WO2015111857A1 - Dérivé peptidique et composition cosmétique fonctionnelle contenant ce dernier - Google Patents

Dérivé peptidique et composition cosmétique fonctionnelle contenant ce dernier Download PDF

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WO2015111857A1
WO2015111857A1 PCT/KR2015/000139 KR2015000139W WO2015111857A1 WO 2015111857 A1 WO2015111857 A1 WO 2015111857A1 KR 2015000139 W KR2015000139 W KR 2015000139W WO 2015111857 A1 WO2015111857 A1 WO 2015111857A1
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acid
aliphatic carboxylic
carboxylic acid
dipeptide
group
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PCT/KR2015/000139
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Korean (ko)
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이동희
정하나
최하영
유지원
김병일
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(주)셀인바이오
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Priority to JP2016566587A priority Critical patent/JP2017505341A/ja
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    • 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
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/88—Polyamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to peptide derivatives, and more particularly, to peptide derivatives having improved skin permeability and no cytotoxicity, and functional cosmetic compositions containing the same as active ingredients.
  • Functional cosmetics can be used to: 1) prevent the deposition of melamine pigments on the skin or thin the color of the melanin pigments; and 2) to improve skin wrinkles by providing elasticity to the skin.
  • Cosmetics 3) It can be divided into cosmetics that help to burn skin finely or protect skin from ultraviolet rays by preventing strong sun, blocking or scattering UV rays.
  • TDS transdermal delivery systems
  • the skin is formed on the outermost side of the living body to protect the living body from external dangerous substances, but is prone to aging by various external stimuli. Wrinkles on the skin are the main cause of skin aging due to natural aging (endogenous aging) and photo-aging (exogenous aging). As skin cells age, the elasticity of collagen and elastin decreases due to a decrease in cell regeneration ability, lipid peroxide is generated by active oxygen, or biological components are oxidized and denatured. That is, as the skin tissue ages, when the biosynthetic ability of the fibers and the substrate constituting the skin tissue decreases, the thickness of the skin becomes thin and the elasticity of the skin decreases, thereby forming wrinkles. Therefore, to prevent aging or to improve wrinkles, functions such as promoting collagen synthesis and antioxidant activity are required.
  • ingredients that control the differentiation and regeneration of epidermal cells by stimulating skin turnover e.g. Retinoids, alpha-hydroxy acids (AHAs), mevalonic acid ( Mevalonic acid (MA)
  • MMP-1 matrix metalloproteinase-1
  • ECM extracellualr matrix
  • ROS scavenger reactive oxygen
  • Anti-inflammatory components such as glycyrrhizinate hizic acid derivatives
  • Ingredients that protect against damage to the DNA damaged by UV rays or by repairing the DNA to prevent skin damage caused by UV rays e.g. Creatin, Candlebush extract, Photolyase from phytoplankton
  • Botox-like peptides that decrease muscle movement e.g. Creatin, Candlebush extract, Photolyase from phytoplank
  • Peptides function as hormones in the human body or may be involved in immunity. In addition to skin cells, peptides perform functions such as wound healing and skin-barrier repair for damaged skin. Peptides administered to the human body as active ingredients or auxiliaries for drugs or cosmetics include signal peptides, enzyme inhibitory peptides, neurotransmitter inhibitory peptides, and carriers that promote the transport of active ingredients into cells. It can be divided into peptides. Among the peptides used in the cosmetic field, signal peptides that promote or induce the synthesis of specific proteins in skin tissue are used.
  • Peptides however, have hydrophilic functional groups. Thus, peptides used as components of transdermal cosmetics do not penetrate the skin and do not actually function. In addition, since peptides are vulnerable to enzymes present in the skin in significant amounts, even if the peptides are absorbed, these peptides may be degraded and may not be effective. In addition, some peptide derivative components are known to exhibit cytotoxicity and are therefore not suitable as active ingredients in cosmetics.
  • Another object of the present invention is to provide a functional cosmetic containing the peptide derivative compound as an active ingredient.
  • the present invention relates to a glycyl (hydroxy) proline dipeptide derivative compound modified with aliphatic carboxylic acid and a functional cosmetic composition containing the derivative compound as an active ingredient.
  • the present invention provides a dipeptide derivative compound wherein C 4 -C 10 aliphatic carboxylic acid is introduced at the terminal of the dipeptide, which is glycylproline or glycylhydroxyproline.
  • the dipeptide derivative compound may be represented by the following formula (I) or formula (II).
  • R 1 is hydrogen or a hydroxyl group
  • R 2 is a C 4 -C 10 aliphatic carboxylic acid bonded through a carboxy group.
  • R 1 and R 2 are the same as defined in formula (I);
  • R 3 is C 1 -C 20 alkylene, C 3 -C 10 cycloalkylene and C 6 -C Selected from the group consisting of arylene of 20 ; each of A and B is independently an -NH group or an oxygen atom
  • the aliphatic carboxylic acid may be saturated fatty acid or unsaturated aliphatic carboxylic acid, specifically the aliphatic carboxylic acid may be butyric acid, pentanic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid.
  • Aliphatic monocarboxylic acid selected from the group consisting of:
  • the aliphatic carboxylic acid may be selected from the group consisting of butanoic acid, pentanic acid, octanoic acid and decanoic acid.
  • the aliphatic carboxylic acid may be C 5 -C 8 aliphatic carboxylic acid.
  • the present invention comprises a dipeptide derivative compound having a C 4 -C 10 aliphatic carboxylic acid introduced at the terminal of a dipeptide which is glycylproline or glycylhydroxyproline as an active ingredient. It provides a cosmetic composition for improving wrinkles.
  • the dipeptide derivative compound prevents aging of the skin by a method of inducing collagen biosynthesis in skin tissue and / or promoting the activity of prolidase in the skin tissue. This can alleviate wrinkles.
  • the dipeptide derivative compound may be contained in the cosmetic composition at a concentration of 0.1 to 1000 ⁇ M, preferably at a concentration of 1 to 500 ⁇ M, more preferably at a concentration of 10 to 200 ⁇ M. .
  • the present invention comprises a dipeptide derivative compound having a C 4 -C 10 aliphatic carboxylic acid introduced at the terminal of a dipeptide which is glycylproline or glycylhydroxyproline as an active ingredient. It provides an anti-aging cosmetic composition.
  • the present invention proposes a derivative compound in which a lipophilic aliphatic carboxylic acid is introduced into the terminal of glycylproline or glycylhydroxyproline dipeptide.
  • the derivative compound in which an aliphatic carboxylic acid is introduced into the glycyl (hydroxy) proline dipeptide is greatly improved in permeability to skin cells and induces the proliferation of skin cells.
  • This derivative compound not only promotes biosynthesis of collagen in skin cells, but also enhances the activity of prolidase, an enzyme involved in the regeneration of collagen, and does not cause cytotoxicity. Therefore, the derivative compound synthesized according to the present invention can be utilized as an active ingredient of cosmetics for anti-aging and / or wrinkle improvement of skin.
  • FIG. 1 is a fiber obtained by administering a glycyl (hydroxy) proline dipeptide derivative having a C 4 -C 10 aliphatic carboxylic acid introduced thereto into dermal fibroblasts according to an exemplary embodiment of the present invention. It is a graph measuring the result of analyzing the proliferation effect of the blast cells through the Wst-1 assay. Glysyl substituted with glycyl (hydroxy) proline dipeptide (GP), propanoic acid (C 3 ), lauric acid (C 12 ) and palmitic acid (C 16 ) not substituted with aliphatic carboxylic acid as a control (Hydroxy) proline dipeptide was used.
  • GP glycyl (hydroxy) proline dipeptide
  • C 3 propanoic acid
  • lauric acid C 12
  • palmitic acid C 16
  • Figure 2 is a glycyl (hydroxy) proline dipeptide derivative introduced with a C 4 -C 10 aliphatic carboxylic acid in accordance with an exemplary embodiment of the present invention after administration to human dermal fibroblasts, It is a graph measuring the degree of collagen biosynthesis. Glysyl substituted with glycyl (hydroxy) proline dipeptide (GP), propanoic acid (C 3 ), lauric acid (C 12 ) and palmitic acid (C 16 ) not substituted with carboxylic acid as a control Hydroxy) proline peptide was used.
  • GP glycyl (hydroxy) proline dipeptide
  • C 3 propanoic acid
  • lauric acid C 12
  • palmitic acid C 16
  • Figure 3 is a glycyl (hydroxy) proline dipeptide derivative introduced with a C 4 -C 10 aliphatic carboxylic acid in accordance with another exemplary embodiment of the present invention after administration to the fibroblasts, the prolida in the cell lysate It is a graph measuring the activity of an aze.
  • Negative control (NT), glycyl (hydroxy) proline dipeptide (GP), propanoic acid (C 3 ), lauric acid (C 12 ) and palmitic acid (C 16 ) unsubstituted with carboxylic acid as control
  • a glycyl (hydroxy) proline dipeptide substituted with was used, and an insulin-like growth factor (IGF) known to induce the activity of prolidase was used as a positive control.
  • IGF insulin-like growth factor
  • FIG. 4 is a glyczyl (hydroxy) proline dipeptide derivative to which a C 4 -C 10 aliphatic carboxylic acid is introduced, according to another exemplary embodiment of the present invention, to a hairless mouse, and then using a Franz cell test method. It is a graph measuring skin permeability. Glysyl substituted with glycyl (hydroxy) proline dipeptide (GP), propanoic acid (C 3 ), lauric acid (C 12 ) and palmitic acid (C 16 ) not substituted with carboxylic acid as a control Hydroxy) proline dipeptide was used.
  • GP glycyl (hydroxy) proline dipeptide
  • C 3 propanoic acid
  • lauric acid C 12
  • palmitic acid C 16
  • Figure 5 is a graph measuring the results of international clinical trials after administering a glycyl (hydroxy) proline dipeptide derivative prepared according to another exemplary embodiment of the present invention.
  • the glycyl (hydroxy) proline dipeptide derivatives of the present invention significantly reduced the area and length of skin wrinkles.
  • Compounds which are dipeptide derivatives modified with aliphatic carboxylic acids synthesized according to the invention are C 4 -C 10 , preferably C 5- , at the ends of glycyl (hydroxy) proline or glycylhydroxyproline dipeptide.
  • C 10 more preferably C 5 -C 8 aliphatic carboxylic acid is introduced.
  • aliphatic carboxylic acids may be directly linked to the ends of the dipeptides, as well as indirectly via suitable linkers or cross linkers.
  • one aspect of the present invention relates to derivatives conjugated with aliphatic carboxylic acid at the N-terminus and / or C-terminus of the glycyl (hydroxy) proline dipeptide.
  • aliphatic carboxylic acid bound to the terminal of the glycyl (hydroxy) proline dipeptide may improve stability by promoting penetration of the dipeptide into cells or tissues.
  • conjugation or “conjugated” refers to the interaction between a dipeptide and an aliphatic carboxylic acid component introduced at the end of the dipeptide, so that the components are connected to each other to maintain proximity. Action, eg, covalent, ionic or hydrophobic interaction.
  • Derivative compounds produced by binding to the ends of the glycyl (hydroxy) proline dipeptides according to the present invention should be interpreted to include salts, optical and / or geometric isomers, diastereomers or mixtures thereof.
  • the derivative compounds of the present invention may be in the form of possible optical and / or geometric isomers of dipeptides and / or aliphatic carboxylic acids or mixtures of these isomers, or pharmaceutical, food engineering, cosmetic engineering of aliphatic carboxylic acids.
  • aliphatic carboxylic acids may bind to the dipeptide via a linker or crosslinker, which terms are used interchangeably herein and bind / link two components together and add one or more components.
  • Peptide as used herein also encompasses "peptide analogs", ie, analogues that are one or more substituted for the side chain or alpha-amino acid backbone of L-amino acids. Examples of side chain or backbone modified peptide analogs include hydroxyproline in which the pyrrolidine ring is substituted with a hydroxy group, or an N-methyl glycine "peptoid".
  • the dipeptide derivative compound of the present invention is a compound in which an aliphatic carboxylic acid is introduced through an amide conjugation to the N-terminus of the glycyl (hydroxy) proline dipeptide of the dipeptide. It may be represented by (I).
  • R 1 is hydrogen or a hydroxyl group
  • R 2 is a C 4 -C 10 aliphatic carboxylic acid bonded through a carboxy group.
  • aliphatic carboxylic acids may be linked to the ends of glycyl (hydroxy) proline via linkers or crosslinkers.
  • the functional group (reactive group) of the linker used to form a covalent bond between the linker and glycyl (hydroxy) proline dipeptide and / or between the linker and aliphatic carboxylic acid may be an amine group, a hydroxyl group, a hydrazino group, a thiol Group, maleimido group, carbonyl group and carboxyl group.
  • Linkers having these functional groups at least at one end are for example C 1 -C 20 straight or branched alkyl groups; C 1 -C 20 linear or branched heteroalkyl group having a hetero atom such as O, N, S or the like; A cycloalkyl group of C 3 -C 10 ; A C 3 -C 10 cycloalkyl group having the aforementioned hetero atom; C 6 -C 20 aryl group having 1-3 rings; It may be a C 6 -C 20 hetero aryl group having 1-3 rings and containing 1-4 hetero atoms, such as N, O, S and the like.
  • these functional groups may be identical (homologous groups) and may have different types of functional groups (heterologous groups).
  • the functional group of the linker may be selected from an amine group, a carboxyl group, a hydroxyl group and a maleimido group, and optionally, if necessary, includes a short sequence of 1-4 amino acid residues having a thiol group which is a mediator to which the linker binds to the dipeptide. can do.
  • the linker can be independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aldehyde, acid, ester, anhydride, sulfhydryl or carboxyl group.
  • 2-functional and multi-functional organic radicals selected from maleimido derivatives, maleimido cyclohexane derivatives, maleimido benzoic acid derivatives, maleimidocaproic acid derivatives and succinimido derivatives, or cyanogen bromide or chloride, Succinimidyl esters or sulfonyl halides or the like or combinations thereof.
  • Crosslinking agents may be used to induce chemical bonds when forming a conjugate of glycyl (hydroxy) proline dipeptide and aliphatic carboxylic acid. Since the N-terminal of the dipeptide has an amine group, the formation of a conjugate by a crosslinking agent is easy. In particular, crosslinking agents which form reversible or irreversible linkages with amino groups may be preferred.
  • Crosslinkers that can be used include 1,5-difluoro-2,4-dinitrobenzene, p, p'-difluoro-N, N'-dinitrodiphenylsulfone, dimethyl adipimidate, phenol-1, 4-disulfonylchloride, hexamethylene diisocyanate, hexamethylene diisothiocyanate, azophenyl-p-diisocyanate, glutaraldehyde (reacts with various side chains), N-3-maleimidopropanoic acid, N-6 -Maleimidocaproic acid, N-11-maleimidodecanoic acid, 4- (N-maleimidomethyl) cyclohexane-1-carboxy-6-amidocaproic acid, 1,4-bis-maleimidobutane (BMB ), 1,11-bis-maleimidotetraethylene glycol (BM [PEO] 4), 1-ethyl-3- [
  • succinimidyl group of the crosslinker reacts with the primary amine forming an amide bond.
  • Some of these crosslinkers have low solubility in water, and hydrophilic groups such as sulfonate groups can be added to the crosslinker to improve solubility in water.
  • linkers having amine groups and / or hydroxy groups at both ends may be used. Between these functional groups, for example, a (hetero) alkylene group of C 1 -C 20 , a cycloalkylene group of C 3 -C 10 , and a (hetero) arylene group of C 6 -C 20 can be formed.
  • a linker having an amine group at both ends the amine group formed at one end of the linker and the carboxyl group of aliphatic carboxylic acid may react to form an amide bond.
  • One end of the linker is linked with an aliphatic carboxylic acid and an amide bond, while the other end of the linker has an open amine group.
  • an amine group located at the other end of the open linker can react with a carboxyl group located at the C-terminus of glycyl (hydroxy) proline to form an amide bond.
  • aliphatic carboxylic acids can be attached to the C-terminus of the glycyl (hydroxy) proline dipeptide, forming amide bonds at both ends of the linker.
  • aliphatic carboxylic acid may be bonded to the C-terminus of the glycyl (hydroxy) proline dipeptide, forming an ester bond at both ends of the linker.
  • the dipeptide derivative compound of the present invention is a compound in which an aliphatic carboxylic acid is introduced through a linker at the C-terminus of the glycyl (hydroxy) proline dipeptide, and may be represented by the following Formula (II): have.
  • R 1 is hydrogen or a hydroxyl group
  • R 2 is a C 4 -C 10 aliphatic carboxylic acid bonded through a carboxy group
  • R 3 is C 1 -C 20 alkylene, C 3 -C Selected from the group consisting of 10 cycloalkylenes and arylene of C 6 -C 20
  • each of A and B is independently a -NH group or an oxygen atom
  • the dipeptide derivative of the present invention consists of glycyl (hydroxy) proline (glycylproline) or glycine and hydroxyproline (Hydroxyproline), which is a dipeptide consisting of glycine and proline.
  • Aliphatic carboxylic acid having an appropriate carbon number at the end of the dipeptide glycylhydroxyproline (glycylhydroxyproline) is a derivative connected through an amide bond.
  • the aliphatic carboxylic acid that can be bound to the glycyl (hydroxy) proline dipeptide can be saturated fatty acid or unsaturated aliphatic carboxylic acid, and can have a straight or branched form.
  • aliphatic carboxylic acids that can be incorporated into the dipeptide are saturated aliphatic carboxylic acids in straight chain form.
  • Non-limiting examples of saturated aliphatic carboxylic acids which can be introduced and bound to the ends of the glycyl (hydroxy) proline dipeptides according to the invention include butanoic acid / butyric acid, butanoic acid / Pentanoic acid / valeric acid, hexanoic acid / caproic acid, heptanoic / enanthic acid, octanoic acid / caprylic acid, Saturated aliphatic monocarboxylic acids such as nonanoic acid / pelargonic acid, decanoic acid / capric acid; Succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic aicd, sebacic acid Aliphatic dicarboxylic acids such as; Aliphatic tricarboxylic acids such as citric acid, isocitric acid, propane-1,2,3-tricarboxylic acid.
  • non-limiting examples of unsaturated aliphatic carboxylic acids that can be introduced and bound to the ends of the glycyl (hydroxy) proline dipeptides according to the present invention include butenoic acid, such as crotonic acid. ), Pentenoic acid, hexenoic acid, heptenoic acid.
  • the aliphatic carboxylic acid which can be introduced into the terminal of the glycyl (hydroxy) proline dipeptide according to the present invention is a C 4 -C 10 saturated aliphatic monocarboxylic acid.
  • aliphatic carboxylic acids that can be conjugated to the ends of the glycyl (hydroxy) proline dipeptides are butanoic acid, pentanic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.
  • the number of carbons of these aliphatic carboxylic acids introduced at the terminal of the glycyl (hydroxy) proline dipeptide is less than 4, unsubstituted glycyl (hydroxy) proline It is difficult to expect improved cell permeability compared to dipeptide. Therefore, even if a glycyl (hydroxy) proline derivative having a carboxylic acid having a carbon number of less than 4 such as formic acid, acetic acid and propionic acid (propanoic acid) is used as an active ingredient of cosmetics, it does not penetrate efficiently into skin cells. can not do it. Therefore, the dipeptide derivative compound having less than 4 carbon atoms in carboxylic acid is introduced, and thus the wrinkle improvement effect is insufficient because improvement in skin cell growth rate, collagen regeneration ability, and activity of prolidase related thereto are not expected. can do.
  • a glycyl (hydroxy) proline derivative having a carboxylic acid having a carbon number of less than 4 such as formic acid
  • glycyl (hydroxy) proline dipeptide derivatives incorporating aliphatic carboxylic acids with more than 10 carbon atoms, such as palmitic acid are rather toxic to skin cells. Therefore, glycyl (hydroxy) proline derivatives incorporating carboxylic acids having more than 10 carbon atoms, such as lauric acid having 12 carbon atoms or palmitic acid having 16 carbon atoms, may be used as skin cells.
  • the biosynthesis of collagen in Eosin may be inhibited, which may adversely affect wrinkle improvement, such as causing aging of skin cells.
  • glycyl (hydroxy) proline derivatives in which aliphatic carboxylic acids having more than 10 carbon atoms are introduced may not only inhibit fibroblast proliferation, collagen biosynthesis and activity of prolidase. Skin permeability is also impaired.
  • the extent to which a particular compound is absorbed into the skin through the skin barrier depends on a variety of factors, among which the molecular weight, melting point, and hydrophobicity / hydrophilicity of the compound are at play.
  • the outermost stratum corneum which is the skin constituent, has a stacked structure of keratin, a highly hydrophobic insoluble protein with a lipid bilayer in between.
  • Peptides are hydrophilic substances having amide bonds capable of hydrogen bonding, and are particularly difficult to diffuse in the outermost stratum corneum of skin epidermal cells, for example, to form hydrogen bonds with other substances present in skin tissue. When the peptide is administered to the skin, penetration into the skin tissue is difficult due to hydrogen bonding with other substances present in the skin tissue.
  • a modified peptide derivative is synthesized by introducing a hydrophobic aliphatic carboxylic acid having an appropriate number of carbon atoms as a lipophilic functional group at the terminal of the glycyl (hydroxy) proline dipeptide to synthesize a modified peptide derivative.
  • the aliphatic carboxylic acid which binds to the terminal of the glycyl (hydroxy) proline dipeptide according to the invention is a saturated or unsaturated aliphatic carboxylic acid in straight or branched chain form of C 4 -C 10 .
  • the carbon number of the aliphatic carboxylic acid binding to the glycyl (hydroxy) proline dipeptide is less than 4, it is difficult to expect a cell permeation effect on the glycyl (hydroxy) proline, and the aliphatic If the carbon number of the carboxylic acid exceeds 10, it has been shown to inhibit skin cell growth and collagen resynthesis closely related to it due to cytotoxicity.
  • the carbon number of the fatty acid amide-bonded to the dipeptide of the present invention has sufficient critical significance, and it is unexpected in the art that the higher fatty acids having 16 or more carbon atoms cause cytotoxicity. .
  • dipeptide derivative compounds in which aliphatic carboxylic acid is introduced at the ends of glycyl (hydroxy) proline can be synthesized according to well known methods.
  • a dipeptide derivative represented by the formula (I) first, a glycyl (hydroxy) proline dipeptide is synthesized.
  • Glysyl (hydroxy) proline dipeptides can be biotechnological or chemical synthetic methods using recombinant expression vectors.
  • recombinant expression vectors suitable for bases encoding glycine (GGA) (GGA, GGC, GGG, GGT) and bases encoding proline (Pro) (CCA, CCC, CCG, CCT), for example histidine
  • GGA glycine
  • Pro proline
  • a recombinant vector is prepared by cloning a dipeptide coding base to a pET vector, a plasmid vector having a His) tag, by using a PCR technique. Subsequently, it can be prepared by mass expression in the form of His-Gly-Pro peptide in the host E. coli, followed by pure purification.
  • the base encoding the glycyl (hydroxy) proline dipeptide and the base encoding another amino acid or peptide may be inserted at the same time and expressed in the form of a fusion protein.
  • Examples of chemical synthesis methods may be classified into liquid phase synthesis and solid phase synthesis, but a method of synthesizing solid phase peptides using an organic synthesis device for peptide synthesis (Solid-phase peptide synthesis, SPPS) may be used (RB Merrifield, Solid).
  • Phase Peptide Synthesis.I The Synthesis of a Tetrapeptide, J. Am. Chem. Soc., 1963, 85 (14): 2149-2154; Dtsch. Med. Schuschr. 109 (49): 1901-2.
  • (hydroxy) proline constituting the carboxyl terminus of the dipeptide is coupled to a suitable resin, followed by synthesis of glycine and (hydroxy) proline.
  • the alpha-amino group of the synthesized amino acid glycine and / or (hydroxy) proline, ie, the N-terminus may be used in a form protected with an appropriate protecting group.
  • Resin which is required for solid phase synthesis, is an insoluble, porous, solid support treated with appropriate units (linkers) and is combined with (hydroxy) proline, which constitutes the C-terminus of the dipeptide.
  • Resins that can be used are polyamide resins, which have good swelling and firmness, as well as polyamide resins, PEG-hybrid polystyrene resins, hydroxymethyl resins, aminomethyl resins, chloromethylated resins or chlorotitanium resins (e.g. For example, 2-chlorotritylchloride (CTC resin) can be used, etc.
  • the coupling reagent for activating the C-terminal carbonyl group of glycine can be used as an activator when synthesizing dipeptides
  • the N-terminal protecting group after coupling can use a suitable deprotection agent.
  • Active agents that can be used to activate the C-terminus in the coupling of peptides include (N-[(dimethylamino-)-1H-1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N -methylmethanaminium hexafluorophosphate N-oxide (HATU) and 1-hydroxy-7-azabenzotriazole (HOAt) or HBTU (N-[(1H-benzotriazol-1-yl) (dimethylamino) methylene] -N-methylmethanaminium hexafluorophosphate N-oxide and 1-hydroxybenzotriazole (HOBt) can be used together with DIEA (N, N-diisopropylethylamine), and N, N'-diisopropyl Bases such as carbodiimides that react with carboxylic acids to form highly reactive O-acylisoureas, such as carbodiimide (DIC
  • the fatty acid derivative is separated from the solid resin by a cleavage solution containing trifluoroacetic acid (TFA), and a derivatization group for removing glycine protecting groups (e.g. fmoc protecting groups) using piperidine or the like is used.
  • TFA trifluoroacetic acid
  • a protective reaction is performed to terminate glycyl (hydroxy) proline dipeptide synthesis. If necessary, a process of separating the dipeptide from which the protecting group has been removed from the resin using an appropriate acid is first performed, followed by a coupling reaction with the carboxylic acid.
  • the aliphatic carboxylic acid is then reacted with the N-terminus of the synthesized dipeptide to form an amide bond.
  • a derivative of the carboxylic acid dipeptide form in the amide-bonded form may be synthesized by dehydration and condensation. This reaction can be carried out, for example, in a state in which the dipeptide and the resin are coupled, thereby producing polymer beads.
  • the N-terminal amine group has an acyl activator having a desired alkyl group, for example, acyllanhydride and DMAP (4- (N, N-dimethylamino) pyridine)) reacts together to form or conjugate amide bonds at the N-terminus with N, N-diisopropylcarbodiimide (DIC), 1-hydroxy -7-azabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt) can be used together to form an amide bond.
  • acyl activator having a desired alkyl group for example, acyllanhydride and DMAP (4- (N, N-dimethylamino) pyridine)
  • an acid aqueous solution such as trifluoroacetic acid is used to cleave and separate the fatty acid dipeptiide derivative from the solid support resin.
  • diethyl ether or the like is added to crystallize the synthesized carboxylic acid-dipeptide, followed by analysis, purification using filtration, drying, HPLC, and the like, and freeze drying and packaging for storage and sale. This can be done further.
  • collagen is a major protein constituting the connective tissue of animals, including the human body, in particular, is a fibrous protein that occupies about 90% of the dermis component in the skin tissue.
  • the basic structural unit of collagen synthesized through various biosynthesis processes in vivo consists of two identical ⁇ 1 chains and three subunits of slightly different ⁇ 2 chains compared to this chain, and the three chains form a helical structure.
  • Tropocollagen In particular, some prolines and serines are converted to hydroxyproline and hydroxyserine by hydroxylation. Intramolecular crosslinks in subunits and intermolecular crosslinks between subunits are formed by these specific amino acids.
  • collagen is a major structural block of connective tissue, providing not only high tensile strength to connective tissues, including the skin, but also the ability to overcome deformation.
  • Collagen for example, maintains skin firmness, is involved in the adhesion of skin tissues, and is involved in cell adhesion and the like. Due to natural skin aging and photoaging by ultraviolet irradiation, the thickness of the skin is thinned, thereby forming wrinkles on the skin.
  • collagen is used for medical purposes such as bone reconstitution, scaffolds for tissue regeneration, materials for tissue reconstitution such as artificial skin substitutes, and materials for wound healing.
  • Type I collagen which is the most collagen form present in vivo, is a substance that provides skin tension and skin elasticity together with elastin in skin tissue, protecting the skin from ultraviolet rays and preventing wrinkles.
  • collagen a constituent protein of fibroblasts that are skin cells, proline (Pro) and hydroxyproline (Hyp) have a repeat structure (Gly-Pro-X or Gly-X-HyP; Gly is glycine and X is other Amino acids).
  • Collagen has a structure in which proline and hydroxyproline are repeated, and fibroblasts do not biosynthesize these amino acids, but show unique physiological properties provided by extracellular matrix (ECM) around cells.
  • ECM extracellular matrix
  • prolidase plays an important role, which is also called Xaa-Pro dipeptidase, which is located at the C-terminus of the peptide, or It is an cytoplasmic enzyme that hydrolyzes a dipeptide with hydroxyproline.
  • collagen has a high content of imino acid such as proline or hydroxyproline
  • prolidase plays an important role in the metabolism of collagen. That is, it is degraded to proline or hydroxyproline, which is the main amino acid or imino acid of collagen, by prolides involved in the final stage of the decomposition process of collagen, and thus the produced proline or hydroxyproline is about 70-90%. This is recycled and used for the synthesis of collagen. Therefore, by promoting the activity of the prolydase, an enzyme that promotes the recycling of (hydroxy) proline, the biosynthesis of collagen is increased to achieve the effect of wrinkle improvement.
  • a dipeptide derivative in which an aliphatic carboxylic acid is introduced at the end of glycyl (hydroxy) proline to the skin not only induces proliferation of fibroblasts constituting skin tissue ( 1) to enhance collagen biosynthesis in dermal fibroblasts (see FIG. 2).
  • the dipeptide derivatives synthesized according to the present invention also enhance the activity of prolides involved in the resynthesis of collagen (see FIG. 3), particularly through the skin barrier to enhance the penetration effect into skin cells ( See FIG. 4).
  • wrinkle generation is significantly reduced (see FIG. 5), and thus, may be used as an active ingredient of cosmetics for improving wrinkles and / or anti-aging.
  • the present invention relates to a cosmetic composition for improving skin wrinkles and / or anti-aging, which contains a dipeptide derivative having good collagen regeneration ability, not only promoting the activity of prolidase, but also having no cytotoxicity, as an active ingredient.
  • Cosmetic active ingredients, the dipeptide derivative in the composition is glycyl (hydroxy) aliphatic carboxylic acid is introduced in the C 4 -C 10 ends of the proline, and a combined compound.
  • the glycyl (hydroxy) proline dipeptide derivative compound in which an aliphatic carboxylic acid is introduced at the terminal is used in a cosmetic composition at a concentration of 0.001 to 1000 ⁇ M, preferably 1 to 500 ⁇ M, more preferably 10 to 200. It may be contained at a concentration of ⁇ M, but the present invention is by no means limited thereto.
  • composition according to the invention contains a cosmetic and / or dermatologically acceptable medium, ie a medium suitable for skin, mucous membranes, hair and scalp.
  • a cosmetic and / or dermatologically acceptable medium ie a medium suitable for skin, mucous membranes, hair and scalp.
  • These are all dosage forms suitable for topical application, in particular emulsions obtained by dispersing the oil phase in an aqueous, aqueous / alcoholic or oily solution, or an aqueous, aqueous / alcoholic or oily gel, or a solid or pasty anhydrous product, an aqueous phase (O / W). Or vice versa (W / O), suspensions, microemulsions, microcapsules, microgranules or ionic (liposomes) and / or nonionic vesicle dispersants.
  • cosmetic compositions can be prepared according to conventional methods in the art.
  • the cosmetic composition according to the invention can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.
  • the amount of various components that may be included in the cosmetic composition according to the present invention may be an amount conventionally used in the art.
  • Octyldodecanol, isostearyl isostearate, cetyloctanoate and neopentyl glycol dicaprate can be used.
  • the solubility of the compound in the solvent is slightly different depending on the kind of the compound and the mixing ratio of the solvent.
  • a person skilled in the art to which the present invention belongs belongs to the characteristics of the product Depending on the type and the amount of the solvent can be appropriately selected.
  • the cosmetic composition of the present invention comprises 1) water-soluble vitamins such as vitamin B1, vitamin B2, vitamin B6, pyridoxine, nicotinic acid, folic acid, vitamin C and salts or derivatives thereof that can be formulated in cosmetics; 2) fat-soluble vitamins such as vitamin A, carotene, vitamin D2, vitamin D3, vitamin E (tocopherol), and derivatives thereof (fatty acid ascorbin or alphatocopherol acetate); 3) high molecular peptides such as collagen, gelatin, elastin and keratin; 4) polymeric polysaccharides such as hydroxyethyl cellulose, sodium hyaluronate, chondroitin sulfate or salts thereof; 5) sphingolipids such as ceramide and phytosphingosine; And / or 6) brown algae / flushing / thickness extracts or seaweed extracts purified from them, such as calatan, arginic acid, sodium arginate / potassium, and the like.
  • the functional cosmetic composition of the present invention may be blended with other components usually formulated into cosmetics as needed.
  • Formulation ingredients that may be added include fats and oils, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, UV absorbers, preservatives, fungicides, antioxidants, antioxidants, plant extracts, pH adjusters, alcohols, Foaming agents, fillers, ultraviolet absorbers, pigments, colorants, gelling or thickening agents, fragrances, blood circulation accelerators, cooling agents, limiting agents, purified water and the like.
  • the oil-fat component is 1) ester fats and oils, such as glyceryl tri2-ethylhexanoate, cetyl 2-ethylhexanoate, and fatty acid alcohol; 2) hydrocarbon-based fats and oils such as squalene, liquid paraffin, isoparaffin, alpha-olefin oligomer and petrolatum; 3) silicone-based fats and oils such as polymethylsilicone, methylphenylsilicone, methylcyclopolysiloxane, octamethylpolysiloxane, dimethylsiloxane-methylcetyloxysiloxane copolymer, alkyl modified silicone oil and the like; 4) fluorine-based fats and oils such as perfluoropolyether; And / or 5) at least one of animal or plant fats and oils, such as avocado oil, olive oil, rapeseed oil, castor oil, sunflower oil, palm oil, jojoba oil, egg yolk oil,
  • Moisturizing agents include: 1) water-soluble low molecular moisturizers such as serine, glutamine, sorbitol, mannitol, sodium pyrrolidone-carboxylate, glycerin, propylene glycol, polyethylene glycol, polyglycerol, lactic acid; 2) fat-soluble low molecular humectants such as cholesterol and cholesterol esters; 3) water-soluble polymers such as carboxyvinyl polymer, polyasparaginate, methylcellulose, hydroxymethylcellulose, water-soluble chitin, chitosan, dextran; And / or 4) at least one of polyvinylpyrrolidone-eicosene copolymers, nitrocellulose, dextran fatty acid esters, fat soluble polymers such as polymeric silicones, and the like.
  • water-soluble low molecular moisturizers such as serine, glutamine, sorbitol, mannitol, sodium pyrrolidone-carboxylate
  • Emollients include at least one of long chain acyl glutamic acid cholesterol, cholesteryl hydroxystearate, 12-hydroxystearic acid, stearic acid, rosin acid, lanolin fatty acid cholesteryl ester, This is not restrictive.
  • the surfactant is 1) self-emulsifying glycerin monostearate, propylene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkyl ether, laurin
  • Nonionic surfactants such as acid alkanolamide and the like
  • Anionic surfactants such as; 3) cationic surfactants such as alkyltrimethylammonium chloride, steary
  • Organic and inorganic pigments include silicic acid, silicic anhydride, talc, sericite, kaolin, clay, bentonite, zirconium oxide, magnesium oxide, titanium oxide, aluminum oxide, calcium sulfate, barium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, chromium oxide Inorganic pigments such as chromium hydroxide, calamine and complexes thereof; Polyamide, Polyester, Polypropylene, Polystyrene, Polyurethane, Vinyl Resin, Urea Resin, Phenol Resin, Fluoro Resin, Silicon Resin, Acrylic Resin, Melamine Resin, Epoxy Resin, Polycarbonate Resin, Cellulose, Silk Powder, CI Pigment At least one of organic pigments such as yellow and the above-described inorganic pigments and organic pigments, but is not limited thereto.
  • the organic powder may be a metal soap such as calcium stearate; Alkyl phosphate metal salts such as zinc sodium cetyl acid, zinc lauryl acid and calcium laurate; Acylamino acid polyvalent metal salts such as N-lauroyl-beta-alanine calcium, N-lauroyl-beta-alanine zinc, and N-lauroylglycine calcium; Amide sulfonic acid polyvalent metal salts, such as N-lauroyl-taurine calcium and N-palmitoyl-taurine calcium; N-epsilon-lauroyl-L-lysine, N-epsilon-palmitolysine, N-alpha-paratoylolnitine, N-alpha-lauroyl arginine, N-alpha-cured fatty acid acyl arginine Acyl basic amino acids; N-acylpolypeptides, such as N-lauroyl glycyl
  • Fungicides are hinokithiol, trichloric acid, trichlorohydroxydiphenyl ether, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zinphylthione, benzalkonium chloride, photosensitive At least one of SO 301, mononitroguicol sodium, undecylenic acid and the like, but is not limited thereto.
  • Antioxidants include, but are not limited to, butylhydroxyanisole, propyl gallic acid, elixolic acid, and the like.
  • Antioxidants include vitamins such as vitamin C and derivatives thereof such as ascorbic acid acetate, phosphate and palmitate; Vitamin A and its derivatives; Folic acid and its derivatives; Vitamin E and its derivatives such as tocopheryl acetate; Flavones or flavonoids; Amino acids such as histidine, glycine, tyrosine, tryptophan and derivatives thereof; Imidazoles such as cis- or trans-urocanoic acid and their derivatives; Peptides such as D, L-carnosine, D-carnosine, L-carnosine and their derivatives; Carotenoids and carotenes such as ⁇ -carotene, ⁇ -carotene; Lycopene; Uric acid and its derivatives; ⁇ -hydroxy acids such as citric acid, lactic acid, malic acid; ⁇ -hydroxyfatty acids such as palmitic acid, phytic acid, lactoferrin; Stilbenes and their derivatives; Mannose and its derivatives; Liphonic acid
  • pH adjusting agents include, but are not limited to, at least one of citric acid, sodium citrate, malic acid, sodium malate, fmaric acid, sodium pmarate, succinic acid, sodium succinate, sodium hydroxide, sodium dihydrogen phosphate, and the like.
  • the alcohol includes higher alcohols such as cetyl alcohol.
  • Blowing agents are for example disodium N-carboxyethoxyethyl-N- (cocoylamidoethyl) aminoacetate, sodium lauryl ether sulfate, sodium lauroyl sarcosinate, triethanolamine lauryl sulfate And at least one of a mixture of sodium cocoyl isethionate and coconut fatty acid, and the like.
  • Fillers include, but are not limited to, at least one, such as acrylic copolymers such as ethylene glycol dimethacrylate / lauryl methacrylate copolymer, commercially available from Dow Corning under the name of Polytrap. Do not.
  • UV absorber paraaminobenzoic acid, ethyl paraaminobenzoate, amyl paraaminobenzoic acid, octyl paraaminobenzoate, ethylene glycol salicylate, phenyl salicylate, octyl salicylate, benzyl salicylate, paramethoxy cinnamic acid-2-ethoxyethyl, Paramethoxy octylate, diisopropyl diisopropyl cinnamic acid ester mixture, urokanoic acid, ethyl urokanoate, hydroxymethoxy benzophenone, hydroxymethoxy benzophenone sulfonic acid and its salt, dihydroxy methoxy benzophenone , At least one of dihydroxy benzophenone, tetrahydroxy benzophenone and the like.
  • Pigments and powders with pigment-like effects are iron oxides, aluminum silicates such as ocher, titanium oxide, mica, kaolin, manganese containing clay, calcium carbonate, french chalk, mica-titanium oxide, mica-titanium oxide-ironic acid At least one of a cargo, bismuthoxychloride, nylon beads, ceramic beads, powdered natural organic compounds, such as ground algae, ground plant parts, and the like.
  • colorant treated or untreated dyes can be used.
  • gelling agent or thickening agent natural rubber (xanthan rubber), polysaccharide (hydroxypropylmethylcellulose or carboxymethylcellulose), carboxyvinyl polymer (carbomer), acrylic copolymer can be used.
  • the compounding component which may be added other than this is not limited to this, Moreover, although all said components can be mix
  • Cosmetics of the present invention may take the form of solutions, emulsions, viscous mixtures and the like.
  • Ingredients included in the cosmetic composition of the present invention may include ingredients commonly used in cosmetic compositions in addition to the compound as an active ingredient, for example, conventional auxiliaries such as stabilizers, solubilizers, vitamins, pigments and flavorings. And carriers.
  • Cosmetic composition of the present invention can be applied to a variety of cosmetics, face wash and shampoo having an anti-aging effect.
  • the cosmetic composition of the present invention may be formulated in any formulation commonly prepared in the cosmetic industry, and includes, for example, latex, cream, lotion, pack, foundation, lotion, essence, hair cosmetic, and the like.
  • cosmetics such as various creams, lotions, skins, and the like, shampoos, rinses, cleansing agents, face washes, soaps, treatments, essences, and the like.
  • cosmetic composition of the present invention skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizing cream, hand cream, foundation, essence, nutrition essence, It may be formulated in various formulations such as packs, soaps, cleansing foams, cleansing lotions, cleansing creams, body lotions and body cleansers.
  • the formulation of the present invention is a paste, cream or gel
  • animal carriers vegetable fibers, waxes, paraffins, starches, tracantes, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide, etc.
  • carrier components can be used as carrier components.
  • lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular, in the case of a spray, additionally chlorofluorohydrocarbon, propane / butane Or propellants such as dimethyl ether.
  • a solvent, solvating agent or emulsifying agent is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethyleneglycol or sorbitan.
  • the formulation of the present invention is a suspension
  • water liquid diluents such as ethanol or propylene glycol
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline Cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.
  • the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide.
  • Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
  • a SHIMADZU C18 assay column was used as a column, A buffer was 0.05% TFA / H 2 O and B buffer 0.05% TFA / acetonitrile as the developing solvent. The concentration gradient of acetonitrile was from 0 to 60% over 30 minutes, the flow rate was 1 ml / min, the injection volume was 100 ⁇ l (0.5 mg / ml), and the wavelength of 230 nm.
  • Example 2 The procedure of Example 1 was repeated except that pentanic acid having 5 carbon atoms was bound to the N-terminus of the glycylproline dipeptide.
  • Purified pentanic acid glycylproline (Pentyl-GP, C5) was analyzed by mass spectrometry through HPLC analysis to determine the molecular weight of the purified compound.
  • Purified pentanic acid glycylproline was lyophilized at -40 ° C for 2 days using a lyophilizer, then packaged in a packaging container and stored at low temperature of -15 ° C to be used for subsequent experiments.
  • Example 2 The procedure of Example 1 was repeated except that the octanoic acid having 8 carbon atoms was bound to the N-terminus of the glycylproline dipeptide.
  • the molecular weight (299.1 Da) of the purified compound was analyzed by mass spectrometry of the purified (purity 95.8%) octanoic acid glycylproline (Octyl-GP, C8) corresponding to the peak measured at retention time 26.250 minute through HPLC analysis. Checking the structural formula (C 15 H 26 N 2 O 4 ) to confirm that the intended dipeptide derivative was synthesized.
  • Purified octanoic acid glycylproline was lyophilized at -40 ° C for 2 days using a lyophilizer, then packaged in a packaging container and stored at a low temperature of -15 ° C to be used for subsequent experiments.
  • the results of NMR analysis for the synthesized octanoic acid glycylproline are shown below.
  • Example 2 The procedure of Example 1 was repeated except that decanoic acid having 10 carbon atoms was bound to the N-terminus of the glycylproline dipeptide.
  • the molecular weight (327.3 Da) of the purified compound was analyzed by mass spectrometry of the purified (dep. 94.5%) decanoic acid glycylproline (Decanoyl-GP, C10) corresponding to the peak measured at retention time 15.125 minute through HPLC analysis.
  • the structural formula (C 17 H 30 N 2 O 4 ) was confirmed.
  • Purified decanoic acid glycylproline was lyophilized at -40 ° C for 2 days using a lyophilizer, then packaged in a packaging container and stored at a low temperature of -15 ° C to be used for subsequent experiments.
  • Example 1 except that glycylproline dipeptide unsubstituted with carboxylic acid and the N-terminus of the dipeptide were combined with 3 carbonic propanoic acid, 12 lauric acid and 16 palmitic acid, respectively.
  • glycylproline dipeptide unsubstituted with carboxylic acid and the N-terminus of the dipeptide were combined with 3 carbonic propanoic acid, 12 lauric acid and 16 palmitic acid, respectively.
  • glycylproline GP, C0; Comparative Example 1
  • propanoic acid glycylproline Propyl-GP, C3; Comparative Example 2
  • lauric acid glycylproline Longryl-GP, C12, Comparative Example 3
  • palmitic acid glycylproline Palmityl-GP, C16; Comparative Example 4
  • Butyl-GP, Pentyl-GP, Octyl-GP and Decanoyl-GP synthesized in Example 1-4 was confirmed the cell proliferation induction effect.
  • GP Pentyl-GP, Lauryl-GP, and Palmityl-GP, to which no fatty acid was bound, were used.
  • Human dermal fibroblast (neonatal) was used, and ELISA showed that formazan chromophore was produced using water-soluble tetrazolium salt (Wst) -1 assay to determine cell proliferation capacity.
  • Wst water-soluble tetrazolium salt
  • the number of cells can be determined by comparing the color intensity since succinatetrzolum Reductase, a dehydrogenase present in the mitochondrial electron transport system of metabolically active cells, is effective only in living cells.
  • Human dermal fibroblasts were placed in each well of a 48-well plate at 2 ⁇ 10 3 cells / well and incubated for 24 hours in an incubator at 37 ° C., 5% CO 2 . After incubation, the medium of each well was removed and replaced with fresh serum-free medium.
  • the dipeptide derivative synthesized in the above and the dipeptide (derivative) of the control group by concentration (10, 50, 100, 200 ⁇ M), and further incubated for 72 hours. After incubation was completed, 30 ⁇ l of Wst-1 solution (Ez-Cytox) was added to each well. After 2 more hours of incubation, the absorbance (OD) was measured at 540 nm using a spectrometer. Based on the measured absorbance (OD sample ) of each sample and the absorbance (OD control ) of the negative control sample treated with deionized water (DW), the cell proliferation rate was converted by the following formula (I).
  • FIG. 1 A graph measuring the growth promotion rate of fibroblasts according to the treatment of the dipeptide derivatives according to the present embodiment is shown in FIG. 1, and the results are shown in Table 1.
  • GP which was not modified with aliphatic carboxylic acid had no effect of promoting growth
  • Propyl-GP (C3) had little effect of inducing cell growth. Therefore, it is thought that the cell permeability of the dipeptide modified with aliphatic carboxylic acid having an appropriate number of carbon atoms is improved.
  • Lauryl-GP (C12) and Palmityl-GP (C16) were rather inhibited in cell growth rate, and it is presumed that these aliphatic carboxylic acids rather induced cytotoxicity.
  • Butyl-GP, Pentyl-GP, Octyl-GP and Decanoyl-GP synthesized in Example 1-4 was confirmed the collagen biosynthesis induction effect.
  • GP Pentyl-GP, Lauryl-GP, and Palmityl-GP, to which no fatty acid was bound, were used.
  • Human dermal fibroblasts Human dermal fibroblast, neonatal
  • Procollagen Type I ELISA assay kit Takara, MK101
  • Fibroblasts were placed in each well of a 48-well plate at 5 ⁇ 10 3 cells / well and incubated for 24 hours in an incubator at 37 ° C., 5% CO 2 . After incubation, the medium of each well was removed and replaced with fresh serum-free medium. After another 24 hours of incubation, each well was treated with a dipeptide derivative synthesized above and a dipeptide (derivative) of the control group by concentration (10, 50, 100, 200 ⁇ M), and after the culture was completed, the manufacturer's instructions Therefore, ELISA for Procollagen Type I was performed.
  • a graph measuring the collagen biosynthesis increasing effect according to the present example is shown in FIG. 2, and the results are shown in Table 2 below. As shown in FIG.
  • a dipeptide derivative modified with Butyl-GP (C4), Pentyl-GP (C5), Octyl-GP (C8) and Decanoyl-GP (C10) synthesized according to the present invention Administration significantly increased the biosynthesis of collagen. In particular, collagen biosynthesis was significantly induced in Pentyl-GP and Octyl-GP.
  • administration of GP that was not modified with aliphatic carboxylic acid had no effect on inducing collagen biosynthesis, and propyl-GP (C3) also showed minimal induction of collagen biosynthesis. Lauryl-GP (C12) and Palmityl-GP (C16) inhibited collagen biosynthesis due to cytotoxicity.
  • aliphatic carboxylic acids with less than 4 carbon atoms have limitations in induction of cell proliferation and collagen biosynthesis, and aliphatic carboxylic acids with more than 10 carbon atoms damage cell membranes due to excessive hydrophobicity, causing cytotoxicity resulting in cell proliferation and collagen It can be seen that it is not suitable as an aliphatic carboxylic acid for administering dipeptide to cells because it inhibits biosynthesis.
  • a prolydase activity assay was performed. Butyl-GP, Pentyl-GP, Octyl-GP and Decanoyl-GP synthesized in Example 1-4 was confirmed the collagen biosynthesis induction effect. Fatty acid-bound GP, Pentyl-GP, Lauryl-GP, Palmityl-GP, and IGF were used as a positive control. Each was treated by concentration and incubated for 72 hours. Prolidase activity in the cell lysate was measured and 94 mmole glycylproline was used as the substrate of the enzyme.
  • Figure 3 shows the results of measuring the prolidase activity by glycylproline modified with aliphatic carboxylic acid according to the present embodiment, the results are shown in Table 3 below.
  • Butyl-GP (C4), Pentyl-GP (C5), Octyl-GP (C8) and Decanoyl-GP (C10) synthesized according to the present invention all increased prolidase activity significantly, especially prolidase activity in C5 and C8. It was close to the case of treatment with IGF, which is known to have the best promoting effect and increase the activity of prolidase.
  • GP C0
  • Propyl-GP C3
  • Lauryl-GP decreased the degree of prolidase activity induction compared to GP
  • Palmityl-GP significantly inhibited prolidase activity due to excessive cytotoxicity.
  • the glycylproline derivative modified with aliphatic carboxylic acid having carbon of C 4 -C 10 is excellent in cell permeability, increasing intracellular proldiase activity and increasing the recycling efficiency of proline, resulting in collagen biosynthesis rate in dermal fibroblasts. It is thought to induce cell proliferation by increasing.
  • the amount of detection was insignificant 24 hours after skin patching, but in the case of GP fatty acid derivatives, skin permeability was improved by 30 times or more.
  • the dipeptide derivative into which the C 4 -C 10 aliphatic carboxylic acid was introduced showed a great skin permeability.
  • Dipeptides modified with C12, C16 were not only toxic but also had poor cell permeability. This damages the skin a lot and was not expected to be detected in the lower layer.
  • the glycyl (hydroxy) proline (Octyl-GP, C8) modified with octanoic acid prepared in Example 3 was administered to the human body to evaluate the skin wrinkle improvement effect over time.
  • the subjects were 20 females with normal skin ages 44-61 years old who were commissioned by Spincontrol Asia (head office France, branch Thailand, Bangkok). Evaluate the improvement of skin wrinkles at the beginning, 4 weeks and 8 weeks through Replica Analysis by administering 0.005% (50 ppm) of glycan octanoate (hydroxy) proline twice daily. It was. 5 is a graph showing the results of clinical trials according to the present example, and the results are shown in Table 5 below.
  • the glycyl (hydroxy) proline derivatives modified with fatty acids according to the invention had a great effect in reducing wrinkles.

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Abstract

L'invention concerne un dérivé peptidique auquel un acide carboxylique aliphatique est lié et modifié, ainsi qu'un cosmétique fonctionnel contenant le dérivé peptidique comme principe actif. Le dérivé peptidique synthétisé selon l'invention présente une bonne perméabilité vis-à-vis des cellules cutanées, une excellente capacité à régénérer les cellules productrices de collagène, et ne pose aucun problème de cytotoxicité. Le dérivé peptidique de l'invention peut être utilisé comme principe actif dans des compositions cosmétiques visant à atténuer les rides et/ou à lutter contre le vieillissement.
PCT/KR2015/000139 2014-01-27 2015-01-07 Dérivé peptidique et composition cosmétique fonctionnelle contenant ce dernier WO2015111857A1 (fr)

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