WO2022031044A1 - Dérivé de l'acide ascorbique et composition le comprenant - Google Patents

Dérivé de l'acide ascorbique et composition le comprenant Download PDF

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WO2022031044A1
WO2022031044A1 PCT/KR2021/010279 KR2021010279W WO2022031044A1 WO 2022031044 A1 WO2022031044 A1 WO 2022031044A1 KR 2021010279 W KR2021010279 W KR 2021010279W WO 2022031044 A1 WO2022031044 A1 WO 2022031044A1
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group
formula
ascorbic acid
alkyl
peptide
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PCT/KR2021/010279
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Korean (ko)
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이동희
정진
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주식회사 레미바이오
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • 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
    • 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
    • A61K8/67—Vitamins
    • 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
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • 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

Definitions

  • the present invention relates to an ascorbic acid derivative, and more particularly, to an ascorbic acid derivative having improved bioavailability and a composition comprising the same.
  • vitamin C that is, ascorbic acid
  • Ascorbic acid has an endol group connected to one double bond carbon with two hydroxyl groups.
  • Ascorbic acid was discovered as a substance having a specific effect on scurvy, and now, 2-keto- is a hydrolyzed diisopropylidene derivative produced by condensing sorbose, a monosaccharide, with acetone in the presence of sulfuric acid and oxidizing it with potassium permanganate. It is industrially synthesized through L-gulonic acid. Most mammals can synthesize ascorbic acid from glucose, but since humans do not have ascorbic acid synthase in the body of ascorbic acid, ascorbic acid is one of the essential vitamins that must be ingested through food.
  • Ascorbic acid and its derivatives are representative antioxidants with very strong reducing properties and improve the immune function of the human body.
  • ascorbic acid and its derivatives promote the production of collagen, which is a component of human cartilage, capillaries, muscles, etc. Not only does it prevent damage, it prevents wrinkles on the skin, keeps the skin healthy, is involved in the healing of damaged skin tissue, prevents the formation of histamine, which is known to cause allergic reactions, and prevents the skin from aging during the aging process. It is known to play an anti-aging role by preventing the formation of melamine, which fades the skin. Accordingly, ascorbic acid and its derivatives are expected to be utilized not only as active ingredients in cosmetics, but also in pharmaceutical compositions or health functional foods.
  • ascorbic acid and its derivatives have a structure similar to gamma-lactone and are very unstable, they are sensitive substances that are easily decomposed and oxidized by external environments such as heat, light, water, and oxygen.
  • the oxidation reaction of ascorbic acid and its derivatives occurs by two successive electron transfer processes. First, as one electron is lost from ascorbic acid, an intermediate, semi-hydroascorbate radical, is formed. Subsequently, as the second electron is lost from two molecules of semi-dihydroascorbate radicals, it is known that one molecule of ascorbic acid and dehydroascorbic acid are generated.
  • ascorbic acid since ascorbic acid is easily decomposed and has hydrophilicity, the permeability to cells is very low. Therefore, in order for ascorbic acid to maintain its biological activity, a large amount of ascorbic acid must be used.
  • An object of the present invention is to provide an ascorbic acid derivative having excellent stability and tissue and cell permeability.
  • Another object of the present invention is to provide an antibacterial composition and a cosmetic composition comprising the ascorbic acid derivative.
  • a compound having a structure of Formula 1 is disclosed.
  • R 1 and R 2 are each independently hydrogen or a structure of Formula 2 below, and at least one of R 1 and R 2 has a structure of Formula 2 below.
  • R 3 is a C 1 ⁇ C 20 alkyl group, C 2 ⁇ C 20 alkenyl group, C 2 ⁇ C 20 alkynyl group, C 1 ⁇ C 20 alkyl disulfide group, C 4 ⁇ C 30 alicyclic group ), as a first group selected from the group consisting of C 6 ⁇ C 30 aryl group and C 1 ⁇ C 30 heteroaryl group, the C 4 ⁇ C 30 alicyclic, the C 6 ⁇ C 30 aryl group and the C 1 ⁇ C 30 heteroaryl group is each independently unsubstituted or substituted with at least one functional group selected from the group consisting of a C 1 ⁇ C 20 alkyl group, a C 6 -C 20 aryl group and a C 3 -C 30 heteroaryl group,
  • the C 4 ⁇ C 30 alicyclic, the C 6 ⁇ C 30 aryl group and the C 1 ⁇ C 30 hetero aryl group are each independently a first group connected directly or through a C
  • R 1 of Formula 1 may be hydrogen, and R 2 may have a structure of Formula 2.
  • L in Formula 2 may be a C 1 ⁇ C 10 alkylene group.
  • At least one of R 1 and R 2 of Formula 1 may have a structure of Formula 3 below.
  • q and s are different, r and t are different, and the ratio of the unit units represented by q and s in the entire molecule may be 30 to 70%.
  • At least one of R 1 and R 2 of Formula 1 may have a structure of Formula 4 below.
  • R 4 is the same as defined in Formula 2; any one of R 5 and R 6 is the first group defined in Formula 2, and the other of R 5 and R 6 is the second group defined in Formula 2; Z is an integer from 3 to 10.
  • the first group is connected directly or directly or through a C 1 -C 20 alkylene group, and includes an unsubstituted or substituted C 1 -C 30 azole group with a C 1 -C 10 alkyl group
  • the second group The group may include a C 1 -C 20 alkyl amino group and a C 1 -C 20 alkyl guanidyl group.
  • a functional cosmetic composition comprising, as an active ingredient, a compound having a structure of Formula 1 to Formula 4 or a cosmetically acceptable salt thereof, for example, at least one of whitening, wrinkle improvement and skin aging prevention.
  • a cosmetic composition having a function.
  • an antibacterial composition comprising a compound having the structure of the aforementioned Chemical Formulas 1 to 4, and a pharmaceutically acceptable salt thereof, as an active ingredient is disclosed.
  • an anti-inflammatory composition comprising a compound having the structure of the aforementioned Chemical Formulas 1 to 4, and a pharmaceutically salt thereof as an active ingredient is disclosed.
  • At least one neutral amino acid and a derivative thereof and at least one positively charged amino acid and at least one peptide having a positively charged amino acid and a derivative thereof are conjugated to ascorbic acid, and the stability and tissue and cell permeability are improved compared to ascorbic acid.
  • the ascorbic acid derivative not only promotes collagen production and prevents the formation of melamine, but also promotes an immune response and has excellent antibacterial activity.
  • ascorbic acid has almost no skin permeability, so the clinical bioefficiency is low. Since the ascorbic acid derivative according to the present invention has good skin permeability and cell permeability, it exhibits physiological effects even at low concentrations, thereby improving bioefficiency.
  • the ascorbic acid derivative can be applied as an active ingredient such as a cosmetic for skin wrinkle improvement, whitening and/or skin aging prevention and/or a drug for antibacterial or immune promotion, or a health functional food.
  • FIG. 1 is a graph showing the results of high-performance liquid chromatography (HPLC) analysis of ascorbic acid derivatives synthesized according to an exemplary embodiment of the present invention.
  • FIG. 2 is a graph showing the results of MS (mass spectrometry) analysis of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
  • FIG. 3 is a graph showing the results of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention to promote collagen synthesis.
  • FIG. 4 is a graph showing the results of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention inhibiting melamine production.
  • FIG. 5 is a graph showing the anti-inflammatory effect of an ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
  • FIG. 6 is a graph showing the antibacterial effect of an ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
  • FIG. 7 is a graph showing the results of measuring the temperature stability of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
  • FIG. 8 is a graph showing the results of measuring the in vitro skin tissue permeability of an ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention using pig skin.
  • the ascorbic acid derivative of the present invention eliminates the disadvantages of pure ascorbic acid having low tissue and cell permeability as well as being unstable because it is easily oxidized by conjugation of a peptide consisting of 6 or more amino acids to ascorbic acid.
  • the peptide bound to ascorbic acid may consist of an amino acid having a neutral or hydrophobic side branch and an amino acid having a positively charged side branch in an in vivo environment.
  • the ascorbic acid derivative according to the present invention has the structure of Formula 1 below.
  • R 1 and R 2 are each independently hydrogen or a structure of Formula 2 below, and at least one of R 1 and R 2 has a structure of Formula 2 below.
  • R 3 is a C 1 ⁇ C 20 alkyl group, C 2 ⁇ C 20 alkenyl group, C 2 ⁇ C 20 alkynyl group, C 1 ⁇ C 20 alkyl disulfide group, C 4 ⁇ C 30 alicyclic group ), as a first group selected from the group consisting of C 6 ⁇ C 30 aryl group and C 1 ⁇ C 30 heteroaryl group, the C 4 ⁇ C 30 alicyclic, the C 6 ⁇ C 30 aryl group and the C 0 ⁇ C 30 heteroaryl group is each independently unsubstituted or substituted with at least one functional group selected from the group consisting of a C 1 ⁇ C 20 alkyl group, a C 6 -C 20 aryl group and a C 3 -C 30 heteroaryl group,
  • the C 4 ⁇ C 30 alicyclic, the C 6 ⁇ C 30 aryl group and the C 1 ⁇ C 30 hetero aryl group are each independently a first group connected directly or through a
  • 'unsubstituted' refers to a hydrogen atom bonded thereto, and in this case, the hydrogen atom includes light hydrogen, deuterium and tritium.
  • 'substituent' is unsubstituted or substituted with halogen C 1 ⁇ C 20 alkyl (eg, -CF 3 ), unsubstituted or substituted with halogen C 1 ⁇ C 20 Alkoxy group, halogen, cyano group, hydroxy group, carboxy group, carbonyl group, amino group, C 1 ⁇ C 10 alkyl amino group, C 6 ⁇ C 30 aryl amino group, C 3 ⁇ C 30 hetero aryl amino group, nitro group, hydra hydrazyl group, sulfonic acid group, C 1 ⁇ C 20 alkyl silyl group, C 1 ⁇ C 20 alkoxy silyl group, C 3 ⁇ C 30 cycloalkyl sily
  • the peptide moiety is an amino acid or a derivative thereof having a first group of hydrophobic or neutral substituents (hereinafter, hydrophobic amino acid or derivative thereof) and an amino acid having a side branch of a second group that is a positively charged substituent or derivatives thereof (hereinafter, positively charged amino acids or derivatives thereof) are included.
  • Each of the C 1 -C 20 alkyl groups that may be substituted for each group may be a C 1 -C 10 alkyl group.
  • the C 2 -C 20 alkenyl group that is part of the aliphatic substituent is a C 2 -C 10 alkenyl group
  • the C 2 -C 20 alkynyl group is a C 2 -C 20 alkynyl group
  • the alkyl disulfide group may be a C 1 to C 10 alkyl disulfide group.
  • the C 1 ⁇ C 20 alkyl amino group constituting the second group and the C 1 ⁇ C 20 alkyl amino group that may be substituted with the C 0 ⁇ C 30 heteroaryl group having at least one nitrogen atom are each C 1 ⁇ C 10 alkyl It may be an amino group.
  • the C 1 -C 20 alkyl guanidyl group constituting the second group may be a C 1 -C 20 alkyl guanidinyl group
  • the C 1 -C 20 alkyl polyamine may be a C 1 -C 20 alkyl polyamine.
  • C 1 ⁇ C 20 alkylene group connecting the side branch that is a C 1 ⁇ C 30 heteroaryl group having at least one nitrogen atom and the peptide backbone, and the C 1 ⁇ C 20 alkylene group constituting L are each independently It may be a C 1 ⁇ C 20 alkylene group.
  • an aliphatic chain constituting a side branch or a linker that is, an alkyl group, an alkenyl group, an alkynyl group, an alkyl disulfide group, an alkyl amino group, an alkyl guanidyl group, an alkylene group constituting R 3 or L in Formula 2, respectively
  • each may have a linear structure or a branched structure.
  • the C 4 -C 30 alicyclic ring constituting R 3 is a C 4 -C 30 cycloalkyl group, for example, a C 4 -C 20 cycloalkyl group or a C 4 -C 30 cycloalkenyl group, Examples include, but are not limited to, a C 4 to C 30 cycloalkenyl group.
  • C 6 ⁇ C 30 aryl group and C 3 ⁇ C 30 hetero aryl group constituting R 3 as the first group in Formula 2 are each a C 6 ⁇ C 20 aryl group (eg, C 6 ⁇ C 15 aryl group) and C 3 -C 20 heteroaryl group (eg, C 6 -C 15 heteroaryl group), but is not limited thereto.
  • a C 0 ⁇ C 30 heteroaryl group having at least one nitrogen atom as the second group is a C 0 ⁇ C 20 heteroaryl group (eg, a C 1 ⁇ C 20 heteroaryl group or a C 0 ⁇ C 15 heteroaryl group), but is not limited thereto.
  • the C 6 -C 30 aryl group constituting R 3 as the first group is each independently unsubstituted, or a C 1 -C 10 alkyl group, a C 6 -C 20 aryl group, and a C 3 -C 30 hetero Phenyl, biphenyl, terphenyl, naphthyl, anthracenyl, pentalenyl, indenyl, indenoindenyl, heptalenyl, biphenylenyl, indacenyl, phenyl substituted with at least one functional group selected from the group consisting of an aryl group Renyl, phenanthrenyl, benzophenanthrenyl, dibenzophenanthrenyl, azulenyl, pyrenyl, fluoranthenyl, triphenylenyl, chrysenyl, tetraphenyl, tetracenyl, pleidaenyl
  • the C 3 -C 30 aryl groups constituting R 3 as the first group in Formula 2 are each independently unsubstituted or C 1 -C 10 alkyl group, C 6 -C 20 aryl group, and C 3 -C 30 heteroaryl pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, imidazolyl, pyrazolyl, indolyl, isoindolyl, substituted with at least one functional group selected from the group consisting of , indazolyl, indolizinyl, pyrrolizinyl, carbazolyl, benzocarbazolyl, dibenzocarbazolyl, indolocarbazolyl, indenocarbazolyl, benzofurocarbazolyl, benzothienocarbazolyl, quinolinyl, Isoquinolinyl,
  • the side branch R 3 is a ring-type consisting of a C 4 -C 30 alicyclic group, a C 6 -C 30 aryl group, and a C 3 -C 30 heteroaryl group
  • it is represented by Formula 2
  • At least one of the ring-type side branches constituting the amino acid or derivative thereof included in the represented peptide or derivative thereof is at least one C 1 -C 10 alkyl group, C 6 -C 20 aryl group and C 3 -C 30 heteroaryl group It may be substituted with a functional group selected from the group consisting of.
  • the C 1 ⁇ C 30 heteroaryl group having at least one nitrogen atom constituting R 3 as the first group in Formula 2 may be an azole group.
  • the azole group is an imidazole group, a pyrazole group, a 1,2,3-triazole group, a 1,2,4-triazole group, a tetrazole group, an azole group consisting of only nitrogen atoms as a hetero atom such as a pentazole group, as well as an oxa group Zol group, isoxazole group, 1,2,3-oxadiazole group, 1,2,4-oxadiazole group, 1,2,5-oxadiazole group, 1,3,4-oxadiazole group, thiazole group, iso Others such as oxygen or sulfur, such as thiazole group, 1,2,3-thiidazole group, 1,2,4-thiadiazole group, 1,2,5-thiadiazole group, 1,3,4-thiadiazole group It may include
  • the first group is connected directly or through a C 1 -C 20 alkylene group, unsubstituted or substituted with a C 1 -C 10 alkyl group C 1 -C 30 azole group, for example, a hetero atom is It includes an azole group consisting only of nitrogen, and the second group may include a C 1 -C 20 alkylamino group and a C 1 -C 20 alkyl guanidyl group, but is not limited thereto.
  • arylene group and the hetero arylene group constituting L in Formula 2 may be an aromatic or heteroaromatic linking group corresponding to the aforementioned aryl group and heteroaryl group, respectively.
  • p which is the total number of unit units in Formula 2, may be 6 to 12, for example, 6 to 10 or 6 to 8.
  • nucleic acid' is meant to include DNA (eg, cDNA) and RNA, and includes nucleotides in addition to natural nucleotides (adenine, thymine, guanine, cytosine, uracil). It is meant to include an analog in which the constituting sugar or base region is modified.
  • 'peptide' refers to proteins, fragments of proteins, peptides isolated from naturally occurring or synthesized by recombinant techniques or chemically, as well as 'peptide analogs (analogs)'. )', ie, an analog in which one or more of the side branches of L-amino acids and/or the backbone of alpha-amino acids are substituted.
  • amino acid side chains and/or backbones are modified peptide analogs (peptidomimetics), hydroxyproline in which a pyrrolidine ring is substituted with a hydroxyl group, or N- A 'peptoid' in which a substituent such as an alkyl group is attached to an amino group, such as methyl glycine, may be included, but is not limited thereto.
  • the terms 'neutral' or 'positive charge' in relation to the side branches included in amino acids or analogs thereof are based on physiological conditions in vivo.
  • peptides and nucleotides referred to herein are isolated.
  • An 'isolated' nucleotide or peptide has been removed from its original environment.
  • a peptide in its natural state is isolated by removing all or some of the substances present together in that state.
  • amino acids constituting a peptide may have the same function even if they are mutated into other amino acids.
  • amino acids constituting the peptide may have the same function even if they are mutated into other amino acids.
  • the biological function of the corresponding peptide is not at all affected or the function of the original peptide is enhanced. Accordingly, one or more amino acids may be substituted and/or added to the amino acid sequence constituting the peptide.
  • Such so-called 'conservative substitution' can be determined according to relative similarity, such as hydrophobicity/hydrophilicity, size, and charge, of substituents forming a side chain of amino acids, in particular. For example, conservative substitution may be considered in consideration of a hydrophobic index or a hydrophilic value according to each amino acid side branch.
  • hydrophobic amino acids alanine (A), valine (V), isoleucine (I), leucine (L), methionine (M), phenylalanine (F), tyrosine (W), tryptophan (W), proline (P) variation between;
  • alanine (A), glycine (G) and serine (S) have similar sizes, it is possible to form a mutant without significant change in protein activity.
  • a 'substitutional variant' refers to a molecule in which one or more amino acids are replaced or deleted in an amino acid sequence, but retains characteristics specifically recognized by cells.
  • the amino acid sequence of the replaceable variant preferably has at least 80% identity with the original amino acid sequence, more preferably at least 90% or more.
  • the peptide or its analog can be isolated after preparation by recombinant means or chemical synthesis.
  • the nucleotide encoding the amino acid constituting the peptide having the structure of Formula 2 is cloned into an appropriate recombinant expression vector by using PCR technique to prepare a recombinant vector, and then an appropriate host After mass expression in the form of a peptide in cells, it can be produced by pure purification.
  • Suitable host cells include prokaryotes, yeast, and eukaryotes, for example, E. coli, yeast or mammalian cell lines (such as Cos or CHO) may be used as host cells, but are limited thereto.
  • the supernatant containing the recombinant protein secreted into the culture medium obtained from the aqueous host/vector system is concentrated using a commercially available filter.
  • the obtained concentrate is purified using an appropriate purification matrix such as an affinity matrix or an ion exchange resin.
  • pure recombinant peptide can be obtained by performing reverse phase HPLC in one or several steps.
  • peptide fragments or peptide variants consisting of less than 100 amino acids, generally less than 50 amino acids, can be prepared by chemical synthesis.
  • peptides may be synthesized using commercially available solid-phase techniques, that is, a Merrifield solid-phase synthesis method in which amino acids are sequentially added to a growing amino acid chain.
  • the chemical synthesis method of the peptide may include a method of synthesizing a solid-phase peptide using an organic synthesizer for peptide synthesis.
  • an amino acid constituting the carboxy terminus (C-terminus) of a peptide or an analog thereof is coupled to an appropriate resin for solid-phase synthesis, thereby swelling the C-terminal amino acid binding resin.
  • the resin for solid phase synthesis may be an insoluble, porous solid support treated with an appropriate linker (linker).
  • the resin binding to the C-terminus of the peptide is a polystyrene resin, polyamide resin, PEG-hybrid polystyrene resin, hydroxymethyl resin, aminomethyl resin, chloromethylated resin or Chlorotritity resin (eg, 2-chlorotrityl chloride resin (2-chlorotritylchloride, CTC resin)) may be used, but is not limited thereto.
  • C-terminal amino acids or analogs thereof are loaded into these resins to , C-terminal amino acids or analogs thereof are ester-linked to these resins.
  • amino acids or analogs thereof are sequentially coupled in the amino-terminal (N-terminal) direction of the peptide through a solid-phase synthesis reaction.
  • a protecting group for protecting the alpha-amino group contained in amino acids or analogs thereof t-BOC (t-butyloxycarbonyl), Fmoc (9-fluorenyl methoxyarbonyl), benzyloxy-carbonyl (Z) ( benzyloxy-carbonyl (Z)) and the like can be used, and in particular, Fmoc, which can be removed even in weak alkaline conditions and does not require special equipment, can be used.
  • a coupling reagent for activating the carbonyl group located at the C-terminus may be used as an activator, and an appropriate deprotecting agent may be used for the protecting group at the N-terminus after coupling.
  • the activator that can be used to activate the C-terminus of the peptide in the coupling of the peptide is (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'-diiso With bases such as propylcarbodiimide (DIC) and dicyclohexylcarbodiimide (DCC), which react with carboxylic acids
  • 1-hydroxy-benzotriazole such as 6-chloro-1-hydroxy-1H-benzotriazole or 1-hydroxy Triazoles, such as -7-aza-benzotriazole (HOAt), can be used.
  • These triazoles react with O-acylisourea formed by the reaction of a carboxyl group and carbodiimides to form an ester with weak reactivity, thereby preventing racemization.
  • the fatty acid derivative is separated from the solid resin by a cleavage solution containing trifluoroacetic acid (TFA), and a deprotection reaction is performed to remove a protecting group (eg, fmoc protecting group) using piperidine. to terminate the peptide synthesis.
  • a process of separating the peptide from which the protecting group has been removed from the resin using an appropriate acid is first performed, and then a binding reaction with a carboxylic acid may be performed.
  • ascorbic acid or a derivative thereof in which a hydroxyl group at a specific position is substituted with an imidazole ester group may react with an amino group located at the end of the peptide to form an amide bond.
  • a strong acid such as hydrochloric acid
  • TFA trifluoroacetic acid
  • CH 2 Cl 2 trifluoroacetic acid
  • the N-terminus of the synthesized peptide and ascorbic acid modified with a carboxyl group at a specific position are combined (conjugation).
  • carboxyl group present at the terminal of ascorbic acid and the amino group at the N-terminus of ditide react, an amide-bonded ascorbic acid derivative can be synthesized by dehydration and condensation. This reaction may be performed, for example, in a state in which a peptide and a resin are coupled, thereby generating polymer beads.
  • the N-terminal amino group is an acyl activator having a desired alkyl group, for example, acylanhydride and DMAP (4-(N, N-dimethylamino)pyridine)) together to form an amide bond at the N-terminus of the peptide, or ascorbic acid carboxylic acid which is conjugated with N,N-diisopropylcarbodiimide (DIC), 1-hydroxy Roxy-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, acylanhydride and DMAP (4-(N, N-dimethylamino)pyridine)
  • an aqueous acid solution such as trifluoroacetic acid (TPA) is used to cut and separate the peptide-bound ascorbic acid derivative from the solid support resin.
  • TPA trifluoroacetic acid
  • diethyl ether is added to crystallize the synthesized ascorbic acid derivative, and analysis and purification processes using filtration, drying, HPLC, etc. are performed, and processes such as freeze-drying and packaging are additionally performed for storage and sale. can proceed.
  • amino acids having R 3 as a first group as a neutral or hydrophobic side branch and analogs thereof are alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M) ), natural amino acids such as phenylalanine (F), tyrosine (Y) and tryptophan (W); modified amino acids in which the side branches constituting these natural amino acids are partially substituted (for example, modified amino acids having as a side branch an aryl group substituted with at least one alkyl or heteroaryl group); It includes, but is not limited to, amino acids with side branch modifications such as L-2-naphthylalanine and L-biphenylalanine.
  • the unit amino acid having R 3 as a second group having a positively charged side branch and its analogs are natural amino acids such as arginine (R), histidine (H) and lysine (K) as well as natural amino acids constituting these natural amino acids. including, but not limited to, modified amino acids in which side branches are partially or fully substituted.
  • the positively charged side branch that may be included in the second group may include C 1 to C 20 polyamines.
  • C 1 ⁇ C 20 polyamines capable of forming positively charged side branches as natural amino acid analogs include alkyl diamines such as putrescine and cadaverine; Bis(3-aminopropyl)amine (bis(3-aminopropyl)amine), spermidine, N,N'-bis(3-aminopropyl)-1,3-propanediamine (N,N'-bis Linear having one or more amino groups in the middle of an aliphatic chain, such as (3-aminopropyl)-1,3-propanediamine), spermine, thermospermine, caldopentamine and caldohexamine alkyl polyamines; branched alkyl polyamines such as, but not limited to, tris(3-aminopropyl)amine and tetrakis(3-aminopropyl)ammonium.
  • alkyl diamines such as putrescine and cadaverine
  • Bis(3-aminopropyl)amine bis(
  • an appropriate anion such as a halogen anion may be incorporated, and below is an example in which spermine is linked to the amino acid backbone as a side branch.
  • the structure in which the polyamine side branch is linked to the amino acid backbone is not limited to those exemplified below.
  • the number of peptides constituting the ascorbic acid derivative is 6 to 20, for example, 6 to 15, 6 to 12, 6 to 10, 6 to 8, It consists of amino acid or its analog residue, and the amino acid and its analog residue having a positively charged side branch, and the amino acid and its derivative residue having a neutral or hydrophobic side branch are linked through an amide bond, respectively.
  • An ascorbic acid derivative having a positively charged amino acid or an analog residue thereof has improved permeability to a cell membrane, for example, a skin cell membrane.
  • an amino acid residue stably forming the alpha-chain of the peptide such as arginine (R) or lysine (K) as a positively charged amino acid residue and/or alanine (A) as a hydrophobic amino acid residue
  • R arginine
  • K lysine
  • A alanine
  • the peptide having the structure of Formula 2 includes an amino acid or a derivative thereof having a neutral (neutral) or hydrophobic (hydrophobic) side branch.
  • the side branches constituting these hydrophobic amino acids or derivative residues thereof are oriented by hydrophobic interaction, a peptide structure having a rigid alpha-helical conformation is induced. Accordingly, a stable ascorbic acid derivative can be synthesized while the ascorbic acid moiety having the structure of Formula 1 and the peptide moiety having the structure of Formula 2 are combined.
  • a peptide having a positively charged amino acid residue and a hydrophobic amino acid residue is electrostatically bound to negatively charged molecules in bacterial cell membranes such as lipopolysaccharide and teichoic acid, and the peptide is inserted into the lipid bilayer constituting the bacterial cell membrane. Then, a hole is made in the cell membrane of the bacteria, the potential of the cell membrane is lost, and antibacterial activity is exhibited.
  • the unit amino acid having a first group in which R 3 is a hydrophobic or neutral branch or a derivative thereof is 30 to 70%, for example 40 to 60%, preferably from the total amino acids constituting the peptide. may be included in a proportion of 45 to 55%.
  • the ascorbic acid moiety and the peptide moiety are linked via an amide bond.
  • the ascorbic acid moiety and the peptide moiety constituting the ascorbic acid derivative administered to the living body may be separated into respective moieties by a peptide degrading enzyme or the like. Accordingly, while maintaining a stable structure in vitro, the ascorbic acid derivative can exhibit physiological activity unique to ascorbic acid while being decomposed into an ascorbic acid moiety in the body.
  • the ascorbic acid moiety and the unit amino acid or derivative thereof constituting the peptide or derivative thereof may each be L-form, but is not limited thereto.
  • ascorbic acid-binding peptides and analogs thereof include an amino acid having a positively charged side branch and an amino acid having a hydrophobic side branch linked via an amide bond, or an amino acid having a positively charged side branch or a hydrophobic side branch.
  • Amino acids can be linked in series via amide bonds.
  • Such a peptide or an analog thereof may have the structure of Formula 3 below.
  • q and s may be different, and r and t may be different, and the ratio of the unit units represented by q and s in the entire molecule may be 30 to 70%, for example 40 to 60%. .
  • the total number of each unit unit q + r + s + t may be 6 to 12, for example 6 to 10 or 6 to 8.
  • the peptide binding to ascorbic acid may have a structure in which an amino acid having a positively charged side branch or an analog thereof and an amino acid having a hydrophobic or neutral side branch are alternately linked in series via an amide bond.
  • Such a peptide or an analog thereof may have the structure of Formula 4 below.
  • R 4 is the same as defined in Formula 2; any one of R 5 and R 6 is the first group defined in Formula 2, and the other of R 5 and R 6 is the second group defined in Formula 2; Z is an integer from 3 to 10.
  • Z may be an integer of 3 to 6, for example, 3 to 5 or 3 to 4.
  • any one of R 5 and R 6 may have at least one chain amino group and/or a cyclic (eg aromatic) amino group, and the other one of R 5 and R 6 .
  • collagen is a major structural block of connective tissue in animals including the human body, and provides high tensile strength to connective tissue, including skin, as well as the ability to overcome deformation.
  • type I collagen which is the most type of collagen present in the body, is a substance that provides skin tension and elasticity together with elastin in the skin tissue, and protects the skin from UV rays and suppresses the formation of wrinkles in the skin.
  • Ascorbic acid promotes collagen synthesis by inducing the production of hydroxyproline, a major amino acid constituting collagen. It is known that intracellular delivery of ascorbic acid in skin tissue occurs through sodium-dependent vitamin C transporter 1 (SVCT1) and SVCT2, but the expression of skin cells is lower than that of other epithelial tissue cells. However, since the ascorbic acid derivative of the present invention has good bioefficiency, it can efficiently induce collagen synthesis even at a lower concentration than ascorbic acid (see FIGS. 3 and 8 ).
  • melanin is a phenolic high molecular compound widely present in nature, and is a black pigment present in the epidermal layer of the skin.
  • Melanin absorbs the light energy of ultraviolet (UV) light to protect the skin from UV damage, and it protects the skin from external harmful factors such as amines, free radicals, harmful oxygen and pre-radicals generated within the skin. to protect If melanin does not disappear because melanin is synthesized excessively or keratinization of the skin does not occur normally, it not only damages the skin, but also causes pigmentation of the skin to form spots and freckles, and can cause skin cancer.
  • UV ultraviolet
  • Melanocytes cells that make melanin, exist in the basal layer located at the bottom of the epidermis.
  • an enzyme called tyrosinase oxidizes tyrosine in the melanocytes, and the oxidized tyrosine makes melanin.
  • the newly created skin cells push up the old skin cells, the old cells become keratin and fall off.
  • new skin cells containing the generated melanin pass through the granular layer and the stratum corneum to the stratum corneum, the skin appears black. Since there is no enzyme to break down melanin in the human body, melanin is removed from the skin when keratinocytes are separated from the epidermis.
  • the ascorbic acid derivative of the present invention inhibits the production of melamine, and acts on skin whitening. In particular, since it inhibits the production of melamine even at a low concentration compared to the ascorbic acid derivative, the ascorbic acid derivative of the present invention has excellent cell permeability, cell efficiency and bioefficiency (see FIG. 4 ).
  • the ascorbic acid derivative according to the present invention not only inhibits the secretion of TNF- ⁇ , which is an important factor in the inflammatory response (see Fig. 5), soft tissue infection (cellulitis, pyogenic myositis), suppurative arthritis, suppurative osteomyelitis, otitis media, It also shows good antibacterial activity against Staphylococcus aureus ( S. aureus ), a representative strain that causes pneumonia, post-operative wound infection, bacteremia, endocarditis, food poisoning, atopic dermatitis, and the like (see FIG. 6).
  • the ascorbic acid derivative of the present invention is not easily decomposed even in an external environment such as heat, and thus has excellent stability (see FIG. 7 ), and the skin tissue permeability is greatly improved (see FIG. 8 ). Therefore, it can be used in various industrial fields such as pharmaceuticals, food, cosmetics, etc. by supplementing the disadvantages of ascorbic acid.
  • composition comprising an ascorbic acid derivative
  • the ascorbic acid derivative not only has excellent stability and tissue and cell permeability, but also exhibits antibacterial and anti-inflammatory activity, promotes collagen synthesis, and inhibits melamine production.
  • the present invention provides an antibacterial composition, an anti-inflammatory composition, and an anti-inflammatory composition comprising, as an active ingredient, an ascorbic acid derivative having the structure of the aforementioned Chemical Formulas 1 to 4, a pharmaceutically, food engineering and/or cosmetically acceptable salt thereof.
  • an antibacterial/anti-inflammatory drug relates to antibacterial/anti-inflammatory drugs, health functional foods and cosmetics, including.
  • these compositions may be a pharmaceutical composition, a food composition, and a cosmetic composition, respectively, and may be applied to treat and/or prevent atopic dermatitis or to alleviate atopic dermatitis.
  • the present invention relates to a functional cosmetic composition and cosmetics comprising as an active ingredient an ascorbic acid derivative or a cosmetically acceptable salt thereof having the structures of Chemical Formulas 1 to 4 described above.
  • the functional cosmetic composition may have functions such as skin aging improvement, skin wrinkle improvement, and/or skin whitening.
  • food engineering and/or cosmetically acceptable salts may include acid addition salts or basic salts formed with pharmaceutically, food engineering and/or cosmetically acceptable free acids, but not limited
  • Acid addition salts can be prepared by conventional methods, for example, by dissolving an ascorbic acid derivative in an excess of an aqueous acid solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. have. Equal molar amounts of compound and acid or alcohol (eg glycolmonomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • acid or alcohol eg glycolmonomethyl ether
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Pharmaceutical/food engineering and/or cosmetically non-toxic salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate Chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, tolu
  • bases can be used to make pharmaceutically/food engineering and/or cosmetically acceptable metal salts.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving an ascorbic acid derivative in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the content of ascorbic acid derivatives and salts thereof in the above composition is not particularly limited, but is included in a concentration of 0.1 to 1000 ⁇ M, for example, a concentration of 1.0 to 500 ⁇ M, preferably 1.0 to 200 ⁇ M.
  • a concentration of 1.0 to 500 ⁇ M preferably 1.0 to 200 ⁇ M.
  • the pharmaceutical composition related to antibacterial and/or anti-inflammatory may include, as an active ingredient, an ascorbic acid derivative having a structure of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof alone, and other formulations, use
  • additional ingredients that is, pharmaceutically or nutritionally acceptable carriers, excipients, diluents or sub-components may be additionally included.
  • a pharmaceutical composition comprising an ascorbic acid derivative and a pharmaceutically acceptable salt thereof can be prepared according to a conventional method for oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, It can be formulated and used in the form of suppositories and sterile injectable solutions.
  • ascorbic acid derivatives or pharmaceutically acceptable salts thereof may be administered in various oral or parenteral formulations during clinical administration.
  • fillers When formulated, commonly used fillers, extenders, binders, wetting agents, surfactants , may further include diluents or excipients such as anti-aggregating agents, lubricants, wetting agents, fragrances, emulsifiers or preservatives, and may be used orally or parenterally.
  • diluents or excipients such as anti-aggregating agents, lubricants, wetting agents, fragrances, emulsifiers or preservatives, and may be used orally or parenterally.
  • carriers, excipients and diluents that may be included in a pharmaceutical composition comprising an ascorbic acid derivative or a pharmaceutically acceptable salt thereof include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch. , acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • dextrin calcium carbonate, propylene glycol, liquid paraffin
  • dextrin calcium carbonate
  • propylene glycol propylene glycol
  • liquid paraffin and may be one or more selected from the group consisting of physiological saline, but is not limited thereto, and all conventional carriers, excipients or diluents may be used.
  • Ingredients other than the active ingredient may be added independently or in combination.
  • solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include ascorbic acid derivatives or pharmaceutically acceptable salts thereof with one or more excipients, for example, starch , calcium carbonate, sucrose or lactose, gelatin, etc. are mixed and prepared.
  • excipients for example, starch , calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid formulations for oral administration include suspensions, solutions, emulsions and syrups, and various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • As a base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, glycerogelatin, and the like can be used.
  • the pharmaceutical composition of the present invention may be administered through subcutaneous injection, intravenous injection or intramuscular injection.
  • Forms for parenteral administration include toothpaste, mouthwash, topical administration agents (creams, ointments, dressing solutions, sprays, other coating agents, etc.).
  • topical administration agents creams, ointments, dressing solutions, sprays, other coating agents, etc.
  • a pharmaceutical composition containing an active ingredient may be impregnated in a carrier such as gauze made of natural or synthetic fibers.
  • a cream or ointment it may be suitable for direct application to the affected area or inflamed area related to atopic dermatitis.
  • a spray except that it contains an active ingredient, it can be prepared by a conventional spray preparation method, and it is filled and packaged in a compression container or other spray container and sprayed frequently on the affected area or inflamed area caused by inflammatory diseases or bacteria disease can be prevented or treated.
  • a dressing solution except that it contains an active ingredient, it can be prepared by a conventional method for preparing a dressing solution, and is used for dressings in diseased areas or other bacterially infected areas, and diseases caused by inflammatory diseases or bacteria can be prevented or treated.
  • the dosage form of the pharmaceutical composition of the present invention may be in a preferred form depending on the method of use, particularly by adopting a method known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • specific formulations include warning agents, granules, lotions, liniments, limonades, powders, syrups, eye ointments, liquids, aerosols, EXTRACTS, elixils, ointments, fluid extracts, emulsions, suspensions, ointments, infusions, eye drops, tablets, suppositories, injections, spirits, capsules, creams, pills, soft or hard gelatin capsules, and the like.
  • the pharmaceutical composition may contain, in addition to the active ingredient, nutrients, vitamins, electrolytes, flavoring agents, coloring agents, thickeners, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives , glycerin, alcohol, a carbonation agent used in carbonated beverages, and the like may be additionally contained.
  • the pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes.
  • Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the preferred dosage of the pharmaceutical composition comprising the ascorbic acid derivative of the present invention or a pharmaceutically acceptable salt thereof varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, may be appropriately selected.
  • the pharmaceutical composition comprising an ascorbic acid derivative or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 100 mg/kg per day, preferably at 0.001 to 100 mg/kg. Administration may be administered once a day, or may be administered in several divided doses.
  • the above dosage does not limit the scope of the present invention in any way.
  • food compositions and health functional foods for alleviating inflammation and/or antibacterial include ascorbic acid derivatives having the structures of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • examples of the food composition of the present invention include food, food additives, beverages or beverage additives.
  • food may include all of food, food additives, health functional food, and beverage.
  • foods containing ascorbic acid derivatives or food engineering acceptable salts thereof include meat, sausage, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gums, and dairy products including ice cream.
  • various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexes and includes all health foods in the ordinary sense.
  • food includes special nutritional food (eg, formula milk, infant/infant food, etc.), processed meat products, fish meat products, tofu, jelly, noodles (eg, ramen, noodles, etc.), health supplements, seasoned foods ( Ex, soy sauce, soybean paste, red pepper paste, mixed soy sauce, etc.), sauces, sweets (eg snacks), dairy products (eg fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi, pickles, etc.), beverages ( Examples include, but are not limited to, fruit and vegetable beverages, soy milk, fermented beverages, ice cream, etc.), natural seasonings (eg, ramen soup, etc.), vitamin complexes, alcoholic beverages, alcoholic beverages and other health supplements.
  • the food, beverage or food additive may be prepared by a conventional manufacturing method.
  • the food composition and/or health functional food may include food engineering-acceptable food supplement additives in addition to the active ingredient, and may further include appropriate carriers, excipients and diluents commonly used in the manufacture of functional food.
  • the health functional food of the present invention may include the form of tablets, capsules, pills, liquids, etc., as an active ingredient, other than containing an ascorbic acid derivative or a cosmetically acceptable salt thereof, special ingredients
  • an active ingredient other than containing an ascorbic acid derivative or a cosmetically acceptable salt thereof
  • special ingredients there is no limitation, and it may contain food supplement additive ingredients such as flavoring agents or natural carbohydrates as additional ingredients.
  • natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose, sucrose and the like; Common sugars such as polysaccharides such as dextrin and cyclodextrin, as well as sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring/sweetening agents such as taumatine, stevia extract (eg rebaudioside A, glycyrrhizin) as flavoring or sweetening agents other than those described above; Synthetic flavoring/sweetening agents such as saccharin and aspartame may be used.
  • food compositions and/or health functional foods contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and salts thereof , alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, carbonation agents used in alcoholic carbonated drinks, and the like.
  • the food composition according to the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages. These components may be used independently or in combination.
  • the antibacterial and/or anti-inflammatory composition of the present invention contains carbohydrates, proteins, lipids, vitamins and minerals in addition to ascorbic acid derivatives as active ingredients or pharmaceutically/food engineering and/or cosmetically acceptable salts thereof.
  • sorbitol, xylitol, maltitol, and the protein is a milk-derived protein such as casein and whey protein, soybean protein, an animal-derived enzyme such as trypsin and pepsin of these proteins, and neutrase ), may be a hydrolyzate by alkilase, and the lipid is sunflower oil, rapeseed oil, olive oil, safflower oil, corn oil including a primary saturated fatty acid and polyunsaturated fatty acid.
  • soybean oil, palm oil, various plant-derived oils such as palm oil, middle-chain fatty acids, EPA, DHA, soybean-derived phospholipids, and milk-derived phospholipids
  • the minerals include potassium phosphate, potassium carbonate , potassium chloride, sodium chloride, calcium lactate, calcium gluconate, calcium pantothenate, calcium caseinate, magnesium chloride, ferrous sulfate, sodium hydrogen carbonate, but is not particularly limited by each example.
  • cosmetic compositions and cosmetics for anti-inflammatory, antibacterial, skin wrinkle improvement, skin aging prevention and/or skin whitening include ascorbic acid derivatives having structures of Formulas 1 to 4 or a cosmetically acceptable salt thereof.
  • the cosmetic composition contains a cosmetically and/or dermatologically acceptable medium, ie a medium suitable for the skin, mucous membranes, hair and scalp.
  • compositions can be prepared according to conventional methods in the art.
  • the 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.
  • a functional cosmetic composition At least one selected from decanol, isostearyl isostearate, cetyl octanoate and neopentyl glycol dicaprate may be used.
  • the solubility of the compound in the solvent is slightly different depending on the type of the compound and the mixing ratio of the solvent. Depending on the type of solvent and the amount used can be appropriately selected.
  • the cosmetic composition according to the present invention may further include an excipient for cosmetics.
  • an excipient for cosmetics for example, moisturizers, powder ingredients, UV absorbers , antioxidants, cosmetic ingredients, glycolipids, plant extracts, preservatives, fragrances, pH adjusters, pigments, viscosity modifiers or gelling agents, etc.
  • known ingredients used in conventional cosmetics for example, moisturizers, powder ingredients, UV absorbers , antioxidants, cosmetic ingredients, glycolipids, plant extracts, preservatives, fragrances, pH adjusters, pigments, viscosity modifiers or gelling agents, etc. may be included as auxiliary components.
  • Non-limiting examples of humectants include propylene glycol, isoprene glycol, 1,2-heptanediol, 1,3-butylene glycol, dipropylene glycol, hexanediol, polyethylene glycol glycerin, glycerin, diglycerin, triglycerin, polyglycerin, Glycols such as neopentyl glycol, sorbitol, erythritol, pentaerythritol, glucose, and galactose, fructose, sucrose, maltose, xylose, xylobiose, reduced products of oligosaccharides, protein, mucopolysaccharide, collagen, elastin, keratin, or and triethanolamine.
  • humectants include propylene glycol, isoprene glycol, 1,2-heptanediol, 1,3-butylene glyco
  • Non-limiting examples of powder components include white inorganic pigments such as titanium oxide, siliconized titanium oxide, zinc oxide and barium sulfate, colored inorganic pigments such as iron oxide, carbon black, titanium/titanium oxide sintered product and ultramarine blue, talc, silicone treatment Talc, muscovite, kaolin, silicon carbide, bentonite, smectite, silicic anhydride, aluminum oxide, magnesium oxide, zirconium oxide, diatomaceous earth, calcium silicate, barium silicate, magnesium silicate, calcium carbonate, magnesium carbonate, hydroxyapatite and boron nitride
  • White sieving powder titanium dioxide coated mica, iron oxide mica titanium, siliconized mica titanium, young gourd, polyethylene-based resin, fluorine-based resin, cellulose-based resin, and organic polymer resin powder such as silicone resin, zinc stearate and N-acylysine Organic low molecular weight powder, natural organic powder such as starch, silk powder and cellulose powder, organic
  • Organic powder pigments such as zirconium, barium or aluminum lake, gold foil powder such as mica, gold powder, and It may be a composite powder, such as titanium oxide-coated microparticles
  • Non-limiting examples of the ultraviolet absorber may be benzophenone derivatives, paraaminobenzoic acid derivatives, methoxycinnamic acid derivatives, urokanic acid, and the like.
  • Non-limiting examples of antioxidants may be BHT, BHA, vitamin C, vitamin E, derivatives thereof, salts thereof, and the like.
  • Non-limiting examples of the cosmetic ingredient may be vitamins including the above vitamins, derivatives thereof and salts thereof, anti-inflammatory agents, herbal medicines, and the like.
  • Non-limiting examples of glycolipids may be sphingoglycolipids and the like.
  • Non-limiting examples of the plant extract may be extracts of aloe vera, witch hazel, hammeris, cucumber, lemon, lavender and rose.
  • Non-limiting examples of the preservative may be methyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and ethanol.
  • Non-limiting examples of the fragrance may be camphor oil, tangerine oil, peppermint oil, jasmine absolute, pine oil, lime oil, lavender oil, rose oil and musk oil.
  • Non-limiting examples of pH adjusting agents may be edetic acid, sodium edetate, sodium chloride, quenic acid, sodium quenate, sodium hydroxide, potassium hydroxide, triethanolamine, and the like.
  • Non-limiting examples of the pigment may be Blue No. 1, Blue No. 204, Red No. 3 and Yellow No. 201, and the like.
  • Non-limiting examples of viscosity modifiers include polyvinyl alcohol (PVA), methylcellulose (MC), ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, other cellulose derivatives, polyvinylpyrilidone (PVP), Carboxymethyl cellulose, xanthan gum, alginic acid or its salt, carrageenan, quince seed pod, alkaligenes-produced polysaccharide, carboxyvinyl polymer, acrylate, acrylic acid polymer (chain type, crosslinked type) and acrylic acid/alkyl methacrylate copolymer etc.
  • PVA polyvinyl alcohol
  • MC methylcellulose
  • PVP polyvinylpyrilidone
  • Carboxymethyl cellulose xanthan gum
  • alginic acid or its salt carrageenan
  • quince seed pod alkaligenes-produced polysaccharide
  • carboxyvinyl polymer acrylate
  • acrylic acid polymer chain type, crosslinked type
  • Non-limiting examples of gelling agents include (behenic acid/eicoic acid diacid) glyceryl and (behenic acid/eicoic acid diacid) polyglyceryl-10, fatty acid metal salts, hydroxystearic acid, dextrin fatty acid esters, inulin fatty acid esters, sugar fatty acids Hydrocarbon wax such as ester, acylated cellulose, dibenzylidene sorbitol, amino acid gelling agent, silicic anhydride, organomodified clay mineral, fumed silica, alumina, crosslinked organopolysiloxane, polyethylene wax or paraffin wax, carnauba wax, or Vegetable waxes such as candelilla wax, agar, and gelatin may be used.
  • the cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing agent , oil, powder foundation, emulsion foundation, wax foundation, spray, etc., but is not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, a nourishing lotion, a cream, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray, or a powder.
  • a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing agent , oil, powder foundation, emulsion foundation, wax foundation, spray, etc. but is not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, a nourishing lotion, a cream, a nourishing cream, a massage cream, an essence, an eye
  • the cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers to be formulated in cosmetics, and conventional ingredients include, for example, oil, water, surfactant, humectant, lower alcohol, and thickener. , a chelating agent, a colorant, a preservative, a fragrance, and the like may be appropriately mixed, but the present invention is not limited thereto.
  • the cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the formulation.
  • the cosmetic formulation according to the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, etc. this can be used
  • the formulation of the cosmetic according to the present invention is a powder or a spray
  • lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydro It may contain a propellant such as carbon, propane/butane or dimethyl ether.
  • a solvent, solubilizer or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
  • a carrier component such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate
  • propylene glycol and 1,3-butyl glycol oil and in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol fatty ester, fatty acid ester of polyethylene glycol or sorbitan, etc. may be used.
  • the cosmetic formulation of the present invention is a suspension
  • a liquid diluent such as water, ethanol or propylene glycol, ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester , microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracanth may be used.
  • the cosmetic formulation of the present invention is a surfactant-containing cleansing agent
  • fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative or ethoxylated glycerol fatty acid ester and the like can be used.
  • cosmetics according to the present invention are skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nourishing lotion, massage cream, nourishing cream, moisture cream, hand cream, essence, nourishing essence, pack, soap , shampoo, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, emulsion, press powder, loose powder or eye shadow.
  • NaHCO3 (2.91g, 34.7mmol) was added to a DMSO solution (30ml) in which L-Ascorbic acid Acetonide (5g, 23.1mmol) was dissolved, reacted at room temperature for 20 minutes, and after addition of benzyl bromoacetate (6.36g, 4.35mmol) 8 stirred for hours.
  • the reaction solution was diluted with DW, extracted with EtoAc, the organic solvent layer was washed with brine, anhydrous MgSO 4 was added, and then dried under reduced pressure.
  • Rink amide MBHA resin was put into the reactor of the synthesizer, DCM was slowly added to the reactor, the resin was sufficiently inflated by stirring, and DMF was added to the remaining resin, followed by stirring, and the solvent was removed. After the piperidine solution was added, stirred and removed, DMF solvent was added to the remaining resin and stirred to wash the resin. This process was repeated 5 more times, followed by washing.
  • Tryptophan (Fmoc-Tbt-OH) modified to have an indole group substituted with tert-butyl constituting the C-terminus of the peptide was dissolved in DMF, injected into the reactor, and HBTU (Hexafluorophosphate Benzotriazole Tetramethyl Uronium) dissolved in DMF and N- Methylmorpholine was injected sequentially and reacted for 1 hour. After draining the reaction solution, adding DMF to the resin, stirring, and repeating the coupling process to remove the solvent, coupling was performed up to the N-terminal amino acid, Fmoc-arginine-OH. After the piperidine solution was added and stirred and removed, DMF solvent was added to the remaining resin, stirred, and the resin was washed. This process was repeated 5 more times, and then washed.
  • HBTU Hydrophosphate Benzotriazole Tetramethyl Uronium
  • the ascorbic acid derivative bound to the peptide was precipitated in cold ether.
  • the precipitated ascorbic acid derivative was filtered using a pressure reducing device, and the dried ascorbic acid derivative was recovered and vacuum dried.
  • the ascorbic acid derivative synthesized in this synthesis example is referred to as 'AA-RB109'.
  • the synthesized ascorbic acid derivative was analyzed by HPLC and MS, and the results of each analysis are shown in Table 1 and FIGS. 1 and 2 below. With respect to MS analysis, the expected molecular weight of the ascorbic acid derivative was 1428.7 Da, and it was analyzed to have 1428.0 Da. HPLC analysis conditions are as follows.
  • Example 1 Induction of collagen synthesis by ascorbic acid derivatives
  • HDF a human fibroblast cell line
  • a human fibroblast cell line was plated on a 96-well plate at a concentration of 5 ⁇ 10 3 cells/well, and treated with ascorbic acid and AA-RB109 at concentrations ranging from 0.08 to 10 ⁇ M, respectively.
  • DMEM serum-free medium
  • ELISA analysis Procollagen Type 1 C-peptide EIA Kit, MK101 was performed to confirm the concentration of Type 1 collagen in the conditioned media. The analysis results are shown in FIG. 3 .
  • Pure ascorbic acid did not show collagen synthesis-inducing activity at a concentration lower than 2 ⁇ M, but AA-RB109 showed an inducing activity even at a low concentration of 80 nM. It was indirectly confirmed that AA-RB109 had superior cell permeability and cell efficiency compared to ascorbic acid.
  • B16F10 cells a melanoma cell line
  • ⁇ -MSH melanocyte stimulating hormone
  • DMEM 10% FBS
  • cells were harvested using a cell scraper, dissolved at 95°C using 10% DMSO (in 1N NaOH) solution, and absorbance was measured at OD490. The measurement result is shown in FIG.
  • Ascorbic acid did not show melanin synthesis inhibitory activity at a concentration lower than 40 ⁇ M, but AA-RB109 showed a concentration-dependent inhibitory activity in a concentration range of 10 to 40 ⁇ M. It was confirmed that AA-RB109 had superior cell permeability and cell efficiency compared to ascorbic acid.
  • Monocyte cell line RAW264.7 (KCLB No 40071) cells were plated in a 96-well plate at a concentration of 5 ⁇ 10 4 cells/well, and then treated with LPS (lipopolysaccharide) to induce TNF- ⁇ synthesis in a model with ascorbic acid. and AA-RB109 were treated in a concentration range of 2.5 to 150 ⁇ M. After culturing for 4 hours (DMEM, 10% FBS), the conditioned media was collected and the TNF- ⁇ content in the conditioned media was measured using a mouse TNF- ⁇ ELISA Kit. The measurement result is shown in FIG.
  • LPS lipopolysaccharide
  • Ascorbic acid showed an inhibitory effect of about 23.4% at a high concentration of 150 ⁇ M, but AA-RB109 showed an inhibitory effect of about 44% even at a concentration of 10 ⁇ M. It was confirmed again that the cell permeability and cell efficiency of AA-RB109 were excellent compared to ascorbic acid.
  • Strain S. aureus was inoculated into LB medium and cultured with shaking for 18 hours at 37°C and 180 rpm. After the cultured bacterial solution was diluted 1000 times with LB medium (10 5 ⁇ 10 6 CFU/ml), the diluted bacterial solution and LB medium containing AA-RB109 were mixed, and then again at 37°C and 180 rpm for 18 hours. Shake culture. The absorbance value of the cultured bacterial solution was measured at OD 610 to determine the concentration (MIC) at which the growth of the bacteria did not occur. The analysis results are shown in FIG. 6 . The growth of S. aureus was confirmed through absorbance analysis at OD610, and at a concentration of 1000 nM or higher, it showed strong antibacterial activity. Regarding the excellent antibacterial effect on S. aureus , which shows the most correlation with the imbalance of skin flora, the possibility of ascorbic acid derivatives as a material for application to atopic-related skin diseases was confirmed.

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Abstract

La présente invention concerne un dérivé de l'acide ascorbique dans lequel au moins un peptide consistant en au moins un acide aminé neutre ou hydrophobe ou un analogue de ce dernier et au moins un acide aminé positivement chargé ou un dérivé de ce dernier est conjugué à l'acide ascorbique ; et une composition cosmétique fonctionnelle et une composition antibactérienne comprenant le dérivé de l'acide ascorbique en tant que matière active. Le dérivé de l'acide ascorbique présente une excellente stabilité et une excellente perméabilité vis-à-vis des tissus et des cellules de la peau et présente des activités physiologiques telles que des propriétés antibactériennes, une activité anti-inflammatoire, une induction de la synthèse du collagène et une inhibition de la production de mélamine.
PCT/KR2021/010279 2020-08-05 2021-08-04 Dérivé de l'acide ascorbique et composition le comprenant WO2022031044A1 (fr)

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Publication number Priority date Publication date Assignee Title
KR100325972B1 (ko) * 1993-08-09 2002-07-27 바이오메져 인코퍼레이티드 치료성펩타이드유도체
US20080188553A1 (en) * 2007-02-06 2008-08-07 Waheed M Roomi Novel ascorbic acid compounds, methods of synthesis and application use thereof
KR101413939B1 (ko) * 2007-10-20 2014-06-30 재단법인서울대학교산학협력재단 펩타이드가 결합된 아스코르빈산 유도체
KR20160063976A (ko) * 2014-11-27 2016-06-07 (주)셀트리온 펩타이드가 결합된 안정한 아스코르빈산 유도체, 그의 제조방법 및 그를 포함하는 화장료 조성물
KR20170133845A (ko) * 2016-05-26 2017-12-06 (주)셀트리온 펩타이드가 결합된 안정한 아스코르빈산 유도체를 포함하는 피부 염증 완화용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100325972B1 (ko) * 1993-08-09 2002-07-27 바이오메져 인코퍼레이티드 치료성펩타이드유도체
US20080188553A1 (en) * 2007-02-06 2008-08-07 Waheed M Roomi Novel ascorbic acid compounds, methods of synthesis and application use thereof
KR101413939B1 (ko) * 2007-10-20 2014-06-30 재단법인서울대학교산학협력재단 펩타이드가 결합된 아스코르빈산 유도체
KR20160063976A (ko) * 2014-11-27 2016-06-07 (주)셀트리온 펩타이드가 결합된 안정한 아스코르빈산 유도체, 그의 제조방법 및 그를 포함하는 화장료 조성물
KR20170133845A (ko) * 2016-05-26 2017-12-06 (주)셀트리온 펩타이드가 결합된 안정한 아스코르빈산 유도체를 포함하는 피부 염증 완화용 조성물

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