WO2022230959A1 - シワ改善のための皮膚外用剤 - Google Patents

シワ改善のための皮膚外用剤 Download PDF

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WO2022230959A1
WO2022230959A1 PCT/JP2022/019181 JP2022019181W WO2022230959A1 WO 2022230959 A1 WO2022230959 A1 WO 2022230959A1 JP 2022019181 W JP2022019181 W JP 2022019181W WO 2022230959 A1 WO2022230959 A1 WO 2022230959A1
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external preparation
skin
acid
mass
fatty acid
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English (en)
French (fr)
Japanese (ja)
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誠 坪井
泰子 阪田
祥吾 濱本
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Refine Holdings Co Ltd
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Refine Holdings Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/39—Derivatives containing from 2 to 10 oxyalkylene groups
    • 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
    • A61K8/86—Polyethers
    • 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 external skin preparation for wrinkle improvement containing a pentadecanoic acid triglyceride mixture and a specific surfactant.
  • the epidermis and dermis of the skin are composed of epidermal cells, fibroblasts, and an extracellular matrix such as collagen that is outside these cells and supports the skin structure.
  • the proliferation of fibroblasts is active, and the interaction of skin tissue maintains homeostasis to ensure moisture retention, flexibility, elasticity, etc., and the skin is externally taut and glossy. Maintained in a fresh state.
  • certain external factors such as ultraviolet irradiation, extreme dryness of the air, excessive skin washing, etc., and aging, the proliferative ability of fibroblasts declines, and the extracellular matrix becomes weaker.
  • the production amount of the constituents is reduced, and elasticity is reduced due to cross-linking.
  • Patent Document 1 reports that this composition promotes type I collagen production in human dermal fibroblasts and has an effect of maintaining skin moisturization when orally administered to mice.
  • An object of the present invention is to provide an external skin preparation for wrinkle improvement containing pentadecanoic acid triglyceride obtained from nature by solving such problems.
  • a triglyceride mixture composed of saturated fatty acids mainly containing pentadecanoic acid (hereinafter sometimes referred to as "PdATG") and a specific
  • PdATG pentadecanoic acid
  • Formula (I) below (wherein R 1 , R 2 and R 3 are each saturated fatty acid residues, at least one of which is a pentadecanoic acid residue). and a wrinkle-improving skin external preparation containing a nonionic surfactant.
  • the triglyceride mixture is derived from algae.
  • the triglyceride mixture contains pentadecanoic acid in an amount of 50% by mass or more based on the total fatty acid mass contained in the mixture. .
  • the triglyceride mixture contains 20 to 40% by mass of even-chain fatty acids relative to the total fatty acid mass contained in the mixture, and the even-chain fatty acids are Fatty acids are shown to include palmitic acid and/or myristic acid.
  • the algae are microalgae belonging to the genus Schizochytrium or Aurantiochytrium of Labyrinthulids.
  • the low-polymer PEG-containing nonionic surfactant is polyoxyethylene fatty acid glycerin type, polyoxyethylene hydrogenated castor oil fatty acid ester type, or polyoxyethylene. It is one or more selected from the group consisting of hydrogenated castor oil type, PCA polyoxyethylene isostearate hydrogenated castor oil type, polyoxyethylene fatty acid type, polyoxyethylene sorbitol type and polyoxyethylene alkyl ether type. is shown.
  • the aqueous composition contains 0.0004 to 0.5% by mass of the triglyceride mixture.
  • Another aspect of the present invention that solves the above problems is the use of a composition containing the above triglyceride mixture and a nonionic surfactant containing low polymerized PEG as an external skin preparation for improving wrinkles. be.
  • pentadecanoic acid triglyceride particularly naturally obtained pentadecanoic acid triglyceride
  • a low-polymer PEG-containing nonionic surfactant it is possible to provide an external preparation for skin that is confirmed to have wrinkle-improving effects. can be done.
  • FIG. 1 shows the results of examining the effect of PdATG on type I collagen production of human fibroblasts.
  • FIG. 2 shows the results of visual evaluation of changes in wrinkle grades of subjects who applied a PdATG-containing lotion or a PdATG-free lotion.
  • FIG. 3 shows the results of determining the change in the maximum depth of wrinkles in subjects who applied a lotion containing PdATG or a lotion not containing PdATG by the replica wrinkle measurement method used in the product evaluation test according to the anti-wrinkle guidelines. .
  • a skin external preparation in one embodiment of the present invention contains a pentadecanoic acid triglyceride mixture as an active ingredient and a surfactant.
  • the saturated fatty acids are linear or branched saturated fatty acids, butyric acid (C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid ( C9), capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), margaric acid (C17), stearic acid (C18), arachidic acid (C20), behenic acid (C22) linear saturated fatty acids such as lignoceric acid (C24) and cerotic acid (C26); Branched saturated fatty acids can be mentioned.
  • the active ingredient of the present invention may be a mixture containing two or more pentadecanoic acid triglycerides, and the fatty acid composition in each triglyceride is not limited. It preferably contains an acid.
  • the triglyceride mixture as an active ingredient preferably contains 20 to 40% by mass of even-chain fatty acids relative to the total fatty acid mass contained in the mixture, and the even-chain fatty acids are palmitic acid and / or myristic acid. including.
  • the active ingredient of the present invention may be present in a mixture with triglycerides other than the compounds of formula I, relative to the total amount of triglycerides, at least 1% by weight, preferably 50% by weight or more, more preferably 90% by weight. If it is contained in the above purity, the mixture itself can exhibit its function as an active ingredient.
  • the source of the triglyceride mixture which is the active ingredient of the present invention, is not particularly limited.
  • the triglyceride mixture is particularly preferably naturally occurring and includes lipids produced in the body by organisms such as livestock and poultry fats, fish and shellfish fats, vegetable oils or lipid-producing microorganisms. From an industrial productivity point of view, microorganisms such as algae, bacteria, fungi (including yeast), and/or protists are preferred.
  • microorganisms include those selected from the group consisting of golden algae (such as microorganisms of the Stramenopile kingdom), green algae, diatoms, dinoflagellates, yeasts, and fungi of the genera Mucor and Mortiera.
  • golden algae such as microorganisms of the Stramenopile kingdom
  • green algae diatoms, dinoflagellates, yeasts, and fungi of the genera Mucor and Mortiera.
  • Members of the microbial community Stramenopile include microalgae.
  • Microalgae refer to organisms that perform oxygen-generating photosynthesis, excluding bryophytes, fern plants, and seed plants, and having a cell size of 1 ⁇ m to 100 ⁇ m in diameter.
  • Labyrinthulids, closely related protists of microalgae are also included.
  • Labyrinthulids are heterotrophic marine eukaryotic microorganisms that do not perform photosynthesis, and are widely distributed mainly in subtropical and tropical regions.
  • Labyrinthula is roughly divided into Labyrinthulidae and Thraustochytriidae, and Labyrinthula, Aurantiochytrium, Schizochytrium ), Thraustochytrium, Aplanochytrium, Oblongichytrium, Botryochytrium, Japonochytrium, and the like.
  • Labyrinthula can be cultured by any culture method such as batch culture, continuous culture, or fed-batch culture.
  • Labyrinthula can be cultured by an appropriate culture method such as shaking culture, aerobic culture, aerobic stirring culture, airlift culture, and static culture. Among these culture methods, aeration and agitation culture or airlift culture is more preferable.
  • a culture apparatus used for culturing Labyrinthula for example, a mechanically stirred reactor, an airlift reactor, a packed bed reactor, a fluidized bed reactor, or the like can be used.
  • the culture vessel various vessels such as tanks, jar fermenters, flasks, dishes, culture bags, tubes, and test tubes can be used depending on the purpose of culture, culture capacity, and the like.
  • the culture vessel may be made of appropriate materials such as inorganic materials such as stainless steel and glass, and organic materials such as polystyrene, polyethylene terephthalate copolymer, and polypropylene.
  • Labyrinthula can be cultured under appropriate temperature conditions, pH conditions, aeration conditions, etc.
  • the culture temperature is preferably 5° C. or higher and 40° C. or lower, more preferably 10° C. or higher and 35° C. or lower, even more preferably 10° C. or higher and 30° C. or lower.
  • the pH is preferably 2 or more and 11 or less, more preferably 4 or more and 9 or less, and even more preferably 6 or more and 8 or less.
  • Labyrinthula can be cultured by subculturing at appropriate intervals according to the genus and species of the Labyrinthulea, medium composition, culture conditions, etc.
  • Labyrinthulids complete the logarithmic growth phase in about 2 days after starting the culture, and enter the death phase in about 7 days. Therefore, passage of Labyrinthula is preferably performed at intervals of 1 to 10 days, more preferably at intervals of 2 to 7 days, and preferably at intervals of 2 to 5 days. is more preferred.
  • the Labyrinthula can be cultured for an appropriate time depending on the genus and species of the Labyrinthula, medium composition, culture conditions, purpose of culture, and the like.
  • Aurantiochytrium algae it is preferable to use strains with excellent ability to produce desired triglycerides.
  • Such algal strains may be naturally collected and isolated, cloned through mutagenesis and screening, or established using genetic recombination techniques.
  • may For example, Aurantiochytrium Sp. Strains SA-96, NIES-3737, Aurantiochytrium NB6-3, or Aurantiochytrium mh1959 contain triglycerides containing the odd-chain fatty acid pentadecanoic acid (PDA) and the highly unsaturated fatty acid docosahexaenoic acid.
  • PDA odd-chain fatty acid pentadecanoic acid
  • the culture of the Aurantiochytrium genus algae is performed by a method established in the technical field. That is, normal maintenance culture is carried out by seeding algae in a medium whose components are appropriately prepared and following a standard method.
  • a medium for culturing Aurantiochytrium algae essentially contains salt, a carbon source and a nitrogen source.
  • GTY medium artificial seawater 10-40 g/L, D(+) glucose 20-100 g/L, tryptone 10-60 g/L, yeast extract 5-40 g/L
  • GTY medium artificial seawater 10-40 g/L, D(+) glucose 20-100 g/L, tryptone 10-60 g/L, yeast extract 5-40 g/L
  • Carbon sources include sugars such as glucose, fructose, and sucrose. These carbon sources are added, for example, at a concentration of 20-120 g per liter of medium.
  • Algae of the genus Aurantiochytrium are marine algae, and an appropriate amount of artificial seawater is added to the medium.
  • the artificial seawater has a final medium salinity of about 10% (v/v) to about 100% (v/v) of seawater (3.4% (w/v) salinity), such as It is added so that the concentration is about 1.0-3.0% (w/v).
  • microalgae culture media contain organic nitrogen such as sodium glutamate and urea, or inorganic nitrogen such as ammonium acetate, ammonium sulfate, ammonium chloride, sodium nitrate, ammonium nitrate, or yeast extract, corn steep liquor, polypeptone, Various nitrogen sources can be added, such as biological digests such as peptones, tryptones, and the like.
  • cell extracts obtained by extracting liquid components from cells of various animals are preferably used as nitrogen sources to be added to media used for culturing Aurantiochytrium algae.
  • Use of cell extracts that are rich in nutrients such as cell-derived amino acids, nucleic acids, vitamins, and minerals and that are available at low cost when cells must be mass-cultured on an industrial scale to obtain cultured cell products. is extremely advantageous.
  • the present inventors cultured Aurantiochytrium algae in an algae culture medium prepared by adding a strong acid-treated cell extract, and compared with the case where the cell extract without the treatment was added. have found that the production of odd-chain fatty acids dramatically increases, and have already reported a method for producing triglycerides containing odd-chain fatty acids as main components (Japanese Patent Application Laid-Open No. 2017-063633).
  • This basal medium contains at least 2% glucose and 0.5-4% monosodium glutamate, 0.1-2% yeast extract, 1-3.3% sea salt, 2-20% whey (animal or vegetable 2% or more of the culture solution of Aurantiochytrium precultured at 20 to 30° C. for 72 hours is added.
  • the Aurantiochytrium-loaded culture is aerated and gently agitated. Cultivation is carried out at 20 to 30° C. and a pH of 5.0 to 8.5 (using a 1.0 M NaOH solution for pH adjustment) for 48 to 200 hours.
  • Aurantiochytrium cells that have produced pentadecanoic acid triglyceride can be recovered by centrifugation (see WO2020/054804 pamphlet).
  • the pellet collected by centrifugation or filtration from the culture solution obtained by the above method is dried by freeze-drying or drying by heating.
  • the culture medium in which the algal cells are suspended may be directly used for the triglyceride extraction step. Extraction may be performed multiple times with different organic solvents.
  • the organic solvent a mixture of a polar solvent and a weakly polar solvent such as n-hexane/ethanol mixed solvent, chloroform/methanol mixed solvent, or ethanol/diethyl ether mixed solvent can be used.
  • the resulting extract is purified by methods known to those skilled in the art.
  • a fractionation technique known to those skilled in the art is adopted. Separation and purification may be carried out using various physicochemical properties such as polarity, solubility in solvents, melting point, specific gravity and molecular weight of triglyceride molecules to be fractionated, preferably using column chromatography techniques.
  • the conditions for the triglyceride separation means can be set by a person skilled in the art by routine examination of the conditions, depending on the composition of the triglyceride mixture and the types of triglycerides to be fractionated.
  • Algae of the genus Schizochytrium and Aurantiochytrium can synthesize and accumulate both odd-chain fatty acid triglycerides and polyunsaturated fatty acid triglycerides in their cells. Therefore, ethanol, hexane or ethyl acetate is added to the obtained algal cells to extract lipids, and then the solvent is distilled off to obtain algal lipids. Pentadecanoic acid triglyceride can be precipitated by allowing this lipid to stand at 5°C.
  • the composition of the purified pentadecanoic acid triglyceride “PdATG” can be analyzed by HPLC-MS, HPLC, gas chromatography and the like.
  • Algae of the genus Aurantiochytrium can synthesize and accumulate both odd-chain fatty acid triglycerides and polyunsaturated fatty acid triglycerides in their cells. Therefore, hexane or ethyl acetate is added to the obtained aurantiochytrium cells to extract lipids, and then hydrogen peroxide solution is added to the lipid solution or ozone is passed through it to oxidatively decompose the unsaturated fatty acids. After completion of the reaction, oxides are removed with sodium hydrogen carbonate and sodium carbonate or an ion exchange resin to obtain pentadecanoic acid triglyceride "PdATG".
  • the composition of the purified pentadecanoic acid triglyceride “PdATG” can be analyzed by HPLC-MS, HPLC, gas chromatography and the like.
  • Nonionic surfactants are preferably used in the external preparation for skin according to the present invention because they are less irritating to the skin.
  • nonionic surfactants include glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol. , polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, alkyl glycoside and the like.
  • a low-polymer polyethylene glycol-containing nonionic surfactant (in the present specification, referred to as a "low-polymer PEG-containing nonionic surfactant”) may be abbreviated) is preferred.
  • low polymerization is not particularly limited, but for example, the degree of polymerization is about (2 to 450), preferably (3 to 100), more preferably about (5 to 30). .
  • This low-polymer PEG-containing nonionic surfactant is a form in which the low-polymer PEG as described above is bound to other hydrophobic molecules, such as higher alcohols having about 12 to 18 carbon atoms, and is an ester type, an ether type, or the like.
  • the oligomeric PEG-containing nonionic surfactant is selected from PEG-6 glyceryl isostearate, PEG-8 glyceryl isostearate, PEG-7 glyceryl cocoate or polyoxyethylene (20) sorbitan monooleate.
  • concentration of the low-polymer PEG-containing nonionic surfactant in the present embodiment is not particularly limited as long as the effects of the present invention can be exhibited, but it is preferably 0.1 to 10% by mass, more preferably 0.1% by mass. It is 3 to 5% by mass.
  • Examples of external preparations for skin include basic cosmetics such as lotions, milky lotions, creams, ointments, lotions, oils, packs, skin cleansers such as soaps, cleansing creams, cleansing lotions, facial cleansers, shampoos, rinses, Hair washing cosmetics such as treatments, hair creams, hair sprays, hair tonics, hair gels, hair lotions, hair oils, hair essences, hair waters, hair waxes, hair styling agents such as hair foams, hair restorers, hair tonics, foundations, face powders, Make-up cosmetics such as face powder, lipstick, blusher, eyeshadow, eyeliner, mascara, eyebrows, and eyelashes; finishing cosmetics such as nail polish; oral compositions such as perfumes, toothpastes, and mouthwashes; Cosmetic compositions, external medicinal preparations, ointments, poultices, bath agents, medicated toothpastes, medicated oral compositions such as mouth fresheners, medicated cosmetics, hair dyes, hair
  • These external preparations for skin contain other ingredients commonly used in cosmetics, quasi-drugs and pharmaceuticals, such as powder ingredients, liquid oils and fats, solid oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, Moisturizers, water-soluble polymers, thickeners, film agents, UV absorbers, sequestering agents, lower alcohols, polyhydric alcohols, sugars, amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, Vitamins, antioxidants, antioxidant aids, fragrances, water, etc. can be blended as needed, and production can be carried out by conventional methods.
  • ingredients commonly used in cosmetics, quasi-drugs and pharmaceuticals such as powder ingredients, liquid oils and fats, solid oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, Moisturizers, water-soluble polymers, thickeners, film agents, UV absorbers, sequestering agents, lower alcohols, polyhydric alcohol
  • ingredients that can be blended in external skin preparations include, for example, preservatives (ethylparaben, butylparaben, etc.), antiphlogistic agents (e.g., glycyrrhizic acid derivatives, glycyrrhetic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc.).
  • preservatives ethylparaben, butylparaben, etc.
  • antiphlogistic agents e.g., glycyrrhizic acid derivatives, glycyrrhetic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc.
  • whitening agents e.g., ascorbic acid and its derivatives, placenta extract, saxifrage extract, arbutin, etc.
  • various extracts e.g., Phellodendron bark, coptis, rhizome, peony, Japanese juniper, birch, sage, loquat, carrot, aloe, mallow, iris, grape, coix seed, luffa, lily, saffron, cnidium, ginger, hypericum, ononis, garlic, red pepper, chimp, angelica root, seaweed, etc.
  • activators e.g., royal jelly, photosensitizer, cholesterol derivatives, etc.
  • Blood circulation promoters e.g., nonylic acid valenylamide, nicotinate benzyl ester, nicotinic acid ⁇ -butoxyethyl ester, capsaicin, gingerone, cantharis tincture, ictamol,
  • the subject of administration of the external preparation for skin of the present embodiment is preferably a warm-blooded vertebrate, more preferably a mammal.
  • mammals include, for example, humans and non-human mammals such as monkeys, mice, rats, rabbits, dogs, cats, cows, horses, and pigs.
  • the external preparation for skin of the present embodiment is preferably applied to a human subject who desires promotion of collagen production in the skin, improvement of wrinkles, impartation of firmness or stiffness to hair, or improvement of feel of hair.
  • the amount of the active ingredient to be applied to the skin in the external preparation for skin of the present embodiment can be appropriately determined according to the individual's condition, body weight, sex, age, administration schedule, formulation form, or other factors.
  • the active ingredient can be applied to the skin once to several times a day, or applied to the skin for any duration and interval.
  • the content of the active ingredient is preferably 0.0001% by mass or more, more preferably 0.0004% by mass or more, and still more preferably 0.001% by mass or more in the total amount of the external skin preparation of the present embodiment. Also, it is preferably 1% by mass or less, more preferably 0.5% by mass or less, and even more preferably 0.01% by mass or less.
  • the active ingredient of the present invention is a compound with low polarity, it is difficult to dissolve in an aqueous medium at a high concentration. Therefore, when preparing the skin external preparation of the present embodiment, the water solubility can be improved by coexisting with a nonionic surfactant containing low-polymer PEG. For example, by containing 10% by mass of Chemonic APLI-7 used in Examples described later, the active ingredient can be dissolved up to 0.5% by mass in the aqueous solution. Therefore, the external preparation for skin in a preferred embodiment of the present invention is an aqueous composition containing 0.0004 to 0.5 mass % of triglyceride mixture as an active ingredient.
  • Pentadecanoic acid triglyceride which is the active ingredient of the present invention, contains at least one pentadecanoic acid in the molecule, and odd-chain fatty acids such as pentadecanoic acid function to maintain the TCA cycle normally.
  • Fatty acids are oxidized in the body to become acetyl-CoA with two carbon atoms (C2), enter the citric acid cycle (TCA cycle), and coenzymes NAD (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide). It reduces to NADH2 and FADH2 and produces ATP through the electron transport chain.
  • NAD nicotinamide adenine dinucleotide
  • FAD flavin adenine dinucleotide
  • Propionyl-CoA is converted to methyl-malonyl-CoA at C4 and converted to succinyl-CoA, a member of the TCA cycle, by the enzyme methylmalonyl-CoA mutase, which uses vitamin B12 as a coenzyme.
  • Succinyl-CoA introduced into the TCA cycle becomes succinate by the enzyme succinyl-CoA synthetase.
  • the signaling substance GTP (guanosine triphosphate) is produced. This is the only reaction in the TCA cycle in which GTP is produced. Note that ATP is not produced in the TCA cycle.
  • GTP binds to membrane proteins called G-proteins to transmit signals.
  • GTP-bound active G protein plays an important role in activating various physiological functions of cells. Therefore, it is suggested that odd-chain fatty acids are involved in ATP production starting from C2 acetyl-CoA, as well as cellular physiological activation starting from C3 propionyl-CoA.
  • the TCA cycle may not function properly due to a shortage of any of the constituent molecules.
  • the succinyl-CoA produced by the decomposition of odd-chain fatty acids as described above is recruited into the TCA cycle (this phenomenon is called anaplerosis).
  • Odd-chain fatty acids function to maintain the normal TCA cycle by replenishing succinyl-CoA via propionyl-CoA.
  • the active ingredient of the present invention contains such odd-chain fatty acids, particularly pentadecanoic acid, in an amount of 50% by mass or more relative to the total fatty acid mass in the triglyceride mixture, and 20 to 40% by mass of even-chain fatty acids, preferably , palmitic acid and/or myristic acid, the function of the TCA cycle can be maintained more normally.
  • odd-chain fatty acids particularly pentadecanoic acid
  • even-chain fatty acids preferably , palmitic acid and/or myristic acid
  • the action and effect of the external skin preparation of the present embodiment to enhance the beauty of the skin and at the same time improve wrinkles is not limited to the above mechanism and is not bound by any theory. It has the effect of producing collagen, and in terms of the effect on the granular layer, it is thought that the barrier function tends to improve.Caspase-14 expression induction decomposes filaggrin precursors to create natural moisturizing factors, and the barrier function of the stratum corneum. It contributes to the maintenance of the moisture retention function, and is thought to enhance the beauty of the skin by improving the firmness and transparency of the skin. In addition, it is believed that the wrinkle-improving effect is exhibited due to the internal effect of moisturizing by ferragrin production and collagen production.
  • the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
  • the unit % of numerical values indicating the addition amount of various components means % by mass.
  • basal medium contains 3.6% glucose, 0.5% sodium glutamate, 0.2% yeast extract, 1% sea salt, 10% whey plus 50 mM valine and 25 mM sodium propionate.
  • prepared by adding Cultivation was maintained at 25° C. and pH of 7.40 to 7.75 (1.0 M NaOH solution was used for pH adjustment) and cultured for 72 to 96 hours.
  • composition analysis of pentadecanoic acid triglyceride 0.50 mL of 14% BF 3 -methanol and 0.25 mL of methyl acetate were added to the lipid containing pentadecanoic acid triglyceride obtained in Production Example 1 and heated at 70° C. for 30 minutes to obtain a fatty acid methyl ester (FAME). rice field. Exactly 1.0 mL of n-hexane and 5 mL of physiological saline were added to the reaction solution and vigorously mixed. The mixture was centrifuged at 2800 rpm for 10 minutes, and the n-hexane layer was used as a sample for gas chromatography.
  • the above sample was analyzed using a gas chromatograph GC-2025 manufactured by Shimadzu Corporation.
  • the analysis conditions were to use an Agilent J&W GC column DB-23 (30 m x 0.25 mm), inject 1 ⁇ L of sample, and detect with an FID (flame ionization detector) with a carrier gas (He, 14 psi). did.
  • FID flame ionization detector
  • He carrier gas
  • the molecular species of FAME was identified based on the retention time of fatty acid methyl ester standards (manufactured by GL Sciences).
  • the fatty acid composition was obtained from the area ratio.
  • the calculated composition is a mass ratio.
  • the proportion of odd-chain fatty acids was determined by multiplying the total fatty acid content by the proportion (%) of odd-chain fatty acids (C13, C15, C17). The results obtained are shown in Table 1 below.
  • the content of odd-numbered chain fatty acids in the triglyceride obtained in Production Example 1 was 68.3% by mass. Moreover, it was found that the fatty acid is mainly a triglyceride composed of a pentadecanoic acid residue (C15) and a palmitic acid residue (C16).
  • the lipid containing pentadecanoic acid triglyceride obtained in Production Example 1 was analyzed by mass spectrometry using Thermo Fischer's Orbitrap mass spectrometer Exactive Plus (AMR's DART ion source).
  • AMR's DART ion source Thermo Fischer's Orbitrap mass spectrometer Exactive Plus (AMR's DART ion source).
  • the pentadecanoic acid triglyceride obtained in Production Example 1 was composed of a triglyceride formed only by the pentadecanoic acid residue (C15) and palmitin in two units of the pentadecanoic acid residue (C15). It was found to be a triglyceride mixture mainly containing triglycerides containing one unit of acid residue (C16).
  • Example 1 Verification of type I collagen production promoting effect in human skin fibroblasts
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • the measured values of type I collagen are the mean and standard deviation of 4 samples of each concentration, and compared to the mean when the sample concentration was 0 ⁇ g/mL, in Student's t-test ** indicates significant difference at p ⁇ 0.01. From the results in Table 2 and FIG. 1, an increase in the amount of type I collagen produced by human fibroblasts was observed in a concentration-dependent manner of the pentadecanoic acid triglyceride mixture (PdATG) added to the medium.
  • PdATG pentadecanoic acid triglyceride mixture
  • Example 2 In order to examine the solubility of the pentadecanoic acid triglyceride mixture (PdATG) obtained in Production Example 1 in an aqueous solution, various surfactants were added to the aqueous solution to give final concentrations of 0.01, 0.05 and 0. PdATG was added to 1, 0.2, 0.5, 0.8 and 1.0% by mass, and the maximum solubilization concentration was visually examined. As a result, when coconut oil fatty acid PEG-7 glyceryl (Chemonic APLI-7: (Nippon Lubrizol Co., Ltd.)), which is a nonionic surfactant, was used, PdATG was solubilized up to 0.5% by mass.
  • PdATG pentadecanoic acid triglyceride mixture
  • non-ionic surfactants such as anionic, cationic, and amphoteric surfactants
  • the maximum solubilization concentration is not much different from that of the above nonionic surfactant, it was difficult to properly emulsify the active ingredient.
  • a monitor test was conducted by preparing water and applying it to human subjects.
  • Example 3 An active ingredient composition (containing 1% TdATG and 99% squalane) was prepared by blending 1% PdATG with squalane (Prepure 3759-LQ-(JP): Croda Japan Co., Ltd.). 1 g each of squalane (Prepure 3759-LQ-(JP): Croda Japan Co., Ltd.) and 8 g of coconut oil fatty acid PEG-7 glyceryl (Chemonic APLI-7: Nippon Lubrizol Co., Ltd.) as this active ingredient composition or solvent control substance was taken in a 200 mL beaker and mixed well.
  • Test example 1 A skin application test was conducted on 25 subjects (32 to 58 years old, average age about 46 years old) using the lotion (compounded product or non-compounded product). Subjects: 25 healthy females aged 32 to 58 years who have wrinkle grades 1 to 3 on the left and right outer corners of the eyes (see “Guidelines for Evaluation of Cosmetic Functionality” by the Japanese Cosmetic Science Society). ⁇ Design: Double-blind, randomized controlled trial (half-face comparative trial by the same experimenter) ⁇ Test product: lotion containing 0.001% PdATG (compounded product), non-compounded lotion (non-compounded product) ⁇ Period: Use twice a day, morning and evening. Continuous application for 4 weeks Evaluation items: Visual evaluation by a skilled person (physician) at the same site before starting application of the test product and at the end of the test, and two-dimensional device measurement by replica collection
  • FIG. Figure 2 (A) shows the average score at the start of the test (0W) and after 4 weeks (4W) of the subjects who applied the compounded product
  • Figure 2 (B) shows the test start of the subjects who applied the non-compounded product. Mean score at time (0W) and after 4 weeks (4W).
  • subjects who applied the formulation had a significant (p ⁇ 0.05) reduction in wrinkle grade after 4 weeks compared to the beginning of the study.
  • no significant difference was observed in subjects who applied the non-compounded product at the beginning of the test and after 4 weeks.
  • the wrinkle grade standards are as follows. Grade 1: A few obscure shallow wrinkles are observed. Grade 2: Clear shallow wrinkles are slightly observed. Grade 3: Clear shallow wrinkles are observed.
  • FIG. 3 shows the average values obtained by calculating the maximum wrinkle depth among them.
  • the numerical values of the subjects who applied the non-blended product after 4 weeks were significantly increased, but the subjects who applied the formulated product tended to decrease. Therefore, it is considered that the PdATG-containing lotion prevents the deterioration of wrinkles.
  • the application of the external preparation for skin of the present invention is effective in improving skin wrinkles. Therefore, the external preparation for skin of the present invention may be used as a cosmetic for improving wrinkles.

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JPS601111A (ja) * 1983-06-06 1985-01-07 Lion Corp 化粧料
JPS6115809A (ja) * 1984-06-29 1986-01-23 Lion Corp 細胞賦活剤
JPH01135708A (ja) * 1987-11-20 1989-05-29 Lion Corp 皮膚老化防止用化粧料
JP2002053436A (ja) * 2000-08-11 2002-02-19 Lion Corp 外用組成物
JP2011153122A (ja) * 2009-12-28 2011-08-11 Lion Corp 化粧料組成物
WO2021020514A1 (ja) * 2019-07-31 2021-02-04 リファインホールディングス株式会社 コラーゲン産生促進剤、シワ改善剤、皮膚外用剤および美容飲食品

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JP2002053436A (ja) * 2000-08-11 2002-02-19 Lion Corp 外用組成物
JP2011153122A (ja) * 2009-12-28 2011-08-11 Lion Corp 化粧料組成物
WO2021020514A1 (ja) * 2019-07-31 2021-02-04 リファインホールディングス株式会社 コラーゲン産生促進剤、シワ改善剤、皮膚外用剤および美容飲食品

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CN115845139A (zh) * 2022-12-08 2023-03-28 海南宏正生物科技有限公司 一种促进组织修复与再生的人造皮肤及制备方法

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