3% to 7%) or synthesis equivalent. In another embodiment, emulsifiable paste can comprise polyethylene-liquid paraffin substrate.
In one embodiment, suitable emulsifiable paste comprises the emulsification system together with at least one compound of the present invention presented above of expectation concentration. Emulsification system preferably comprises the polyoxyethylene alcohol of 2% to 10% (such as with trade name CetomacrogolTM1000 provide mixture), the stearyl alcohol of 10% to 25%, the liquid paraffin of 20% to 60% and 10% to 65% water; And one or more preservative, the N of such as 0.1% to 1%; N "-di-2-ethylhexylphosphine oxide [N '-[3-(methylol)-2,5-dioxy-4-imidazolidinyl] urea] (providing with the title of ImidureaUSNF), the 4-HBA Arrcostab mixture of Nipastat (commodity such as provided by NipaLaboratories by name) of 0.1% to 1%, the 4-HBA butyl ester sodium (being provided by NipaLaboratories, commodity are called Nipabutylsodium) of 0.01% to 0.1% and 0.1% to 2% phenyl phenol.
In one embodiment, suitable gel comprises semisolid systems, and wherein liquid phase is limited to and has in highly cross-linked three dimensional polymeric matrix. Liquid phase can comprise water; And the compound of the present invention of desired amount; Water-blendable the additive of such as glycerol, Polyethylene Glycol or the propylene glycol of 0% to 20%; With 0.1% to 10%, preferably 0.5% to 2% thickening agent, it can be the natural product selected from the group including but not limited to Tragacanth, pectin, chondrus ocellatus Holmes, agar and alginic acid, or is selected from the synthesis of the group including but not limited to methylcellulose and carbopol (Carbopol) or semi-synthetic compound; One or more preservative additional, it is selected from including but not limited to the 4-HBA methyl ester (methyl butex) of such as 0.1% to 2% or the group of phenyl phenol-different (differential). Another suitable substrate comprises the compound of the present invention of desired amount; And the Polyethylene Glycol of 70% to 90% (the Polyethylene Glycol emulsifiable paste containing 40% PEG3350 and 60% PEG400 such as prepared according to American National formulary (U.S.NationalFormulary) (USNF)), the water of 5% to 20%, the antioxidant (such as, butylated hydroxy-methylbenzene) of 0.02% to 0.25% and 0.005% to 0.1% chelating agen (such as ethylenediaminetetraacetic acid (EDTA)).
Term soft paraffin used above includes emulsifiable paste or ointment base White soft paraffin and yellow soft paraffin. Term lanoline includes the lanoline of natural wool fat and purification. The derivant of lanoline includes through chemical modification especially to change their lanoline physically or chemically; And the synthesis equivalent of lanoline includes synthesis or semi-synthetic compound and mixture especially, and it is known and is used as the alternative of lanoline in pharmacy and cosmetic field, and can such as be called lanoline substitute.
A kind of suitable synthesis equivalent of operable lanoline is with trade name SoftisanTMThe material being called Softisan649 provided. The Sofisan649 provided by DynamitNobelAktiengesellschaft is the glyceride of natural vegetable fatty acids, isostearic acid and adipic acid; H.Hermsdorf, in Fette, Seifen, Anstrichmittel, IssueNo.84, No.3 (1982), discusses their character in pp.3-6. Above-mentioned other materials as suitable ointment or emulsifiable paste matrix composition and their character are discussed in the work of the Standard reference works of such as pharmacopeia. Cetomacrogol 1000 is formula CH3(CH2)m(OCH2CH2)nOH, wherein m can be 15 or 17, and n can be 20 to 24. Butylated hydroxy-methylbenzene is 2,6-di-t-butyl-paracresol. Nipastat is the mixture of 4-HBA methyl ester, 4-HBA ethyl ester, 4-HBA propyl ester and 4-HBA butyl ester.
The compositions of the present invention can be prepared by conventional phamaceutical techniques. Therefore, above-mentioned composition such as can by mixing soft paraffin at the rising temperature of preferred 60-70 DEG C jointly; Liquid paraffin, if existing; And lanoline or derivatives thereof or synthesis equivalent prepare easily. Mixture can be cooled to room temperature subsequently, and after adding the crystalline hydrate calcium salt of mupirocin and corticosteroid and any other composition, stir fully dispersed to guarantee.
The mode no matter being administered, calculates concrete dosage according to the substantially body weight of host. Improving further of calculating needed for determining the suitable dose of the treatment relating to every kind of above-mentioned preparation is made routinely by those skilled in the art, and without inappropriate experiment in the scope of the normal work to do carried out at them, in particular according to dosage information disclosed herein and mensuration. These dosage can by using for determining that the mensuration set up of dosage is determined with suitable dose response data coupling.
Known synthetic method can be utilized or via the improvement of known synthetic method to be easily synthesized the tyrosinase inhibitor of the present invention. As those skilled in the art easily recognize, following method allows synthesis to have the compound of multiple substituent group. The method that the present invention includes synthesizing compound as herein described. Exemplary synthetic procedure is described in example 1 below-5.
The present invention includes the method by using compound disclosed in one or more to prevent or to treat (such as alleviating one or more symptoms) medical conditions situation. Prevention or Therapeutic Method include the tyrosinase inhibitor giving the present invention of therapeutically effective amount to patient in need. The compositions of the present invention can be also used for prophylactic treatment.
The invention provides by suppressing tyrosinase activity or melanic excessive generation to improve the ill disease of institute thus treating individual method. Such method includes the tyrosinase inhibitor as herein described giving individual treatment effective dose.
" treatment " used herein describes for the purpose of Fighting Disease, disease condition or disease, process and treatment to patient, and including giving the compound of the present invention to prevent the generation of symptom or complication, relief of symptoms or complication, or eliminate a disease, disease condition or disease. More specifically, " treatment " includes reversion, alleviates, reduces, suppresses or stop at least one ill symptoms or the impact of disease (disease) state, progression of disease or other aberrant disease conditions. Continued treatment is until symptom and/or pathology improve.
More specifically, present invention also offers the method suppressing B16 cell in individuality in need. Such method includes the compositions giving the compound comprising the present invention of effective dose.
Present invention also offers prevention and the method treating the disease relevant with melanic excessive generation or skewness and disease condition, described method includes inside or administers locally to the Compound Compound of the present invention of individual treatment effective dose in need. The disease relevant with melanic excessive generation or skewness and disease condition include but not limited to the pigmentation speckle, chloasma, hepatopathy, thermal burn and the local wound that are caused by skin aging, the cutaneous pigmentation that the inflammatory conditions caused by fungus, microorganism and viral infection causes, vitiligo, cancer, melanoma and other mammal skin disease conditions.
The skin that described method can be also used for prevention and treatment causes by exposure to the sun, ultraviolet (UV) radiation, chemicals, heat, wind and dry environment is dark-coloured and damages. Finally, described method may be used for prevention and treatment wrinkle, lax skin, the wrinkle of around eyes and black eye, and lax sensitive skin is, and the prevention dermatosis situation relevant with other anaphylaxiss with treatment dermatitis.
Purposes except they preventions and treatment skin disease as above and disease condition, therapeutic combination as herein described provides effective compositions, which give following benefit: there is aging, the young outward appearance that strengthens and the structure of the colour of skin of improvement, the elasticity of enhancing, minimizing and delay and the pliability strengthened, hardness, smoothness and adaptive smooth and young skin appearance.
Still in another embodiment, the compound derivatives of the present invention may be used for food industry to suppress brown stain in water fruits and vegetables, juice and other food and variable color.
Below in conjunction with specific embodiment, the present invention is expanded on further. Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention. The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition, such as Sambrook et al., molecular cloning: laboratory manual (NewYork:ColdSpringHarborLaboratoryPress, 1989) condition described in, or according to manufacturer it is proposed that condition. Unless otherwise indicated, otherwise percentage ratio and number are percentage by weight and parts by weight.
Material used in following example all can obtain from commercially available channel, and wherein, Agaricus bisporus (Agaricusbisporus) tryrosinase is purchased from Sigma-Aldrich company (T3824-50KU); S91melanoma cell B16-F1 is purchased from ATCC (CRL-6323); People's neonate dermal fibroblast is purchased from wonderful logical (Shanghai) bio tech ltd (2310). Method described in Chinese patent application CN201310192210.0 is adopted to prepare the compound shown in Formulas I.
Embodiment 1 measures tyrosinase inhibitory activity
To mix containing different 60 μ L sample of test compounds substrate concentration and the phosphate buffer (pH6.8) containing 1mML-tyrosine of 100 μ L. Then, add 40 μ L Agaricus bisporus tryrosinase (100U/mL), hatch 25 minutes for 37 DEG C.
Absorbed the accumulation monitoring color products (dopachrome) by the light at 450nm place, calculate tyrosinase inhibition rate (dopachrome suppression ratio). Without in the matched group of testing compound, tyrosinase inhibition rate is 0.
Result
Often group test carries out in triplicate, and experimental result is as it is shown in figure 1, show in Fig. 1 that tryrosinase is had inhibitory activity significantly, IC by the compound of the present invention50Value is about 8mM.
Embodiment 2 melanin generates inhibition experiment
In the cell growth medium of 100 μ l, with 2 × 105B16-F1 cell is seeded on 96 hole flat boards of clear bottom by cells/well.
Cell culture condition: DMEM/ high glucose, is supplemented with the streptomycin of glutamine, Sodium Pyruvate, the hyclone of 10% dialysis, 1% non essential amino acid, the penicillin of 50 units/mL and 50 μ g/mL; 37 DEG C, 95% air and 5%CO2。
Within second day, in cell culture fluid, add testing compound, the final concentration of testing compound respectively 1 μM, 10 μMs, 100 μMs and 1000 μMs, be subsequently adding the α-MSH of 100nM, cell is kept 24 hours at 37 DEG C. After cultivation completes, the 1NNaOH adding 120 μ L dissolves melanin 1h at 65 DEG C. Then melanic content is detected under 405nm absorbance again.
Result
Often group test carries out in triplicate, experimental result is as shown in Figure 2, under the stimulation of α-MSH, the melanin production of B16-F1 cell significantly improves, and it is simultaneously introduced in the experimental group of α-MSH and the compounds of this invention, melanic yield substantially reduces, and shows the inhibition that melanin is produced by the compound of the present invention in Fig. 2, does not wherein add α-MSH and testing compound in matched group. Depositing in case at the compounds of this invention of 100 μMs, compared with the experimental group that only with the addition of α-MSH, melanin production reduces about 40%.
Embodiment 3 skin lightening effects is tested
Utilize and rebuild skin model (purchased from MatTek company, MelanodermTM) research testing compound skin lightening effects.
Co-culture on the surface of film of coating collagen protein from Normal human epidermal's keratinocyte of dark skin donor and normal person's melanocyte to form multilamellar, well differentiated skin histology. This tissue is maintained at the CO of 37 DEG C2In incubator. The top surface rebuilding skin is exposed in air, and lower surface still maintains culture medium with the 5mL containing the skin differentiation factor (EPI-100-NNM-113) and contacts.
Test compound is formulated in the aqueous solution of propylene glycol of 80%: 10mg every kind is tested compound and is dissolved in 1mL propylene glycol, 0.2 μm of filter is degerming, and to be diluted to ultimate density in sterilized water/propylene glycol be 0.1% (w/v), 0.2% (w/v) and 0.4% (w/v). The concentration of propylene glycol in all samples is maintained at 80%. Matched group is respectively as follows: 1% kojic acid in sterilized water, 80% propylene glycol and water.
Test compound is applied to the surface of cultured tissue: 1% kojic acid (positive control) of the testing compound of 10 μ l, 80% propylene glycol (vehicle control) of 10 μ l, the sterilized water (negative control) of 25 μ l and 25 μ l. Every other day using once, continue 15 days, all samples is tested in duplicate.
Result
In rebuilding skin model, the skin lightening effects of compound is tested in research further. This model is made up of normal people source epidermal keratinocytes and melanocyte, co-cultures them to form multilamellar, well differentiated people's epidermis. In this study, highly Pigmented donor melanocyte is obtained.
By variable concentrations test compound, 80% propylene glycol (vehicle control), water (negative control) or 1% kojic acid (positive control) repeatedly be applied topically to rebuild skin surface, continue 15 days. Found that use the compounds of this invention of 0.2% concentration can show the significant whitening effect of dermal melanin cell, without causing any detectable change of cellular morphology. After experiment starts, 0.2% concentration experiment group can be observed the obvious effect brightened to skin model at the 5th day, and namely 0.4% concentration experiment group can be observed the effect brightened to skin model at the 3rd day.
Embodiment 4 prevents ultraviolet injury from testing
Cell is cultivated
Cell uses commercially available people's neonate dermal fibroblast. Described cell is with 2 × 105Individual/mL is inoculated in culture dish, adds 10% hyclone (culture medium I) and cultivate in culture medium D-MEM (1g/L glucose). Condition of culture is, 37 DEG C, 5%CO2And cultivate 24 hours when saturated steam.
Then, culture medium is replaced by BSO culture medium (medium ii), it is added with the BSO (L-buthionine-(S, R)-sulfoximine) of the biosynthesis inhibitor as glutathion of 0.001%, at 37 DEG C, 5%CO2And cultivate 24 hours when saturated steam. Described BSO culture medium is prepared as follows: in described ordinary culture medium, the preservation stock solution being dissolved with 0.1%BSO in ethanol is diluted 100 times.
Before irradiation ultraviolet radiation 24 hours, it is replaced by the BSO culture medium (medium ii) of the compounds of this invention solution being added with 100 μ L. Using without compound as negative control.
Iron chloride is dissolved in distilled water according to the concentration of 0.002% (weight), with containing calcium ion, magnesium ion phosphate buffer PBS (+) dilution 200 times after, as medium ii I, be previously heated to 37 DEG C standby.
Before irradiating UV-A, culture medium is replaced into medium ii I. When removing culture dish lid, from the about 30cm in the top of culture dish, with 10J/cm2Irradiate the ultraviolet of 320nm to 400nm. Positive control is irradiation ultraviolet radiation not, and the living cell rate taking positive controls is 100%.
Then, in culture medium, ALMA blue (alamarBlue) is added according to the mode that ultimate density is 10%, after 3 hours, measure the fluorescence intensity of supernatant according to the methods of (J.Immunol.Method.170,211-224 (1994)) such as AhmedS.A. and the description of manufacturer with excitation wavelength 544nm, wavelength of fluorescence 590nm and calculate living cell rate (%).
Table 2 prevents ultraviolet injury from testing
| Sample | Living cell rate (%) |
| Positive control | 100 |
| Negative control | 38 |
| A | 54 |
| B | 68 |
| C | 70 |
| D | 73 |
| E | 76 |
In experimental group A-F, the final concentration of testing compound respectively 4mM, 8mM, 16mM, 32mM, 64mM in test system.
As can be known from the above results, the compounds of this invention can be obviously enhanced cell to ultraviolet tolerance level, by increasing capacitance it is possible to increase living cell rate, alleviates cell death. Compared with negative control group, the living cell rate of 30% can be improved under 8mM concentration.
The preparation of embodiment 5 cosmetic composition
Composition preparing cosmetics compositions shown according to the form below, in table, each component is parts by weight. It is first according to the proportioning in following table formulation components I, II and III respectively, then component I, II and III stirring is mixed and obtains cosmetic composition. The white translucent thick liquid nano of this cosmetic composition, the frivolous water profit of quality, abnormal smells from the patient is pure and fresh. Without greasy feeling during use, ductility is good, absorbs rapidly, uses the salubrious water of rear skin to run through bright.
Can obviously improve the phenomenon such as facial lines, dim mute, pigmentation, cutis laxa, corse sweat pore, blackhead after life-time service, skin of face is pale, water is tender, fine and smooth, compact, smooth, the colour of skin is homogeneous bright. This cosmetic composition texture and skinfeel after stability test is unchanged, has good stability.
The preferred embodiment of the present invention described in detail above. Should be appreciated that those of ordinary skill in the art just can make many modifications and variations according to the design of the present invention without creative work. Therefore, all technical staff in the art, all should in the protection domain being defined in the patent claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (10)
1. the compound shown in Formulas I or its pharmaceutically acceptable salt, the purposes in preparation compositions or medicine, it is characterised in that
I;
Described compositions or medicine are used for:
(1) tyrosinase activity is suppressed; And/or
(2) melanin is suppressed to produce; And/or
(3) prevent or treat the disease relevant with melanic excessive generation or skewness or symptom; And/or
(4) the brightening of skin or tooth; And/or
(5) blast of skin or tooth; And/or
(6) skin injury is repaired.
2. purposes as claimed in claim 1, wherein, described disease or symptom are selected from: tanned, cutaneous pigmentation, chloasma, vitiligo, and melanoma.
3. purposes as claimed in claim 1, wherein, described skin is mammal skin, and described mammal is preferably people.
4. purposes as claimed in claim 1, wherein, described compositions includes pharmaceutical composition, cosmetic composition, dentifrice composition, food additive, Halth-care composition etc.
5. the compound shown in Formulas I or its pharmaceutically acceptable salt, the purposes in the compositions or medicine of preparation suppression tyrosinase activity
I。
6. a compositions, the compound shown in the contained I of described compositions or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, described compositions is used for,
(1) tyrosinase activity is suppressed; And/or
(2) melanin is suppressed to produce; And/or
(3) prevent or treat the disease relevant with melanic excessive generation or skewness or symptom; And/or
(4) the brightening of skin or tooth; And/or
(5) blast of skin or tooth; And/or
(6) skin injury is repaired;
I。
7. compositions as claimed in claim 1, wherein, described compositions includes pharmaceutical composition, cosmetic composition, dentifrice composition, food additive, Halth-care composition etc.
8. compositions as claimed in claim 7, wherein, described cosmetic composition includes: emulsion, cream for skin care, cream, essence, facial film, sunscreen cream, foundation cream or lip pomade.
9. the method suppressing tyrosinase activity, wherein, described method includes step: contacted with formula I by tryrosinase, thus suppressing tyrosinase activity.
10. the method suppressing B16 cell in individuality in need, wherein, described method includes the compound of formula I giving the present invention that this individuality uses effective dose.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116585335A (en) * | 2023-06-07 | 2023-08-15 | 广东植肤生物科技有限公司 | A skin external composition for inhibiting TYR activity and MC1R expression |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827002A (en) * | 2012-05-29 | 2012-12-19 | 北京正大绿洲医药科技有限公司 | Chemical full-synthetic method of salvinanolic acid A |
| CN102895308A (en) * | 2012-11-13 | 2013-01-30 | 孙海峰 | New application of B Salvianolic acid taken as cosmetics additives with functions of whitening skin, removing freckle and resisting wrinkle |
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2014
- 2014-11-17 CN CN201410655197.2A patent/CN105662903A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827002A (en) * | 2012-05-29 | 2012-12-19 | 北京正大绿洲医药科技有限公司 | Chemical full-synthetic method of salvinanolic acid A |
| CN102895308A (en) * | 2012-11-13 | 2013-01-30 | 孙海峰 | New application of B Salvianolic acid taken as cosmetics additives with functions of whitening skin, removing freckle and resisting wrinkle |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116585335A (en) * | 2023-06-07 | 2023-08-15 | 广东植肤生物科技有限公司 | A skin external composition for inhibiting TYR activity and MC1R expression |
| CN116585335B (en) * | 2023-06-07 | 2024-02-09 | 广东植肤生物科技有限公司 | A skin external composition for inhibiting TYR activity and MC1R expression |
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