WO2023191016A1 - フィブリリン産生促進剤、化粧料組成物又は皮膚外用剤、経口投与剤、及びエラスチン線維産生促進剤 - Google Patents

フィブリリン産生促進剤、化粧料組成物又は皮膚外用剤、経口投与剤、及びエラスチン線維産生促進剤 Download PDF

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WO2023191016A1
WO2023191016A1 PCT/JP2023/013439 JP2023013439W WO2023191016A1 WO 2023191016 A1 WO2023191016 A1 WO 2023191016A1 JP 2023013439 W JP2023013439 W JP 2023013439W WO 2023191016 A1 WO2023191016 A1 WO 2023191016A1
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Prior art keywords
skin
fibrillin
precursor
production
production promoter
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English (en)
French (fr)
Japanese (ja)
Inventor
和也 石毛
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Yamasa Corp
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Yamasa Corp
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Priority to KR1020247035488A priority Critical patent/KR20240167444A/ko
Priority to EP23781024.7A priority patent/EP4501333A4/en
Priority to JP2024512879A priority patent/JPWO2023191016A1/ja
Publication of WO2023191016A1 publication Critical patent/WO2023191016A1/ja
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/92—Oral administration

Definitions

  • the present invention relates to a fibrillin production promoter, a cosmetic composition or skin external preparation, an orally administered agent, and an elastin fiber production promoter.
  • Non-Patent Document 1 studies the relationship between “visual firmness” and “tactile firmness” and finds that “visual firmness” has a strong correlation with “visual moisture feeling”, while “tactile firmness” has a strong correlation with "visual moisture feeling”. There was no correlation between ⁇ firmness'' and ⁇ visual moisture feeling''.
  • Non-Patent Document 1 states that a significant improvement in "visual firmness” was observed with an increase in the moisture content of the stratum corneum, but on the other hand, no significant change was observed in "tactile firmness”. ing.
  • elastic fibers play an important role in "tactile firmness.” Elastin fibers in the skin dermis form a continuous network extending from the basement membrane to the subcutaneous tissue, maintaining skin elasticity. Among the changes in the skin associated with aging, changes due to the degeneration of elastin fibers play a major role, and it is said that the degeneration of elastin fibers is a major cause of skin sagging and wrinkles. It is known that elastin fibers decrease during natural aging.
  • Non-Patent Document 2 In addition to the skin, elastic fibers are abundant in the lungs and arteries, and are responsible for the elasticity of these tissues. Deterioration of elastic fibers associated with aging is a direct cause of emphysematous changes, arteriomedia sclerosis, etc. (Non-Patent Document 2).
  • Non-Patent Document 2 If elastic fibers can be regenerated, it is thought that it will not only improve the tactile firmness of the skin, but also create new preventive and therapeutic methods such as preventing and treating the progression of emphysema and arteriosclerosis.
  • Microfibrils (fibrillin) and amorphous elastin are known as the main components of elastic fibers.
  • Elastic fibers are formed by the deposition of elastin on microfibrils. That is, it is thought that by promoting the production of microfibrils, the production of elastic fibers is promoted.
  • Cytidylic acid and uridylic acid are a type of nucleotide, substances that are widely contained in living organisms and foods, and can be said to be highly safe materials.
  • Patent Document 1 discloses a cosmetic composition containing uridine or a derivative thereof, acetylglucosamine, and the like. The invention described in Patent Document 1 is described to improve the moisturizing properties of the skin, increase the moisture content of the stratum corneum, and keep the skin in a firm state.
  • Non-Patent Document 1 which states that a significant improvement in "visual firmness” was observed as the stratum corneum water content increased, but no significant change was observed in “tactile firmness”.
  • the "firmness" of the skin in Patent Document 1 is understood to be so-called “visual firmness.”
  • Patent Document 1 does not disclose at all that pyrimidine nucleotides or their precursors promote the production of fibrillin and contribute to improving the "tactile firmness" of the skin.
  • Patent Document 2 describes that uridine phosphate ester or a physiologically acceptable salt thereof promotes hyaluronic acid production in cells, contributes to moisturizing, and promotes cell proliferation. Further, Patent Document 2 discloses that wrinkles and sagging of the skin are improved due to promotion of hyaluronic acid production and cell proliferation.
  • Patent Document 2 The improvement of skin wrinkles and sagging disclosed in Patent Document 2 is due to the improvement of so-called "visual firmness" caused by moisturizing the skin by promoting hyaluronic acid production, and the appearance caused by quantitative changes caused by cell proliferation. This is considered to be the above change.
  • Patent Document 2 does not disclose at all that pyrimidine nucleotides or their precursors promote the production of fibrillin and contribute to improving the "tactile firmness" of the skin.
  • Patent Document 3 describes a composition for promoting collagen production that contains a purine-based nucleic acid-related substance and a pyrimidine-based nucleic acid-related substance.
  • the invention substantially disclosed in Patent Document 3 is a composition for promoting collagen production using a combination of adenylic acid and uridylic acid, and there is no substantial disclosure regarding the use of uridylic acid alone and the use of cytidylic acid. do not have.
  • Patent Document 3 does not disclose at all that pyrimidine nucleotides or their precursors promote the production of fibrillin and contribute to improving the "tactile firmness" of the skin.
  • nucleic acid-related substances such as cytidylic acid and uridylic acid have a fibrillin production promoting effect has not been evaluated so far.
  • An object of the present invention is to provide a novel and highly safe fibrillin production promoter, a cosmetic composition or a skin external preparation, and an orally administered preparation, which have a fibrillin production promoting effect.
  • Another object of the present invention is to provide a novel and highly safe elastin fiber production promoter that has an elastin fiber production promoting effect.
  • pyrimidine nucleotides or their precursors which have not been known to have any effect on promoting fibrillin production, are effective in promoting fibrillin production and elastin fiber production. It was discovered for the first time that it has the attribute of promoting
  • the present invention is a fibrillin production promoter containing a pyrimidine nucleotide or its precursor as an active ingredient.
  • the present invention also provides a cosmetic composition or an external skin preparation for promoting fibrillin production, which contains a pyrimidine nucleotide or its precursor as an active ingredient.
  • the present invention is an orally administered agent for promoting fibrillin production, which contains a pyrimidine nucleotide or a precursor thereof as an active ingredient.
  • the present invention is an elastin fiber production promoter containing a pyrimidine nucleotide or its precursor as an active ingredient.
  • the fibrillin production promoter, cosmetic composition or skin external preparation, and oral administration agent of the present invention have a fibrillin production promoting effect and are novel and highly safe. Furthermore, the elastin fiber production promoting agent of the present invention has an effect of promoting elastin fiber production, and is novel and highly safe.
  • FIG. 1 shows the results of quantifying the amount of fibrillin-1 (ng/ ⁇ g-protein) upon CMP and 2Na treatment determined in Example 1.
  • direct treatment shown in dark gray means the measurement results of samples in which normal human fibroblasts were directly processed.
  • K-CM shown in grayish white means the measurement results of a sample obtained by treating normal human fibroblasts with the culture supernatant of normal human epidermal cells.
  • the numerical value written on the horizontal axis means the CMP, 2Na concentration (mM) in each sample.
  • the symbol ** means that the p value is smaller than 0.01 when compared with the result of direct treatment CMP, 2Na concentration 0 (mM) using Student's t test.
  • FIG. 2 shows the results of quantifying the amount of fibrillin-1 (ng/ ⁇ g-protein) upon treatment with UMP and 2Na determined in Example 1.
  • direct treatment shown in dark gray means the measurement results of samples in which normal human fibroblasts were directly processed.
  • K-CM shown in grayish white means the measurement results of a sample obtained by treating normal human fibroblasts with the culture supernatant of normal human epidermal cells.
  • the numerical value written on the horizontal axis means the UMP, 2Na concentration (mM) in each sample.
  • FIG. 3 shows the results of FBN-1 mRNA expression analysis quantified in Example 2.
  • the numerical value written on the horizontal axis means the CMP, 2Na concentration (w/v%) in each sample.
  • the numerical value written on the vertical axis means the relative expression level with the expression level of FBN-1 at CMP, 2Na concentration 0 (w/v%) being 1.00.
  • FIG. 4 shows a photograph of the results of elastica van Gieson staining described in Example 3. The area shown in black in the dermis in the photograph represents elastin fibers.
  • Control indicates the results of the CMP, 2Na concentration 0 (w/v%) treated sample.
  • 1% CMP, 2Na shows the results of the CMP, 2Na concentration 1.0 (w/v%) treated sample, and 2% CMP, 2Na shows the results of the CMP, 2Na concentration 2.0 (w/v%) treated sample. .
  • the present invention relates to a fibrillin production promoter, a cosmetic composition or external skin preparation for promoting fibrillin production, and an oral preparation containing a pyrimidine nucleotide or its precursor as an active ingredient.
  • the present invention also relates to an elastin fiber production promoter containing a pyrimidine nucleotide or its precursor as an active ingredient.
  • the term "fibrillin production promoter” is a concept that contains a pyrimidine nucleotide or a precursor thereof as an active ingredient, and includes the form of a composition that further contains other ingredients.
  • “external skin preparation” and “elastin fiber production promoter” refer to compositions containing pyrimidine nucleotides or their precursors as active ingredients, and further containing other ingredients. It is a concept that encompasses
  • pyrimidine nucleotide means cytidylic acid and/or uridylic acid.
  • Cytidylic acid (cytidine monophosphate, cytidine 5'-phosphate, CMP) is a compound indicated by CAS registration number 63-37-6. When described as cytidylic acid in this specification, salts of cytidylic acid are also included.
  • cytidylic acid when converted to cytidylic acid disodium salt (CMP, 2Na).
  • concentration (%) of the cytidylic acid solution it is assumed to be the mass volume percent concentration (w/v%) unless otherwise specified, and the mass of cytidylic acid is expressed as CMP, 2Na equivalent mass.
  • the mass is calculated as CMP, 2Na, based on the amount of cytidylic acid.
  • Uridylic acid (uridine monophosphate, uridine 5'-phosphate, UMP) is a compound indicated by CAS registration number 58-97-9. When described as uridylic acid in this specification, it is a concept that also includes salts of uridylic acid.
  • uridylic acid when converted to uridylic acid disodium salt (UMP, 2Na).
  • concentration (%) of uridylic acid it is assumed to be the mass volume percent concentration (w/v%) unless otherwise specified, and the mass of uridylic acid is expressed as UMP, 2Na equivalent mass.
  • the mass is calculated as UMP, 2Na, based on the amount of uridylic acid.
  • pyrimidine nucleotide precursor means a compound that can be metabolized to pyrimidine nucleotide, ie, cytidylic acid and/or uridylic acid. Whether or not a compound is included in the pyrimidine nucleotide precursor is determined by whether or not the compound is found to be converted into a pyrimidine nucleotide.
  • cytidine diphosphate, cytidine triphosphate, uridine diphosphate, and uridine triphosphate are known to be phosphorylated to cytidylic acid and/or uridylic acid by the action of kinases.
  • uracil A Orengo, “Regulation of enzymic activity by metabolites. I. Uridine-cytidine kinase of Novikoff ascites rat tumor”, J Biol Chem. 1969 Apr 25;244(8):2204-9.) is used herein. is exemplified as a pyrimidine nucleotide precursor.
  • the fibrillin production promoting effect of the present invention is evaluated by quantifying the amount of fibrillin-1.
  • a specific quantitative method will be described in Examples below.
  • the tactile firmness of the skin refers to the feeling when touching the skin, which is recognized from the elasticity when touched, the feeling of moistness when touched, and the feeling of firmness when touched.
  • Non-Patent Document 1 for the content indicated by the terms "visual firmness of the skin” and "tactile firmness of the skin.”
  • pyrimidine nucleotides or precursors thereof in the present invention include cytidine, cytosine, cytidylic acid, cytidine diphosphate, cytidine triphosphate, uridine, uracil, uridylic acid, uridyl diphosphate, and uridyl triphosphate. Illustrated. Among these, cytidylic acid and uridylic acid are preferred.
  • salts of cytidylic acid include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; basic amino acid salts such as arginine and lysine; ammonium salts and tricyclohexylammonium salts.
  • Ammonium salts such as salts; Various alkanolamine salts such as monoethanolamine salts, diethanolamine salts, triethanolamine salts, monoisopropanolamine salts, diisopropanolamine salts, and triisopropanolamine salts.
  • alkali metal salts such as sodium salts are preferred.
  • specific examples of the alkali metal salt include monosodium cytidylate and disodium cytidylate, with disodium cytidylate being preferred from the viewpoint of ease of handling.
  • salts of uridylic acid include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; basic amino acid salts such as arginine and lysine; ammonium salts and tricyclohexylammonium salts.
  • Ammonium salts such as salts; Various alkanolamine salts such as monoethanolamine salts, diethanolamine salts, triethanolamine salts, monoisopropanolamine salts, diisopropanolamine salts, and triisopropanolamine salts.
  • alkali metal salts such as sodium salts are preferred.
  • specific examples of the alkali metal salt include monosodium uridylate and disodium uridylate, with disodium uridylate being preferred from the viewpoint of ease of handling.
  • the active ingredient pyrimidine nucleotide or its precursor may be used alone, or the pyrimidine nucleotide or its precursor may be used as an active ingredient. More than one species may be used simultaneously, or a pyrimidine nucleotide or its precursor and other active ingredients may be used in combination.
  • the origin of the pyrimidine nucleotide or its precursor in the present invention is not particularly limited, and those derived from natural products such as yeast, bacteria, seafood, animals, and plants are suitable.
  • the fibrillin production promoter of the present invention can be used in oral preparations. Specifically, food and drink products, supplements, infant formula, enteral nutritional supplements, health food and drink products (including foods for specified health uses and foods with functional claims), additives for animal feed, and products for humans and non-human animals. It can be put to practical use as a medicine.
  • the fibrillin production promoter of the present invention is provided as a food or drink, a health food or drink, or a powdered milk
  • the active ingredient can be appropriately added to a known food or drink to produce a food or drink that has a fibrillin production promoting effect.
  • Targeted food and drink products include milk and dairy products, seasonings, beverages, confectionery, breads, noodles, oils and fats, processed meat products, processed seafood products, processed agricultural products, frozen foods, and instant foods. be able to.
  • a new food or drink having the effect of promoting fibrillin production can be produced by mixing pyrimidine nucleotides or their precursors into food or drink materials.
  • Various shapes of the target food and drink can be selected, including tablets, granules, capsules, powders, solutions, syrups, milks, and pastes.
  • various excipients, seasoning ingredients, etc. that can be used as foods may be added as appropriate.
  • the food/drink product may be provided and sold as a food/beverage product labeled with health uses such as the effect of promoting fibrillin production.
  • the act of "displaying” includes all acts to inform the consumer of the above-mentioned use, and if it is an expression that can recall or infer the above-mentioned use, the purpose of the display, the content of the display, the display Regardless of the object or medium used, all fall under the "display" act of this technology.
  • the "display" is expressed in such a way that the consumer can directly recognize the use. Specifically, the act of transferring, handing over, exhibiting for transfer or delivery, or importing food and drink products or products with the above-mentioned usage written on their packaging, advertisements related to products, price lists, or transaction documents. Examples include actions such as displaying or distributing information with the above-mentioned uses written thereon, or writing the above-mentioned uses on information containing these items and providing it by electromagnetic (Internet, etc.) method.
  • the display content is preferably a display approved by the government (for example, a display that has been approved based on various systems established by the government and is performed in a manner based on such approval). Further, it is preferable to attach such display contents to packaging, containers, catalogs, pamphlets, promotional materials at sales sites such as POP, and other documents.
  • the fibrillin production promoter of the present invention when put to practical use as a pharmaceutical for oral administration, a supplement, an enteral nutritional supplement, etc., the active ingredient can be formulated alone or in combination with a formulation auxiliary.
  • the form of the preparation may be a tablet, granule, capsule, granule, powder, solution, syrup, emulsion, or the like.
  • the formulation may contain any formulation auxiliary agents such as excipients, binders, disintegrants, lubricants, flavorings, solubilizing agents, suspending agents, and coating agents. , may be used in appropriate combinations depending on the respective delivery forms.
  • the amount of the active ingredient in the agent of the present invention varies from 0.1% to 30% ( W/W) may be selected as appropriate.
  • the amount of administration or intake of the orally administered agent of the present invention varies depending on the subject's age, body weight, severity of symptoms, administration or intake method, etc., but is appropriately selected within the range of about 1 mg to 800 g per day. do it. Furthermore, the amount of the orally administered agent of the present invention to be administered or ingested per time is preferably 1 to 5000 mg, more preferably 1 to 1000 mg.
  • the fibrillin production promoter of the present invention can also be put to practical use as a cosmetic composition or an external skin preparation.
  • the content of pyrimidine nucleotide or its precursor in the cosmetic composition or skin external preparation of the present invention is preferably 0.05 (w/v%) or more in that fibrillin production is promoted.
  • the content is more preferably 0.075 (w/v%) or more.
  • it is preferably 0.092 (w/v%) or more, more preferably 0.25 (w/v%) or more, and 0.5 (w/v%) or more, since fibrillin production is significantly promoted. It is more preferably at least 1.0 (w/v%), particularly preferably at least 1.0 (w/v%).
  • the content of the pyrimidine nucleotide or its precursor is preferably 10 (w/v%) or less.
  • the cosmetic composition or external skin preparation of the present invention may be prepared in various forms by combining pharmaceutically or cosmetically acceptable bases or carriers in addition to the above-mentioned components.
  • Conventionally known bases or carriers can be used as pharmaceutically or cosmetically acceptable bases or carriers.
  • the cosmetic composition or skin external preparation of the present invention may include various known products that are incorporated into external compositions applied to the skin or mucous membranes, such as cosmetics, external medicines, and quasi-drugs, as needed. Ingredients can be blended.
  • Such ingredients include, for example, surfactants, dyes (dyes, pigments), fragrances, preservatives, bactericides (antibacterial agents), thickeners, antioxidants, sequestering agents, cooling agents, deodorants, Moisturizers, UV absorbers, UV scattering agents, vitamins, plant extracts, skin astringents, anti-inflammatory agents, whitening agents, cell activators, vasodilators, blood circulation promoters, skin function enhancers, etc. can be mentioned.
  • surfactants include higher fatty acid soaps, alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfates, alkyl ether phosphate ester salts, N-acylamino acid salts, and acyl N-methyl taurine salts.
  • Anionic surfactants such as alkyltrimethylammonium chloride and dialkyldimethylammonium chloride; cationic surfactants such as alkyldimethylaminoacetic acid betaine, alkylamidodimethylaminoacetic acid betaine, 2-alkyl-N-carboxy-N-hydroxyimidazolinium Examples include amphoteric surfactants such as betaine; nonionic surfactants such as polyoxyethylene type, polyhydric alcohol ester type, and ethylene oxide/propylene oxide block copolymers. Further, surfactants belonging to polymer surfactants or natural surfactants can also be used without particular limitation.
  • preservatives include ethyl paraoxybenzoate, salicylic acid, and sorbic acid.
  • thickener include xanthan gum, sodium carboxymethylcellulose, and carboxyvinyl polymer.
  • sequestering agent include sodium salt of ethylenediaminetetraacetic acid, phosphoric acid, and citric acid.
  • humectants include polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, caronic acid, atelocollagen, sodium lactate, and bile salts. , dl-pyrrolidone carboxylic acid salt, short-chain soluble collagen, diglycerin (EO) PO adduct, Izayoirara extract, Yarrow extract, Melilot extract, and the like.
  • EO diglycerin
  • vitamins include vitamin A oil, retinol, retinol acetate, retinol palmitate, and other vitamin A; riboflavin, riboflavin butyrate, flavin adenine nucleotide, and other vitamin B2; pyridoxine hydrochloride, pyridoxine dioctanoate, etc.
  • Vitamin B6 types Vitamin C types such as L-ascorbic acid, L-ascorbic acid dipalmitate, L-ascorbic acid-2-sodium sulfate, dl- ⁇ -tocopherol-L-ascorbic acid phosphate dipotassium; pantothene Pantothenic acids such as calcium acid, D-pantothenyl alcohol, pantothenyl ethyl ether, and acetyl pantothenyl ethyl ether; Vitamin D such as ergocalciferol and cholecalciferol; Nicotine such as nicotinic acid, benzyl nicotinate, and nicotinamide Examples include acids; vitamin E such as dl- ⁇ -tocopherol, dl- ⁇ -tocopherol acetate, dl- ⁇ -tocopherol nicotinate, and dl- ⁇ -tocopherol succinate; vitamin P; biotin.
  • the cosmetic composition or external skin preparation of the present invention is used in the form of being applied to the skin (for example, by coating or spraying).
  • the cosmetic composition or external skin preparation of the present invention is used as a cosmetic, a topical drug, a topical quasi-drug, or the like.
  • cosmetics are preferred from the viewpoint of being able to promote fibrillin production on a daily basis.
  • Such cosmetics or external preparations include hair tonics or hair restorers, or various hair cosmetics such as shampoos, conditioners, and hair lotions (including tonics and liquids) that are effective for hair nourishment or hair growth.
  • the form of the cosmetic composition or skin external preparation of the present invention is not particularly limited as long as it can be applied to the skin or mucous membranes, such as paste, mousse, gel, liquid, emulsion, suspension.
  • examples include liquid, cream, ointment, sheet, aerosol, spray, and liniment forms.
  • examples include lotions; emulsions such as emollient emulsions, milky lotions, nourishing emulsions, and cleansing emulsions; creams such as emollient creams, massage creams, cleansing creams, and makeup creams.
  • hair products such as hair tonics and hair restorers
  • examples include tonics, hair creams, hair lotions, aerosols (sprays), mousses, shampoos, conditioners, and liquids.
  • the cosmetic composition or external skin preparation of the present invention can be used as a cosmetic, external medicine, or external quasi-drug by directly applying, spraying, or pasting it on the skin or mucous membrane.
  • the usage rate can be appropriately selected depending on the user (age, sex, intended use, severity of symptoms in the affected area, etc.) and is not particularly limited.
  • an effective amount for promoting fibrillin production may be administered transdermally to the skin from once to five times per day.
  • the amount of pyrimidine nucleotide or its precursor to be applied when applying the cosmetic composition or skin external preparation of the present invention is preferably 1 mg or more, more preferably 1 to 1000 mg, and 5 to 800 mg per application. More preferably, 10 to 500 mg.
  • the present invention has discovered a novel attribute that pyrimidine nucleotides promote fibrillin production, and this attribute allows pyrimidine nucleotides to be used alone as a new fibrillin production promoter.
  • This invention is based on the discovery that it is suitable for use.
  • One aspect of the present invention is an elastin fiber production promoter that promotes the production of elastin fibers.
  • the elastin fiber production promoter of the present invention can promote the production of elastin fibers through the promotion of fibrillin production.
  • the application amount and dosage of the elastin fiber production promoter can be the same as the application amount when applying the above-mentioned cosmetic composition or skin external preparation, and the dosage of the oral preparation.
  • the elastin fiber production promoter of the present invention has one or more effects selected from the following: improving the tactile firmness of the skin, treating pulmonary emphysema, preventing the progression of pulmonary emphysema, treating arteriosclerosis, and preventing the progression of arteriosclerosis through the promotion of fibrillin production. can be played.
  • a cosmetic composition or external skin preparation for promoting fibrillin production containing a pyrimidine nucleotide or its precursor as an active ingredient.
  • An orally administered agent for promoting fibrillin production containing a pyrimidine nucleotide or its precursor as an active ingredient.
  • [9] According to [7] or [8], which exhibits one or more effects selected from improving the tactile firmness of the skin, treating pulmonary emphysema, preventing the progression of pulmonary emphysema, treating arteriosclerosis, and preventing the progression of arteriosclerosis.
  • [13] A method of promoting fibrillin production in the skin by applying the cosmetic composition or skin external preparation according to [4] or [5] to the skin. [14] The method according to [13], wherein the cosmetic composition or the skin external preparation is applied in an amount of 1 to 1000 mg per time. [15] A method for promoting fibrillin production by orally administering the orally administered agent according to [7] or [8]. [16] The method according to [15], wherein the per-time dose of the orally administered agent is 1 to 5000 mg. [17] A method of promoting elastin fiber production by applying to the skin or orally administering the elastin fiber production promoter according to [10] or [11].
  • Example 1 Evaluation of fibrillin production promoting effect The fibrillin production promoting effect of pyrimidine nucleotides was evaluated.
  • the sample solutions included CMP, 2Na 0, 2.5, 5 (mM) (i.e., 0, 0.0918, 0.184 (w/v%)), and UMP, 2Na 0, 2.5, 5 (mM) (ie, 0, 0.092, 0.184 (w/v%)), respectively.
  • Normal human fibroblasts (NHDF; manufactured by Kurabo Industries, Ltd.) were seeded in a 96-well plate at a density of 2.55 ⁇ 10 4 cells/well/100 ⁇ L and cultured at 37° C. for 24 hours. Then CMP,2Na 0, 2.5, 5 (mM) (i.e. 0, 0.0918, 0.184 (w/v%)) and UMP, 2Na 0, 2.5, 5 (mM) ( That is, the medium was replaced with 100 ⁇ L of a medium (HuMedia-KG2; manufactured by Kurabo Industries, Ltd.) adjusted to 0, 0.092, 0.184 (w/v%)), and cultured for 24 hours.
  • a medium HuMedia-KG2; manufactured by Kurabo Industries, Ltd.
  • Figure 1 shows the results of quantifying the amount of fibrillin-1 when treated with cytidylic acid. The results of quantifying the amount of fibrillin-1 when treated with uridylic acid are shown in FIG.
  • Fibrillin production was promoted by addition of the culture supernatant of three-dimensionally cultured epidermis treated with pyrimidine nucleotides. Fibrillin production was also promoted by the addition of pyrimidine nucleotides. When cytidylic acid treatment and uridylic acid treatment were compared, the effects of promoting fibrillin production were comparable.
  • Example 2 Evaluation of mRNA expression level of collagen synthesis-related factors in fibroblasts using three-dimensional culture epidermal culture supernatant Quantification of mRNA expression level of Fibrillin1 (FBN1), an elastin synthesis-related factor, by real time PCR did.
  • FBN1 Fibrillin1
  • Three-dimensional cultured epidermis (LabCyte EPI MODEL 24 J TEC) was set in a 24-well plate to which 500 ⁇ L of the attached assay medium was added, and acclimatized overnight at 37°C. 50 ⁇ L of sample-containing PBS (-) was applied from the stratum corneum side and cultured for 24 hours. After removing the sample-containing PBS(-), it was washed with PBS(-). The medium was replaced with a fresh medium, 50 ⁇ L of sample-containing PBS (-) was newly applied from the stratum corneum side, and cultured for an additional 48 hours. After culturing, the culture supernatant was collected. The CMP and 2Na concentrations in each sample were 0, 1.0, and 2.0 (w/v%).
  • GPDH glyceraldehyde 3-phosphate dehydrogenase
  • Example 3 Ex vivo evaluation test using fresh human excised skin In order to evaluate the effect on actual skin with higher precision, an ex vivo evaluation test using fresh human excised skin was conducted.

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PCT/JP2023/013439 2022-03-30 2023-03-30 フィブリリン産生促進剤、化粧料組成物又は皮膚外用剤、経口投与剤、及びエラスチン線維産生促進剤 Ceased WO2023191016A1 (ja)

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EP23781024.7A EP4501333A4 (en) 2022-03-30 2023-03-30 FIBRILLIN PRODUCTION PROMOTER, COSMETIC COMPOSITION OR TOPICAL SKIN AGENT, ORALLY ADMINISTERED AGENT AND ELASTIN FIBER PRODUCTION PROMOTER
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