WO2013129801A1 - Tripeptide et composition cosmétique le contenant et ayant des effets antivieillissement, antirides, de blanchiment et anti-inflammatoires - Google Patents

Tripeptide et composition cosmétique le contenant et ayant des effets antivieillissement, antirides, de blanchiment et anti-inflammatoires Download PDF

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WO2013129801A1
WO2013129801A1 PCT/KR2013/001407 KR2013001407W WO2013129801A1 WO 2013129801 A1 WO2013129801 A1 WO 2013129801A1 KR 2013001407 W KR2013001407 W KR 2013001407W WO 2013129801 A1 WO2013129801 A1 WO 2013129801A1
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tripeptide
skin
phe
leu
whitening
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Korean (ko)
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이윤섭
최혜정
최하영
김명옥
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미원상사주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic

Definitions

  • the present invention relates to a tripeptide and skin anti-aging and skin wrinkle improvement, whitening, anti-inflammatory cosmetic composition containing the same as an active ingredient, and more particularly, the present invention is the most important factor in the application of anti-aging and wrinkle improvement cosmetics It not only shows excellent effects on the synthesis and expression of phosphorus collagen degrading enzymes and collagen biosynthesis, but also effectively inhibits melanin synthesis and tyrosinase activity, which are important factors for whitening cosmetics application, and reduces the cytokine increased by ultraviolet rays, thereby preventing aging, improving wrinkles, It relates to a novel tripeptide having a whitening and anti-inflammatory effect and a cosmetic composition containing the same as an active ingredient.
  • Skin aging is affected by genetic and environmental exposures (UV irradiation, mechanical shock), hormonal changes, and metabolic processes (reactive compounds such as reactive oxygen species, sugars, and aldehydes). These factors cause cumulative changes in the structure, function, and appearance of the skin.
  • Human skin aging is largely divided into internal aging that occurs over time according to biological processes and external aging (photoaging) caused by the environment such as continuous light exposure, stress, and smoking.
  • external aging photoaging
  • the skin In clinically internally aged skin, the skin is thin, dry, pale, loses its elasticity, and has many fine wrinkles.In the case of aging skin due to external environment such as light and smoking, deep wrinkles, spots, and rough skin are observed. It will have a greater effect on your back skin.
  • UV which is the most harmful factor to the skin
  • UVA 320-400 nm
  • UVB 280-320 nm
  • UVC Divided by (200-280nm).
  • UVC is blocked by the ozone layer
  • UVA radiation is less intense than UVB radiation, but has high skin permeability
  • UVA skin damage is known to include sunburn, cancer, and skin aging.
  • UVB radiation the most dangerous environmental carcinogen associated with human health, is known to cause gene damage and skin cancer in addition to erythema and sunburn.
  • the biggest changes in skin damaged by photoaging occur in the dermis, the deeper part of the skin, leading to breakdown of connective tissue, a decrease in collagen content and the accumulation of modified elastic fibers.
  • skin aging is a change in the composition of extracellular matrix proteins that form a matrix in the dermis of the skin.
  • Collagen proteins in the dermal extracellular tissue provide strength and tension to the skin, which protects the skin from external irritation or force, and accounts for 90% of the dermal layer.Reducing collagen is closely related to skin aging and wrinkle formation. There is this.
  • the main crosslinking components of healthy dermis are type I collagen and type III collagen. However, in skin damaged by photoaging, the precursors of these two collagens are markedly reduced and their decrease is associated with clinical severity.
  • MMPs collagen degrading enzymes
  • MMPs collagen degrading enzymes
  • MMPs are zinc-dependent intracellular proteases that can degrade or restructure components of the extracellular structure of the dermis, of which MMP-1 acts to segment collagen in the dermis. . Therefore, the regulation of the amount and activity of the enzyme is an important factor for wrinkles.
  • Retinol and retinoids are known to be effective in various fields such as psoriasis, aging, cancer, and acne.
  • the retinoids are known to prevent collagen loss by stimulating collagen formation by inhibiting collagenase (MMP-1) when applied to the skin to prevent and restore endogenous and photoaging.
  • MMP-1 collagenase
  • it is known to cause local skin irritation reactions such as erythema, itching, psoriasis, and scaling when applied to the skin. Therefore, there is a need for developing a new anti-wrinkle substance which is safer in vivo and suppresses collagenase (MMP-1) than the existing substance and has good collagen synthesis ability.
  • UV irradiation Damage to the skin by UV irradiation is known to cause inflammation as well as wrinkle formation. Due to biological mechanisms associated with skin damage, the skin is known to secrete numerous cytokines, including Interleukin-1 ⁇ (IL-1 ⁇ ), Interleukin-1 ⁇ (IL-1 ⁇ ), and Interleukin 6 (IL-6). The relationship between chronic inflammation and the production of multiple cancers is not only well known, but has also been shown in many tumor experiments. Keratinocytes induced to produce cytokines by various external stimuli lose cytokine control and eventually cause various skin diseases including cancer. One of the main external stimuli is UVB irradiation.
  • IL-1 ⁇ Interleukin-1 ⁇
  • IL-1 ⁇ Interleukin-1 ⁇
  • IL-6 Interleukin 6
  • UVB irradiation stimulates keratinocytes to secrete extracellular extracellular tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 ⁇ (IL-1 ⁇ ), IL-6, IL-10 and IL-8.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-6 interleukin-1 ⁇
  • IL-8 IL-8
  • the release of these cytokines promotes a sustained inflammatory response. Therefore, there is a need for the development of a substance that inhibits the inflammatory response caused by cytokines and skin aging damaged by UV stimulation.
  • Pigmentation of the skin may be caused by hormones, genetic effects, cosmetics, liver damage, drugs, pregnancy, UV irradiation, etc.
  • the most influential one is the accumulation of melanin formed by UV irradiation.
  • Dark pigments, known as melanin are biosynthesized in specific organelles called melanosomes in the innermost melanocytes of the skin's epidermis, which contain the tyrosinase, TRP-1, and TRP-2, the melanin biosynthesis enzymes.
  • the melanin biosynthesis mechanism is initiated by the oxidation of L-tyrosine present in melanocytes by an enzyme called tyrosinase.
  • DOPA 3,4-dihydroxyphenylalanine
  • L-tyrosine L-tyrosine
  • the complex reactions of the various stages that form the reaction take place automatically.
  • Tyrosinase is an important enzyme for the synthesis of dark brown eumelanin and red peomelanin. It is synthesized in melanosomal ribosomes of the endoplasmic reticulum, glycosylated in the Golgi apparatus, and then transported wrapped in the vesicles in an inactive state to the melanosomes.
  • the produced melanin pigment is transferred from the melanocytes to the keratinocytes (keratinucyte) constituting the epidermis.
  • the over-produced melanin is deposited on the skin, blemishes, freckles and the like.
  • Hydroquinone, kojic acid, arbutin, ascorbic acid and the like are most representative as a whitening raw material, but they have a whitening effect by inhibiting tyrosinase activity, but the safety, stability, and practical efficacy of these substances on the skin are problematic.
  • Hydroquinone has good whitening effect but causes skin irritation and toxicity to melanocytes.
  • Cojixex not only reduces the dendrite and melanin content of melanocytes but also acts as an antioxidant, but is known to cause irritation dermatitis.
  • Vamos-vigyazo L Polyphenol oxidase and peroxidase in fruits and vegetables. Crit Rev Food sci Nutr 1981; 15 : 49-127.
  • the present inventors established an in vitro assay system using human skin fibroblst cell line and UVA / UVB lamp to confirm anti-aging, wrinkle improvement, whitening, and anti-inflammatory effects of the compound tripeptides.
  • the biosynthetic ability of the enzymes (MMPs) was searched and the in vitro assay system using melanoma cell line and melanin stimulating hormone was established to confirm melanin production inhibitory effect and tyrosinase activity inhibitory ability, and keratinocyte (Keratinocyte).
  • MMPs melanin stimulating hormone
  • the present invention was completed by confirming that the compound tripeptides have an effect on wrinkle improvement, whitening and anti-inflammatory.
  • the present invention is to solve the problems of the prior art as described above is an object of the present invention is harmless to the human body and exhibits a novel tripeptide having excellent skin permeability or stability and anti-aging, wrinkle improvement, whitening and anti-inflammatory effect containing the same It is to provide a skin external pharmaceutical composition and a cosmetic composition.
  • the tripeptide according to the present invention for achieving the above object is represented by the following formula (1).
  • R 1 is an alkenyl group selected from hydrogen or an acyl group having 1 to 18 carbon atoms or at least one double bond
  • Leu is D-Leu or L-Leu
  • Phe is D-Phe or L-Phe may also be selected from among amino acids, in particular 20 natural amino acids and non-natural amino acids, phenylglycine, and the C-terminus is a carboxylic acid or amide Can be a form
  • the present invention also provides an anti-aging, anti-wrinkle, whitening and anti-inflammatory cosmetic composition or pharmaceutical composition using the above-described tripeptide as an active ingredient.
  • the above-described tripeptide provides a cosmetic composition or pharmaceutical composition containing 0.0001 to 1% by weight based on the total weight of the composition.
  • the present invention is a cosmetic composition which is any one of the skin, lotion, cream, foundation, essence, gel, pack, forclination, body oil, lipstick, mascara, makeup base or soap form containing the above-described tripeptide as an active ingredient Or a pharmaceutical composition.
  • a composition containing a novel tripeptide having no skin irritation and excellent skin stability as an active ingredient inhibits MMP-1 production, collagen biosynthesis, and inhibits tyrosinase activity and melanin production by inhibiting MMP-1 production, which is a collagen degrading enzyme. It was confirmed that it exhibits a whitening effect and inflammation inhibitory effect, such as to prevent skin pigmentation phenomenon by using it as a skin pharmaceutical composition and cosmetic composition having excellent efficacy in improving wrinkles, whitening and inflammation.
  • Figure 2 is a diagram showing the results of testing the MMP-1 inhibitory ability by tripeptide ( A350_4 ) at a safe concentration confirmed in Figure 1 as an embodiment of the present invention.
  • FIG. 3 is a diagram showing the results of testing the inhibitory ability of the increased amount of MMP-1 produced by UVA irradiation of tripeptide ( A350_4 ) as an embodiment of the present invention.
  • FIG. 4 is a diagram showing the results of testing the inhibitory ability of the increased amount of MMP-1 produced by UVB irradiation of tripeptide ( A350_4 ) as an embodiment of the present invention.
  • Figure 5 is a diagram showing the results of testing the ability to enhance the synthesis of Procollagen1 reduced by UVA irradiation of tripeptide ( A350_4 ) as an embodiment of the present invention.
  • Figure 6 is a diagram showing the results of testing the inhibitory ability of MMP-1 mRNA expression of tripeptide ( A350_4 ) as an embodiment of the present invention.
  • Figure 7 is a diagram showing the results of testing the ability to reduce MMP-1 mRNA expression increased by UVA irradiation of tripeptide ( A350_4 ) as an embodiment of the present invention.
  • FIG. 8 is a table showing the results of comparative tests of retinyl palmitate and tripeptide ( A350_4 ) for inhibition of MMP-1 production increased by UVA irradiation as an embodiment of the present invention.
  • FIG. 9 is a table showing the results of comparative tests of retinol and tripeptide ( A350_4 ) for the inhibition of MMP-1 production increased by UVA irradiation as an embodiment of the invention.
  • FIG. 10 is a diagram showing the results of reducing the fatty acid tripeptides increased tyrosinase activity after ⁇ -MSH treatment as an embodiment of the present invention.
  • Figure 11 is a diagram showing the result of reducing the melanin content increased after the ⁇ -MSH treatment of tripeptide ( A350_4 ) as an embodiment of the present invention.
  • FIG. 12 is a diagram showing a result of reducing the cAMP content increased after the ⁇ -MSH treatment of tripeptides ( A350_4 ) as an embodiment of the present invention.
  • Figure 13 is a diagram showing the results of testing the mRNA expression inhibition of the melanin-related gene of the tripeptide ( A350_4 ) in human melanocytes as an embodiment of the present invention.
  • FIG. 14 is a diagram showing the results of testing the inhibitory ability of IL-1 ⁇ , IL-1 ⁇ and IL-6 cytokine mRNA expression increased by UVB irradiation of tripeptide ( A350_4 ) as an embodiment of the invention.
  • 15 is a chart showing the results of the reduction in the number of wrinkles, wrinkle length, wrinkle area by the tripeptide ( A350_4 ) as an embodiment of the present invention in clinical trials.
  • 16 is a photograph confirming the result of confirming the wrinkle improvement effect by the tripeptide ( A350_4 ) through the image image in the clinical experiment as an embodiment of the present invention.
  • FIG. 17 is a diagram showing the results of quantifying the whitening effect of the tripeptide ( A350_4 ) by L * value in a clinical experiment as an embodiment of the present invention.
  • FIG. 18 is a diagram showing the results of quantifying the whitening effect by tripeptides ( A350_4 ) as ITA * values in clinical trials as an embodiment of the present invention.
  • the present invention provides a tripeptide represented by the formula (1).
  • R 1 is an alkenyl group selected from hydrogen or an acyl group having 1 to 18 carbon atoms or at least one double bond
  • Leu is D-Leu or L-Leu
  • Phe is D-Phe or L-Phe may also be selected from among amino acids, in particular 20 natural amino acids and non-natural amino acids, phenylglycine, and the C-terminus is a carboxylic acid or amide Can be a form
  • R 1 represented by the formula (1) include hydrogen or acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl, Acyl groups such as octadecanoyl may be included.
  • R 1 is preferably selected from hydrogen, acetyl, octanoyl, tetradecanoyl, hexadecanoyl or octadecanoyl, and more preferably R 1 is selected from tetradecanoyl, hexadecanoyl or octadecanoyl. .
  • the amino acid represented by X in Formula 1 may be selected from 20 natural amino acids and phenylglycine which is an unnatural amino acid.
  • Leu may be selected from D-Leu or L-Leu
  • Phe may be selected from D-Phe or L-Phe, and preferably L-Leu and L-Phe.
  • the C-terminus of the tripeptide may be selected from the carboxylic acid or amide form, and preferably has the carboxylic acid form.
  • the tripeptide according to the present invention can be synthesized by a solid phase method using a conventional peptide synthesizer.
  • the amino acids used are used in protected form at the N-terminus and in protected side chains.
  • As the protecting group for protecting the N-terminus 9-fluorenylmethyloxycarbonyl group (Fmoc) is generally used.
  • As the protecting group for protecting the reactive side chain triphenylmethyl, butyloxycarbonyl, t-butyl ester, pentamethylchroman-6-sulfonyl and the like are used.
  • the amino acid used in the present invention may be protected at the N-terminus by a 9-fluorenylmethyloxycarbonyl group (Fmoc).
  • the resin used for the solid phase reaction is applied differently depending on whether the C-terminal form of the polypeptide is carboxylic acid or amide form.
  • the C-terminus is a carboxylic acid
  • HMPA hydroxymethylphenoxyacetyl
  • the terminal of the resin is made of an amine group.
  • trialkoxybenzhydrylamine (Rink amide), methylbenzhydrylamine (MBHA) resin may be used.
  • peptides are synthesized from the C-terminus to the N-terminus.
  • the carboxyl group of the amino acid is activated with an activator, and after coupling, the N-terminal protecting group is removed with piperidine and the next coupling is performed.
  • Carboxylic activators include HATU ( N -[(dimethylamino-)-1 H -1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N -methylmethanaminium hexafluorophosphate N -oxide) and 1-hydride hydroxy-7-aza-benzotriazole (1-hydroxy-7-azabenzotriazole , HOAt) or HBTU (N - [(1 H -benzotriazol-1-yl) (dimethylamino) methylene] - N -methylmethanaminium hexafluorophosphate N -oxide) , and DIEA ( N, N -diisopropylethylamine) can be used together with 1-hydroxybenzotriazole (HOBt), and N-N'-diisopropylcarbodiimide (DIC) and 1- Hydroxy-7-azabenzotriazole (HOAt) or 1-hydroxy
  • the N-terminal amine group has an acyl activator having a desired acyl group, for example, acyl anhydride and DMAP (4- ( N, N -dimethylamino) pyridine)) to form an amide bond at the N-terminus or to carboxylic acid (Fatty acid), N, N -diisopropylcarbodiimide (DIC), 1-hydroxy-7-azabenzotriazole ( HOAt) or 1-hydroxybenzotriazole (HOBt) may be used together to form an amide bond.
  • the polypeptide analogue is then separated from the solid resin by the cleavage solution comprising trifluoroacetic acid (TFA) and the protecting group bound to its side chain is removed.
  • TFA trifluoroacetic acid
  • the present invention also provides an anti-aging agent composition comprising such tripeptides.
  • the compound of Formula 1 is preferably contained in an anti-aging cosmetics at 0.0001 to 1% by weight, more preferably 0.001 to 0.5% by weight. If the content is less than 0.0001% by weight, the activity is insignificant, and if the content is 1% by weight or more, the economical tendency is insufficient.
  • Cosmetics comprising the tripeptide of Formula 1 may be prepared by a known cosmetic preparation method, and is not limited to general skin cosmetics, and may be applied to quasi-drugs and external medicines. These formulations may be prepared in any of the formulations commonly prepared, for example in the form of skins, lotions, creams, foundations, essences, gels, packs, pocleaning, body oils, lipsticks, mascaras, makeup bases or soaps. It may be prepared as, but is not limited thereto. And in the cosmetic composition of each formulation, other components in addition to the above-described tripeptide can be appropriately selected and blended by those skilled in the art without difficulty according to the formulation, purpose of use, and the like of other cosmetics.
  • myr refers to a tetradecanoyl group, that is, a myristoyl group.
  • Fmocamino acid is from HATU ( N -[(dimethylamino-)-1 H -1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N -methylmethanaminium hexafluorophosphate N -oxide) 1-hydroxy-7-azabenzotriazole (HOAt) or HBTU ( N -[(1 H -benzotriazol-1-yl) (dimethylamino) methylene] -N -methylmethanaminium hexafluorophosphate N -oxide) and 1-hydroxybenzo Triazole (HOBt) was used together with DIEA ( N, N -diisopropylethylamine) to extend the chain of the peptide by coupling.
  • HATU N -[(dimethylamino-)-1 H -1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene]
  • Wrinkles in the skin are due to a decrease in collagen synthesis as the skin ages and is exposed to irritation such as ultraviolet rays, increasing the biosynthesis of collagen degrading enzymes (MMPs). Therefore, it is possible to prevent and improve skin wrinkles by reducing the amount of biosynthesis of collagen degrading enzymes such as MMP-1 and by increasing the amount of Type I procollagen1 which is rapidly reduced by ultraviolet rays.
  • MMPs collagen degrading enzymes
  • Hs68 cells human skin fibroblast Hs68 cells (ATCC, USA).
  • Hs68 cells were Dulbecco's modified Eagle medium (DMEM) supplemented with 10% FBS (Gibco Co), 100 ⁇ g / ml streptomycin, and 100 U / ml penicillin at 37 ° C. and 5% CO 2 . Incubator; Thermo-scientific, USA.
  • DMEM Dulbecco's modified Eagle medium
  • FBS Gibco Co
  • streptomycin 100 ⁇ g / ml streptomycin
  • U / ml penicillin 100 ⁇ g / ml penicillin at 37 ° C. and 5% CO 2 .
  • Incubator Thermo-scientific, USA.
  • the surface of the cultured cells was washed with PBS at intervals of three days, followed by treatment with a 0.25% trypsin-EDTA solution for 3 minutes in an incubator, followed by trypsin-EDTA solution
  • the cells were discarded and stored at 37 ° C. for 5 minutes to detach cells.
  • the detached cells were subcultured at 37 ° C. and 5% CO 2 at a split ratio of 1: 5 by transferring 10 ml of DMEM containing 10% FBS to a new culture vessel.
  • Dispense Hs68 Human skin fibroblast
  • Hs68 Human skin fibroblast
  • incubate for 24 hours at 37 ° C and 5% CO 2 and replace the serum-free medium with the diluted sample. Further incubation for 48 hours.
  • MTT solution 3- (4,5-dimethyldiazol-2-yl) -2,5 diphenyltetrazolium bromide
  • the medium is removed.
  • 100 ⁇ l of DMSO (dimethyl sulfoxide) solution was added to each well, and formazan was dissolved. The absorbance was measured at 570 nm using a microplate reader (Tecan). Survival% was converted.
  • Table 2 shows the results of cytotoxicity test after 2ppm treatment of tripeptide. Most tripeptides were found to be nontoxic at 2 ppm concentration.
  • Figure 1 is a test in the above table 1 and no cytotoxicity, as shown in Table 2 MMP-1 inhibitory effect was the best compound A350_3, compound A350_4, compound A350_6, various concentrations of the cytotoxicity of which is one of the compounds A350_7 A350_4 A chart showing the results.
  • MTT assay showed a cell viability of 95% or more from 1 to 10ppm to confirm that Compound A350_4 is a safe raw material.
  • Human skin fibroblasts (Hs68) were dispensed in 6 well plates at a concentration of 1 * 10 6 cells / well and incubated at 37 ° C. and 5% CO 2 for 24 hours until they grew 70-80%. . Replace the serum-free medium with diluted sample and incubate for 48 hours. 100 ⁇ l of the supernatant obtained by separating the culture medium from the dead cells by centrifugation was placed in an anti-MMP-1 antibody coated 96well plate (Merck, USA; Cat #: MK101) and darkened. Incubated at 37 ° C. for 2 hours.
  • the culture solution was removed, washed four times with Phosphate buffer saline (PBS) to which 0.05% Tween20 was added, and 100 ⁇ l HRP-conjugate secondary antibody solution was added and incubated for 1 hour. After washing 4 times with Phosphate buffer saline to which 0.05% Tween20 was added, 100 ⁇ l of TMB solution was added and reacted at room temperature for 15 minutes. Then, 100 ⁇ l of 1M sulfuric acid was added to terminate the reaction. Absorbance was measured at 450/595 nm using a microplate reader (Tecan). MMP-1 production inhibition rate (%) was converted as shown in Equation 2 below.
  • Table 3 below shows the inhibition rate of MMP-1 production by 12 tripeptides showing MMP-1 inhibitory effect among 20 tripeptides as one embodiment of the present invention. After treatment with 2ppm, MMP-1 production was measured by ELISA assay, and it was confirmed that MMP-1 was significantly inhibited in 12 tripeptides.
  • FIG. 2 is a comparison with an embodiment of the present invention there is no cytotoxicity to the method MMP-1 inhibitory effect was the best compound A350_3, compound A350_4, compound A350_6, the retinoic acid positive control for one of A350_4 of compound A350_7
  • This is a table showing the results of MMP-1 synthesis inhibitory test.
  • concentration of A350_4 increased to 0.8, 1.5, and 2ppm
  • MMP-1 inhibitory effect was increased, and 2ppm (48%) showed the greatest inhibitory effect on MMP-1 synthesis than Retinoic acid (41%). It showed a greater MMP-1 inhibitory effect.
  • Human skin fibroblasts (Hs68) were dispensed in 6 well plates at a concentration of 1 * 10 6 cells / well and incubated at 37 ° C. and 5% CO 2 for 24 hours until they grew 70-80%. . 1 ml of PBS was added to each well plate, and 50 mJ / cm 2 ultraviolet rays were irradiated with a UVB irradiator (vilber loumet, France). Remove the phosphate buffer saline (PBS) and replace the serum-free medium with diluted sample and incubate for 48 hours.
  • PBS phosphate buffer saline
  • Table 4 shows the results of testing the inhibitory ability of the MMP-1 production of tripeptides against MMP-1 production by UVA irradiation stimulation by the above method as an embodiment of the present invention.
  • the treatment concentration of each tripeptide is 2 ppm.
  • FIG. 3 is a result of testing the inhibitory effect of MMP-1 synthesis on UVA irradiation of tripeptides ( A350_4 ) as an embodiment of the present invention
  • Figure 4 is MMP-1 synthesis inhibition on UVB irradiation of tripeptides ( A350_4 )
  • the MMP-1 increased by UVA was reduced by 46.5% at 2ppm of tripeptides ( A350_4 ) and 43% by retinoic acid.
  • the tripeptide ( A350_4 ) was found to decrease 82% in 2ppm, 83% in retinoic acid.
  • Human skin fibroblasts (Hs68) were dispensed in 6 well plates at a concentration of 1 * 10 6 cells / well and incubated at 37 ° C. and 5% CO 2 for 24 hours until they grew 70-80%. . 1 ml of PBS was added to each well plate, and 30 J / cm 2 ultraviolet rays were irradiated with a UVA irradiator (Sankyo, Japan). Remove the phosphate buffer saline (PBS) and replace the serum-free medium with diluted sample and incubate for 48 hours.
  • PBS phosphate buffer saline
  • cell lysis buffer 50 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol, 5 mM EGTA, 1 mM sodium orthovanadate, 10 mM NaF, 12 mM bglycerophosphate, 1 mM DTT, 1 mM Cells were lysed with PMSF, 5 mg / ml aprotinin, and 1% NP40). After centrifuging the lysed cells at 26,000 g for 15 minutes to separate the cell extract, measure the amount of protein by BCA method, adjust the same amount, and denature the protein by heating at 95 °C for 5 minutes, and then 20 ⁇ g 10% SDS-PAGE Walk Yeongdong.
  • Electrophoresis gels were transferred to nitrocellulose membranes, and then incubated for 1 hour in 5% skim milk dissolved in TBST buffer, followed by procollagen 1 (Santa Cruze Biotechnology, CA).
  • the antibodies are incubated with shaking for 3 hours in a solution diluted 1: 100 in TBST buffer. After removing the antibody solution and washing three times with Phosphate buffer saline added with 0.05% Tween 20 for 5 minutes, the HRP-conjugate secondary antibody was incubated in a solution diluted 1: 2000 in TBST buffer for 1 hour. After washing the membrane, spray the ECL solution with imaging densitometer [Labworks ver.4.6. (image acquisition and analysis software), UVP, CA].
  • an anti-tubulin antibody (Sigma) was used as a control.
  • FIG. 5 is a diagram illustrating the effect of reducing type I procollagen1 biosynthesis on the UVA irradiation of tripeptide ( A350_4 ) by the above method as an embodiment of the present invention.
  • Negative control group was UVA-irradiated group and showed relative effects on the group treated with tripeptide ( A350_4 ) and the positive control group retinoic acid after UVA irradiation.
  • the tripeptide ( A350_4 ) treated group increased 3.87 times the amount of procollagen biosynthesis compared to the UVA alone irradiated group and showed the same results in retinoic acid. Therefore, it was confirmed that the tripeptide ( A350_4 ) promotes the amount of procollagen biosynthesis reduced by UVA irradiation.
  • Human skin fibroblasts (Hs68) were dispensed in 6 well plates at a concentration of 1 * 10 6 cells / well and incubated at 37 ° C. and 5% CO 2 for 24 hours until they grew 70-80%. .
  • RNA was isolated using an RNA extraction kit (invitrogen, Korea), and then cDNA was synthesized. RT-PCR was performed on the synthesized cDNA to measure the mRNA expression level of MMP-1, Type I procollagen1.
  • the primer sequences of GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) and MMP-1 used are shown in Table 5.
  • 1 ⁇ l (0.5 ⁇ g / ⁇ l) of each primer was added to the synthesized cDNA together with DEPC-Water to PCR-premix tube (Bionia, Korea). Denaturation was performed at 95 °C for 30 seconds and annealing at 60 °C. At 30 seconds, the extension proceeded to 30 cycles for 2 minutes at 72 °C.
  • PCR products were confirmed that there is no non-specific PCR product or primer dimer in 1% agarose gel, the amount of the product was confirmed by EC3 UV illuminator (UVP, USA).
  • Figure 6 is a diagram showing the results of testing the inhibitory ability of the tripeptides ( A350_4 ) MMP-1 mRNA expression in comparison with the positive control group retinoic acid as an embodiment of the present invention.
  • concentration of tripeptide ( A350_4 ) increased to 0.8, 1.5, and 2ppm
  • MMP-1 mRNA expression inhibitory effect was increased, and at the 2ppm showing the largest MMP-1 mRNA expression inhibitory effect, such as retinoic acid It showed an effect.
  • Human skin fibroblasts (Hs68) were dispensed in 6 well plates at a concentration of 1 * 10 6 cells / well and incubated at 37 ° C. and 5% CO 2 for 24 hours until they grew 70-80%. . 1 ml of PBS was added to each well plate, and 80mJ / cm 2 ultraviolet rays were irradiated with a UVB irradiation device (vilber loumet, France). Remove the phosphate buffer saline (PBS), replace the serum-free medium with diluted sample, and incubate for 24 hours. After removing the medium, RNA was isolated using an RNA extraction kit (invitrogen, Korea), and then cDNA was synthesized.
  • PBS phosphate buffer saline
  • RT-PCR was performed on the synthesized cDNA to measure mRNA expression levels of MMP-1 and Procollaen 1.
  • the primer sequences of GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) and MMP-1 used are shown in Table 5. 1 ⁇ L (0.5 ⁇ g / ⁇ L) of each primer was added and the synthesized cDNA was added to the PCR-premix tube (Bionia, Korea) with DEPC-Water. Denaturation was performed at 95 °C for 30 seconds and annealing at 60 °C. At 30 seconds, the extension proceeded to 30 cycles for 2 minutes at 72 °C. PCR products were confirmed that there is no non-specific PCR product or primer dimer in 1% agarose gel, the amount of the product was confirmed by EC3 UV illuminator (UVP, USA).
  • FIG. 7 is a diagram illustrating an effect of inhibiting increased MMP-1 mRNA expression against UVA irradiation of tripeptide ( A350_4 ) by the above method as an embodiment of the present invention.
  • FIGS 8 and 9 are diagrams illustrating the comparative and synergistic effects of retinyl palmitate and retinol used in anti-aging cosmetics as an embodiment of the present invention. As shown in Figures 8 and 9, in the case of retinyl palmitate or retinol did not show a strong inhibitory effect, such as tripeptide ( A350_4 ), it could be confirmed that some synergistic effects when used together.
  • retinyl palmitate or retinol did not show a strong inhibitory effect, such as tripeptide ( A350_4 ), it could be confirmed that some synergistic effects when used together.
  • the cell lines used in this experiment were melanoma B16F10 cells and human primary melanocyte HEMn-LP cells (Cascade Biologics, USA).
  • B16F10 cells were treated with 10% FBS (Gibco Co), 100 ⁇ g at 37 ° C and 5% CO 2 .
  • Culture was incubated using DMEM (Dulbecco's modified Eagle medium) with / ml streptomycin, 100 U / ml penicillin (Incubator; Thermo-scientific, USA).
  • HEMn-LP cells were cultured at 37 ° C., 5% CO 2 using 99% Medium 254 (Cascade Biologics, USA) medium mixed with 1% HMGS (Cascade Biologics, USA) (Incubator; Thermo -scientific, USA).
  • B16F10 and HEMn-LP cells were sufficiently grown in 100 cm 2 flasks (Corning, USA)
  • the cultured cell surfaces were washed with PBS at intervals of three days, followed by treatment with an incubator for 3 minutes in a 0.25% trypsin-EDTA solution.
  • the trypsin-EDTA solution was discarded and stored at 37 ° C. for 5 minutes to detach cells.
  • the detached cells were subcultured at 37 ° C. and 5% CO 2 at a split ratio of 1: 5 by transferring 10 ml of DMEM containing 10% FBS to a new culture vessel.
  • B16F10 melanocytes (or HEMn-LP melanocytes) were added to each well of a 6 well plate in 1x10 5 cell / well (Final volume 3ml), incubated for 24 hours in a 37 ° C, 5% CO 2 incubator. The medium of the wells was removed and replaced with fresh DMEM. Whitening efficacy samples were prepared for each well by concentration and pretreated for 30 minutes.
  • ⁇ -Melanocyte stimulating hormone ⁇ -MSH
  • ⁇ -MSH ⁇ -Melanocyte stimulating hormone
  • the culture medium was removed, 1 ml of PBS was added thereto, and each well was scraped with a cell scraper to separate cells, and then transferred to each 1.5 ml tube.
  • the supernatant was removed by centrifugation at 4 ° C and 1,300 rpm for 3 minutes, and the cell pellet was recovered and 200 ml of lysis buffer (1 mM Triton X-100, 100 mM sodium phosphate buffer containing 1 mM PMSF (pH6.8).
  • the cells were lysed by vortex at intervals of 10 minutes for 30 minutes, and then centrifuged at 4 ° C and 1,300 rpm for 30 minutes to transfer the supernatant to a new 1.5 ml tube.
  • Total protein was quantified using a BCA protein assay kit (PIERCE, USA), and the same amount of the sample was put into each well of a 96 well plate in 40 ml, followed by 2 mg / ml in phosphate buffer (pH 6.8). 120 ml of L-3,4-dihydroxyphenylalanine (L-DOPA) dissolved immediately was added. After reacting for 30 to 60 minutes at 37 ° C, absorbance was measured at 475 nm using an ELISA reader. Based on the negative control group, tyrosinase activity inhibition rate (%) was calculated by the following [Equation 4]. The negative control group was used as a sample treated with DMSO instead of a sample.
  • FIG. 10 is a diagram showing the effect of inhibiting the activity of tyrosinase increased by ⁇ -MSH of tripeptide ( A350_4 ) by the above method as an embodiment of the present invention.
  • % Tyrosinase activity inhibition [(T m -T s ) / (T m -T c )] ⁇ 100
  • T S absorbance of the sample and the group treated with ⁇ -MSH
  • B16F10 melanocytes (or HEMn-LP melanocytes) were added to each well of a 6 well plate in 1x10 5 cell / well (Final volume 3ml), incubated in 37 ° C, 5% CO 2 incubator for 24 hours, and then The medium of the wells was removed and replaced with fresh DMEM. Whitening efficacy samples were prepared for each well by concentration and pretreated for 30 minutes.
  • ⁇ -Melanocyte stimulating hormone ⁇ -MSH
  • ⁇ -MSH ⁇ -Melanocyte stimulating hormone
  • the culture medium was removed, 1 ml of PBS was added thereto, and each well was scraped off with a cell scraper to separate the cells, and then transferred to each 1.5 ml tube. Subsequently, the supernatant was removed by centrifugation at 4 ° C. and 1,300 rpm for 3 minutes, and cell pellets were recovered to obtain 200 ml of Lysis buffer (1% Triton X-100, 1 mM PMSF, 50 mM Tris-HCl, pH 7.0). 2 mM EDTA (pH 8.0), 150 mM NaCl) was added.
  • Lysis buffer 1% Triton X-100, 1 mM PMSF, 50 mM Tris-HCl, pH 7.0
  • 2 mM EDTA pH 8.0
  • FIG. 11 is a diagram showing the effect of inhibiting the production of melanin increased by ⁇ -MSH of tripeptide ( A350_4 ) by the above method as an embodiment of the present invention.
  • the amount of cAMP released into the cells was measured using a cAMP ELISA kit (Assay Design, USA). How much inhibition of the amount of cAMP generated during cell transfer of skin darkening was measured by ELISA method and the result is shown in FIG. 12.
  • B16F10 melanin producing cells or HEMn-LP melanocytes
  • 5x10 5 cells / well Food volume 5ml
  • HEMn-LP melanocytes HEMn-LP melanocytes
  • ⁇ -Melanocyte stimulating hormone ⁇ -MSH
  • ⁇ -MSH ⁇ -Melanocyte stimulating hormone
  • PCR primers were prepared beta-actin, tyrosinase, TRP1, TRP2, MITF, POMC of the mouse, and amplified 30 times under the conditions of 94 ° C 1 minute, 55 ° C 1 minute, 72 ° C 2 minutes.
  • PCR products were loaded on 1% agarose gel and electrophoresed for 30 minutes and identified using EC3 UV illuminator (UVP, USA). Genes that play an important role in melanin synthesis were selected and their Primer sequences are shown in Table 6.
  • the compound tripeptides ( A350_4 ) effectively inhibited the mRNAs of tyrosinase and TRP1, TRP2, POMC, and MITF, which can confirm that the tripeptides ( A350_4 ) are excellent whitening components.
  • Human epidermal keratinocyte cells were used to test the anti-inflammatory effects of compound tripeptides.
  • the relationship between chronic inflammation of the skin and the production of multiple cancers is well known and has been shown in many tumor experiments. Keratinocytes induced to produce cytokines by various external stimuli lose cytokine control and eventually cause various skin diseases including cancer.
  • the cell line used in the experiment was HaCaT cells, a kind of human Keratinocyte.
  • HaCaT cells were 10% FBS (Gibco Co), 100 ⁇ g / ml streptomycin, 100 U at 37 ° C and 5% CO 2 .
  • Culture was incubated using Dulbecco's modified Eagle medium (DMEM) with / ml penicillin added (Incubator; Thermo-scientific, USA).
  • DMEM Dulbecco's modified Eagle medium
  • HaCaT cells were fully grown in 100 cm 2 flasks (Corning, USA), and then washed with PBS at 3 days of culture. The cells were washed with PBS, treated with 0.25% trypsin-EDTA solution for 3 minutes in the incubator, and then trypsin-EDTA solution.
  • the cells were discarded and stored at 37 ° C. for 5 minutes to detach cells.
  • the detached cells were subcultured at 37 ° C. and 5% CO 2 at a split ratio of 1: 5 by transferring 10 ml of DMEM containing 10% FBS to a new culture vessel.
  • HaCaT Human Keratinocyte cells were dispensed in a 60mm dish at a concentration of 6 * 10 5 cells / well and incubated at 37 ° C. and 5% CO 2 for 24 hours until they grew to 70-80%. Was removed and replaced with fresh serum-free DMEM. Anti-inflammatory effect samples were prepared in each well and pretreated for 4 hours. Each well plate was placed in 3 ml of PBS and irradiated with 100mJ / cm 2 UVB by UVB irradiation (vilber loumet, France). Remove the phosphate buffer saline (PBS), replace the serum-free medium with diluted sample, and incubate for 24 hours.
  • PBS phosphate buffer saline
  • RNA was isolated using an RNA extraction kit (invitrogen, Korea), and then cDNA was synthesized. RT-PCR was performed with the synthesized cDNA to measure the expression levels of Interleukin-1 ⁇ (IL-1 ⁇ ), Interleukin-1 ⁇ (IL-1 ⁇ ), and Interleukin 6 (IL-6) mRNA.
  • the primer sequences of GAPDH (Glyceraldehyde-3-phosphate dehydrogenase, Interleukin-1 ⁇ (IL-1 ⁇ ), Interleukin-1 ⁇ (IL-1 ⁇ ), and Interleukin 6 (IL-6) are shown in Table 7.
  • the compound tripeptide ( A350_4 ) effectively inhibited the mRNAs of the cytokines IL-1 ⁇ , IL-1 ⁇ and IL-6 increased by UVB irradiation, and the tripeptides ( A350_4 ) had excellent anti-inflammatory effects. You can see it.
  • the lotion was prepared with the composition shown in Table 8 below, and the wrinkle improvement and whitening effects on the human body were evaluated through actual use tests.
  • the tripeptide, the skin pharmaceutical composition and the cosmetic composition according to the present invention have no skin irritation and have excellent skin stability, and can be usefully used because of excellent wrinkle improvement, whitening and inflammation inhibitory effects.

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Abstract

La présente invention concerne un nouveau tripeptide de formule 1 suivante et une composition cosmétique le contenant en tant que principe actif, la composition cosmétique servant à prévenir le vieillissement cutané et à réduire les rides et ayant un effet de blanchiment et anti-inflammatoire. Selon la présente invention, le tripeptide présente des effets de prévention des rides par inhibition des MMP, qui sont des enzymes dégradant le collagène, et un effet de renforcement de la production et de la biosynthèse du collagène. En outre, le tripeptide a un effet de blanchiment, par exemple la prévention des phénomènes de pigmentation de la peau, par inhibition de l'activité des tyrosinases et de la production de mélanine, et il présente également un effet de suppression des inflammations. Ce tripeptide permet donc d'obtenir un produit cosmétique très efficace pour réduire les rides, pour le blanchiment et pour prévenir une inflammation. Plus particulièrement, le tripeptide de l'invention peut être ajouté à diverses compositions cosmétiques de soin cutané, telles que les pommades, les lotions, les crèmes, les fonds de teint, les essences, les gels, les masques, les mousses nettoyantes, les huiles pour le corps, les rouges à lèvres, les mascaras, les bases de maquillage et les savons. De plus, le tripeptide de l'invention n'est pas irritant pour la peau et est très stable sur la peau. Formule 1 : R1-X-Leu-Phe (dans la formula 1, R1 est un groupe alcényle choisi parmi un hydrogène ou un groupe acyle contenant 1 à 18 atomes de carbone et au moins une double liaison. Leu peut être D-Leu ou L-Leu, et Phe peut être D-Phe ou L-Phe. De plus, X peut être un acide aminé choisi en particulier parmi les 20 acides aminés naturels et la phénylglycine, qui est un acide aminé artificiel, un acide carboxylique ou un amide pouvant être présent à son extrémité C-terminale.)
PCT/KR2013/001407 2012-02-29 2013-02-21 Tripeptide et composition cosmétique le contenant et ayant des effets antivieillissement, antirides, de blanchiment et anti-inflammatoires WO2013129801A1 (fr)

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