WO2023063118A1 - Inducteur ou activateur de macrophages m2 ou de type m2, procédé pour induire ou activer des macrophages m2 ou de type m2, composition pour prévenir et/ou améliorer la pigmentation dermique et procédé pour prévenir et/ou améliorer la pigmentation dermique - Google Patents

Inducteur ou activateur de macrophages m2 ou de type m2, procédé pour induire ou activer des macrophages m2 ou de type m2, composition pour prévenir et/ou améliorer la pigmentation dermique et procédé pour prévenir et/ou améliorer la pigmentation dermique Download PDF

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WO2023063118A1
WO2023063118A1 PCT/JP2022/036772 JP2022036772W WO2023063118A1 WO 2023063118 A1 WO2023063118 A1 WO 2023063118A1 JP 2022036772 W JP2022036772 W JP 2022036772W WO 2023063118 A1 WO2023063118 A1 WO 2023063118A1
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macrophages
extract
pigmentation
inducing
nicotinamide
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English (en)
Japanese (ja)
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聡 堀場
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株式会社 資生堂
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/14—Cupressaceae (Cypress family), e.g. juniper or cypress
    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9755—Gymnosperms [Coniferophyta]
    • A61K8/9761—Cupressaceae [Cypress family], e.g. juniper or cypress
    • 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
    • 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
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning 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
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

  • the present invention provides an agent for inducing or activating M2 or M2-like macrophages, a method for inducing or activating M2 or M2-like macrophages, a composition for preventing and/or improving dermal pigmentation, and dermal pigmentation. It relates to preventive and/or ameliorative methods.
  • the aging phenomenon of human skin can be broadly divided into “natural aging” and “photoaging”.
  • Photoaging is a phenomenon that is recognized site-specifically to light exposure, and is skin-specific.
  • the production of active oxygen and damage to DNA in cells are induced by the effects of UV rays and the like, which is thought to be the cause of phenotypes such as wrinkles and sagging due to damage to dermal fibrous tissue.
  • photoaging of the skin causes phenomena such as reduction of collagen fibers and degeneration of elastin elastic fibers.
  • melanocytes are also damaged, and a large amount of melanin pigment is produced, which causes spots and the like.
  • pigmentation such as spots and dullness is caused by the accumulation of melanin produced by melanocytes in the basal layer of the epidermis.
  • Melanin is normally present in the epidermis and basal layer, but since the epidermis turns over in a relatively early cycle, such melanin is easily excreted.
  • melanin may be present in the dermis layer for reasons such as melanin dropping into the dermis through gaps in the basement membrane. Since the turnover cycle of dermal cells is much slower than that of the epidermis, such melanin is often accumulated without being excreted. For these reasons, amelioration of dermal pigmentation is very difficult.
  • Patent Document 1 discloses a preventive or inhibitor of skin photoaging by preventing inhibition of leukocyte elastase.
  • Patent Document 2 discloses a photoaging inhibitor composition characterized by containing a plant extract of the genus Paphia of the family Amaranthaceae, which has a collagen synthesis-promoting action, and an animal-derived collagen peptide.
  • Non-Patent Document 6 proposes strengthening the basement membrane to prevent melanin from sinking into the dermis.
  • Patent Document 3 discloses an anti-aging cosmetic composition containing a compound that induces autophagy activation along with increased adiponectin expression. It has also been suggested that phagocytosis by macrophages is used to improve dermal pigmentation. In Patent Document 8, dermal blemishes are caused by attracting macrophages to fibroblasts that have taken up melanin that has fallen into the dermis and phagocytizing them. It discloses preventive/improving agents.
  • Macrophages are cells that are localized in various tissues in the body, trigger immune responses against foreign substances and pathogens, and are known to be involved in inflammation. Macrophages are differentiated into M1 type and M2 type from undifferentiated M0 macrophages (hereinafter sometimes abbreviated as M0). M1 macrophages (hereinafter sometimes abbreviated as M1) are known as inflammatory type, and M2 macrophages (hereinafter sometimes abbreviated as M2) are known as repair type (anti-inflammatory type). Imbalance in the balance between M1 macrophages and M2 macrophages has been reported to be associated with diseases such as obesity, type 2 diabetes, and arteriosclerosis (Patent Documents 4-6, Non-Patent Documents 1-5).
  • M1/M2 balance the balance of these M1 macrophages and M2 macrophages
  • regulation especially increasing the ratio of M2 macrophages to M1 macrophages, is particularly important in preventing and improving photoaging and pigmentation in the dermis. Therefore, the present inventors have searched for substances that can prevent and improve photoaging and/or dermal pigmentation using the M1/M2 balance as an index. It was also found that the eucalyptus extract has that effect.
  • An object of the present invention is to provide a new agent or method capable of inducing or activating M2 or M2-like macrophages, which has the effect of preventing and/or improving photoaging and/or dermal pigmentation.
  • the present inventors have extensively searched for an agent for preventing and/or improving photoaging and/or dermal pigmentation, and found that nicotinamide or a mixture of nicotinamide and succinicin extract reduces macrophages to M2. or can be induced or activated into M2-like macrophors. Based on such discoveries, the present invention has been developed. That is, the present invention includes the following aspects.
  • An agent for inducing or activating M2 or M2-like macrophages comprising nicotinamide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the inducing or activating agent according to item 1 which prevents and/or improves pigmentation in the dermis via the M2 or M2-like macrophages.
  • the inducing or activating agent according to item 1 or 2 which suppresses glycolysis of macrophages.
  • the inducing or activating agent according to any one of items 1 to 3 which promotes aerobic respiration of macrophages.
  • the inducing or activating agent according to any one of Items 1 to 4 further comprising a cakushinin extract.
  • a composition comprising nicotinic acid amide or a pharmaceutically acceptable salt thereof and a cinnamon extract.
  • a method for inducing or activating M2 or M2-like macrophages in a subject in need thereof comprising: A method comprising applying nicotinamide or a pharmaceutically acceptable salt thereof to said subject to induce or activate M2 or M2-like macrophages.
  • the method of item 7, wherein pigmentation in the dermis of the subject is prevented and/or improved via the M2 or M2-like macrophages.
  • the method according to any one of items 7 to 10 further comprising a cakushinin extract.
  • a method for preventing and/or improving dermal pigmentation in a subject in need thereof comprising: A method comprising applying to said subject a composition comprising nic
  • nicotinamide or a pharmaceutically acceptable salt thereof for the manufacture of a composition for inducing or activating M2 or M2-like macrophages.
  • the use according to item 13 which prevents and/or improves pigmentation in the dermis of a subject via the M2 or M2-like macrophages.
  • Use according to any one of items 13 to 16 further comprising a cakushinin extract.
  • M2 or M2-like macrophages which have the effect of preventing and/or improving photoaging and/or dermal pigmentation.
  • FIG. 1a shows a schematic of the induction method from THP-1 to M0, M1 and M2 macrophages.
  • FIG. 1b is a photomicrograph of M0, M1 and M2 macrophages induced from THP-1.
  • the upper diagram of FIG. 1c is a graph showing gene expression levels of cytokines (IL-1beta, TNF-alpha, IL-10) produced by M0, M1 and M2 macrophages induced from THP-1.
  • the lower figure in FIG. 1c is a graph showing the mRNA expression levels of cell surface markers (M1: CD86, M2: CD206) of M1 and M2 macrophages.
  • FIG. 2 shows the expression levels (marker/GAPDH value) of each marker of M1 and M2 when each concentration of Hakushinin extract (0.3 ppm, 1.0 ppm, 3.0 ppm) was added, compared with the control (Hakushinin hydrated It is a graph showing a relative value (%) when no decomposition: control) is taken as 100%.
  • Fig. 1 shows the expression levels (marker/GAPDH value) of each marker of M1 and M2 when each concentration of Hakushinin extract (0.3 ppm, 1.0 ppm, 3.0 ppm) was added, compared with the control (Hakushinin hydrated It is a graph showing a relative value (%) when no decomposition: control) is taken as 100%.
  • FIG. 3a shows that 30 ppm of unhydrolyzed Hakushinin (control) or 1.0 ppm or 3.0 ppm of Hakushinin hydrolyzate was added to immature (M0) THP-1 cells 30 days after addition of melanin. Shows how it looks after a minute.
  • FIG. 3b is an enlarged view of FIG. 3a. Black arrows indicate macrophages taking up melanin.
  • Figure 4 shows the intracellular activities of M0 macrophages, M1 macrophages and M2 macrophages in experiment 4 analyzed using a flux analyzer: (A) oxygen consumption rate (OCR), (B) extracellular acidification rate (ECAR). ) and (C) OCR/ECAR results.
  • OCR oxygen consumption rate
  • ECAR extracellular acidification rate
  • C OCR/ECAR results.
  • FIG. 5 shows the results of analysis using a flux analyzer in Experiment 5 on the effect of the addition of the Hakushinin extract on the intracellular activity of M0 macrophages 48 hours after addition.
  • A Normalized OCR
  • B Basal OCR (OCR value at the third point of A measurement).
  • FIG. 6 shows the results of analysis using a flux analyzer in Experiment 5 of the effect of the addition of the Hakushinin extract on the intracellular activity of M0 macrophages 48 hours after addition.
  • A Normalized OCR
  • FIG. 7 shows the results of analysis using a flux analyzer in Experiment 6 of the influence of typical unsaturated fatty acids contained in the extract of Hakushinin alone on the intracellular activity 48 hours after the addition of M0 macrophages.
  • Basal OCR Basal OCR
  • FIG. 8 shows the results of analysis using a flux analyzer in Experiment 7 of the influence of each component contained in the succinicin extract on the intracellular activity of M0 macrophages 24 hours after addition.
  • A Basal OCR,
  • FIG. 9 shows a schematic of the method of Experiment 8.
  • FIG. 10 shows the results of analysis using a flux analyzer in Experiment 8 on the influence of the extract of Chinese cucumber or each component contained in the extract on the intracellular activity during differentiation of M1 macrophages.
  • Basal OCR Basal OCR
  • B OCR of mitochondrial respiration
  • C OCR/ECAR
  • FIG. 11 shows the results of analysis of the intracellular activity of M0 macrophages 24 hours after addition of nicotinamide in Experiment 9 using a flux analyzer.
  • A Schematic of experiment 9,
  • B Basal OCR
  • C OCR of mitochondrial respiration
  • D OCR/ECAR
  • E normalized ECAR.
  • FIG. 12 outlines the method of Experiment 10.
  • FIG. 12 outlines the method of Experiment 10.
  • FIG. 13 shows the results of analyzing the intracellular activity 24 hours after addition of nicotinamide to M1-differentiating macrophages in Experiment 10 using a flux analyzer.
  • Basal OCR Basal OCR
  • B OCR of mitochondrial respiration
  • C OCR/ECAR
  • D normalized ECAR.
  • FIG. 14 outlines the method of Experiment 11.
  • FIG. 15 shows the results of analyzing the intracellular activity 24 hours after addition of nicotinamide to M2-differentiating macrophages in Experiment 11 using a flux analyzer.
  • C OCR/ECAR
  • D normalized ECAR.
  • FIG. 16 shows the results of analysis of intracellular activity 24 hours after addition of succinicin extract, nicotinic acid amide, or a mixture thereof (Mix) to M0 macrophages in experiment 12 using a flux analyzer.
  • A Schematic of experiment 12,
  • B OCR of mitochondrial respiration.
  • Fig. 17 shows the result of analyzing the intracellular activity of macrophages during M1 differentiation 24 hours after addition of cinnamon extract, nicotinamide, or a mixture thereof (Mix) using a flux analyzer in Experiment 13. indicates (A) Schematic of experiment 13, (B) OCR of mitochondrial respiration, (C) OCR/ECAR. Fig.
  • Macrophages are cells that are localized in various tissues in the body, trigger immune responses against foreign substances and pathogens, and are known to be involved in inflammation. Macrophages are differentiated into M1 type and M2 type from undifferentiated M0 macrophages (hereinafter sometimes abbreviated as M0). M1 macrophages (hereinafter sometimes abbreviated as M1) are known as inflammatory type, and M2 macrophages (hereinafter sometimes abbreviated as M2) are known as repair type (anti-inflammatory type).
  • M1/M2 balance the balance between these M1 macrophages and M2 macrophages
  • M1/M2 balance the balance between these M1 macrophages and M2 macrophages
  • the M1/M2 balance is particularly important in preventing and improving photoaging and pigmentation in the dermis. Therefore, the present inventors used the M1/M2 balance as an index to search for substances that can prevent and improve photoaging and/or dermal pigmentation. or can be activated, leading to the development of the present invention.
  • Hakushinin has been reported to have the effect of acting on fibroblasts to proliferate fibroblasts, promoting the production of collagen and hyaluronic acid, and suppressing the production of melanin (Patent Document 9 and 10).
  • nicotinic acid amide is known to have a blood circulation-promoting action, a rough skin-improving action, a whitening action, and the like (for example, Patent Document 12).
  • succinicin and nicotinamide can induce or activate repair-type M2 macrophages or M2-like macrophages, thereby adjusting/improving the M1/M2 balance. .
  • the present invention provides an agent for inducing or activating M2 or M2-like macrophages, comprising nicotinamide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the agent for inducing or activating M2 or M2-like macrophages according to the present invention can prevent and/or improve pigmentation in the dermis through M2 or M2-like macrophages induced or activated by the agent. .
  • the present invention provides a composition comprising nicotinamide or a pharmaceutically acceptable salt thereof and a cinnamon extract.
  • the present invention provides a method of inducing or activating M2 or M2-like macrophages in a subject in need thereof, comprising: A method is provided comprising applying nicotinamide or a pharmaceutically acceptable salt thereof to said subject to induce or activate M2 or M2-like macrophages.
  • the present invention provides a method for preventing and/or improving dermal pigmentation in a subject in need thereof, comprising: A method is provided comprising applying to said subject a composition comprising nicotinamide or a pharmaceutically acceptable salt thereof and a cinnamon extract.
  • the present invention also provides use of nicotinamide or a pharmaceutically acceptable salt thereof for producing a composition for inducing or activating M2 or M2-like macrophages.
  • the present invention also provides use of nicotinamide or a pharmaceutically acceptable salt thereof and succinicin extract for the manufacture of a composition for preventing and/or improving pigmentation in the dermis.
  • pigmentation refers to pigmentation in the dermis and epidermis, and includes, for example, pigmentation such as melanin due to photoaging, as well as artificially injected pigments (e.g., tattoos and tattoos). .
  • the present invention is effective for both the dermis and epidermis, it is highly expected as a countermeasure against dermal pigmentation in the sense that improvement methods are limited other than phagocytosis by melanophages. By applying the present invention, spots, dullness, dark circles, etc. due to pigmentation are improved.
  • the pigment since the pigment is injected into the dermis layer, it is effective for decolorizing tattoos, etc., which are difficult to remove once the pigment is put in.
  • induction or activation of M2 or M2-like macrophages refers to differentiation of macrophages (e.g., M0 macrophages or M1 macrophages) into M2 macrophages, or macrophages (e.g., M0 macrophages, M1 macrophages or M2 macrophages) were compared to intracellular activities possessed by M2 macrophages (e.g., promotion of aerobic respiration (mitochondrial respiration) and/or suppression of glycolysis (preferably, intracellular activity possessed by M1 macrophages). (case)) to induce or activate.
  • macrophages e.g., M0 macrophages or M1 macrophages
  • macrophages e.g., M0 macrophages, M1 macrophages or M2 macrophages
  • intracellular activities possessed by M2 macrophages e.g., promotion of aerobic respiration (mitochondrial respiration) and/or suppression of glycolysis (preferably,
  • M2 or M2-like macrophages may be to increase the absolute number of M2 or M2-like macrophages, the number of M1 or M1-like macrophages relative to the number of M2 or M2-like macrophages , that is, to decrease the ratio (M1/M2 balance).
  • M2-like macrophages refers to the intracellular activity of M2 macrophages (e.g., promotion of aerobic respiration (mitochondrial respiration) and/or suppression of glycolysis (preferably, intracellular activity of M1 macrophages). A macrophage that exhibits )) when compared to and does not necessarily match the marker of M2 macrophages.
  • M1-like macrophages refer to intracellular activities of M1 macrophages (e.g., suppression of aerobic respiration (mitochondrial respiration) and/or promotion of glycolysis (preferably, intracellular activities of M2 macrophages). When compared)), it refers to the macrophages shown and does not necessarily match the markers of M1 macrophages.
  • M1 macrophages can be measured using markers such as CD86, CD80, and iNOS as indicators.
  • M2 macrophages can be measured using markers such as CD206, CD163, Agr1, and the like, for example.
  • Overall macrophage markers, including M1 and M2, include CD11b, CD68, and the like.
  • M1 and M2 macrophages may be measured by quantifying M1-specific cytokines such as IL-1beta, TNF-alpha and M2-specific cytokines such as IL-10.
  • the marker is not limited to the above markers as long as the marker can measure the M1/M2 balance.
  • the M1/M2 balance may refer to the ratio of the number of M1 macrophages and/or M1-like macrophages to the number of M2 macrophages and/or M2-like macrophages as described above. , may refer to the ratio of the mRNA amount of M1 macrophage markers (eg, CD86, CD80, iNOS, etc.) to the mRNA amount of M2 macrophage markers (eg, CD206, CD163, Agr1, etc.). In photoaged skin, the ratio of M1 is high and the ratio of M2 is low, and it is M2 that has high melanophagocytosis.
  • M1 macrophage markers eg, CD86, CD80, iNOS, etc.
  • M2 macrophage markers eg, CD206, CD163, Agr1, etc.
  • the increase may be, for example, an increase with statistical significance (e.g., Student's t-test) with a significance level of 5%, and/or e.g., 1% or more, 5% or more, 10% or more,
  • the increase may be 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more.
  • the adjustment / improvement of the M1 / M2 balance is performed by adjusting the ratio of M2 to M1 (number of M2 / number of M1 and / or mRNA amount of M2 marker / mRNA amount of M1 marker) within a certain range, for example, about It may be 4/6 to about 9/1, about 5/5 to about 8/2, about 5/5 to about 7/3, etc., or it may be close to the above range. It may be maintaining within a range, or maintaining constancy around the above range.
  • the M1/M2 balance may refer to the balance between the intracellular activity of M1 macrophages and the intracellular activity of M2 macrophages, for example, the intracellular activity mainly used by M1 macrophages (e.g. state of glycolysis) and/or an index of intracellular activity (for example, state of aerobic respiration (mitochondrial respiration)) mainly used by M2 macrophages.
  • Intracellular activity can be assessed, for example, by measuring the cellular oxygen consumption rate (OCR value), extracellular acidification rate (ECAR value), or OCR/ECAR value.
  • increasing the ratio of M2 to M1 may refer to increasing intracellular mitochondrial activity primarily used by M2 macrophages, including, for example, M1 macrophages and M2 macrophages.
  • aerobic respiration mitochondrial respiration
  • mitochondrial respiration is elevated in the population (e.g., aerobic respiration (mitochondrial respiration) predominates in a population comprising M1 and M2 macrophages) and/or in a population comprising M1 and M2 macrophages
  • It may refer to a decrease in glycolytic activity, which is anaerobic respiration, e.g., elevated OCR values in a population comprising M1 and M2 macrophages and/or comprising M1 and M2 macrophages.
  • Intracellular activity can be measured by using, for example, an extracellular flux analyzer XFe24 (for 24well) manufactured by Agilent Technologies (formerly Seahorse Bioscience), which is the main energy metabolism pathway of cells, glycolysis, and aerobic respiration by mitochondria. It is possible to non-invasively and highly sensitively measure the state of cells over time, but this device is an example, and intracellular activity can be measured using any device and method for evaluation. Therefore, it is not limited to the use of the device.
  • the ratio of M1 is high and the ratio of M2 is low, and since it is M2 that is more melanophagocytic, the adjustment/improvement of the M1/M2 balance is likely to increase the intracellular activity of M2 relative to M1.
  • the ratio may be, for example, increasing OCR values in a population comprising M1 and M2 macrophages and/or decreasing ECAR values in a population comprising M1 and M2 macrophages.
  • increase or decrease may be, for example, an increase or decrease with a statistically significant difference (e.g., Student's t-test) with a significance level of 5%, and / or, for example, 1% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more increase or It may be a decrease.
  • a statistically significant difference e.g., Student's t-test
  • Hakushinin is a crude drug obtained by drying the seeds of Platycladus orientalis Franco, Thuja orientalis L., and Biota orientalis Endl. of the Cupressaceae family. Although it is preferable to use seed kernels (endosperm portion) as the hakushinin used in the present invention, whole seeds can also be used because active ingredients are contained in whole seeds. Hakushinin may be produced by a conventional method, or a commercially available product may be used.
  • the method for preparing the extract that can be used in the present invention can be produced with reference to known methods (eg, Patent Documents 9 and 10), but is not limited to these.
  • a method for preparing a cinnamon extract that can be used in the present invention a method of subjecting a plant extract obtained by extracting seeds of a plant to alkali treatment (hereinafter referred to as the first method);
  • a method hereinafter referred to as the second method of pulverizing the seeds of A. and maturing them for at least one week at a temperature of 10-35°C and a relative humidity of 20-90%.
  • the extraction solvent used in the first method and the second method may be any volatile solvent that is commonly used for extraction, particularly alcohols such as methanol and ethanol, hydrous alcohols, acetone, ethyl acetate, Polar/nonpolar organic solvents such as hexane and ether can be used alone or in combination, but acetone, ethyl acetate, and hexane are particularly preferred because they are inexpensive and can be easily concentrated under reduced pressure.
  • extraction with supercritical carbon dioxide gas can also be used.
  • an extraction solvent containing a large amount of water is not preferable because extraction of the active ingredient is suppressed.
  • extract for a certain period of time with a solvent that is 1 to 100 times, preferably 1 to 30 times, the mass of the seeds.
  • the seeds to be used can be appropriately pulverized as necessary, but may be used unpulverized if clogging becomes a problem during filtration. It is also possible to repeatedly extract with a small amount of solvent, and a reflux apparatus such as a Soxhlet may be used.
  • extraction can be performed under general conditions of around 40° C. and 20 to 40 MPa.
  • the extracts are hydrolyzed by alkaline treatment.
  • Alkaline treatment is carried out by adding 0.2 to 2 times the volume of concentrated alkaline aqueous solution to the extract after removal of the solvent, thoroughly stirring and mixing, and aging for about 30 minutes to several days.
  • the temperature during mixing is preferably room temperature to 70°C, more preferably 30 to 60°C. It is desirable to appropriately stir during aging so that the hydrophilic component and the lipophilic component do not separate.
  • the concentrated alkaline aqueous solution include aqueous solutions of NaOH, KOH, etc. having a concentration of 1 to 10N.
  • the oily substance will separate.
  • This oily substance has a very high anti-dermal pigmentation effect and is highly safe for the skin.
  • alcohol, acetone, etc. may be added as appropriate after the alkali treatment, and further operations such as decolorization, deodorization, desalting, and distillation may be added thereafter, if necessary.
  • the seeds are moderately pulverized or pressed in the pre-extraction stage, and then aged at around room temperature for a certain period of time.
  • the aging period there is no particular limitation as long as the desired effect can be obtained, but if the aging period is as short as one week or less, it will be difficult to obtain a sufficient whitening effect, and on the other hand if it lasts for several years, it will rot and deteriorate.
  • the problem of oxidative change of smell occurs, which is not preferable.
  • Extraction is performed using the extraction solvent and extraction method described above from the seeds that have matured in this way. After extraction, if necessary, operations such as solvent removal, decolorization, deodorization, and distillation are performed.
  • the extract obtained by pulverizing and ripening such a specific seed has the same anti-dermal pigmentation effect as the above-mentioned alkali-treated extract, but it is highly safe for the skin. show gender.
  • a plant-based, photoaging and/or safe anti-dermal pigmentation effect consisting of an extract prepared by the first method or the second method from the seeds of plants as shown above.
  • An agent for preventing and/or improving dermal pigmentation can be provided, and an external preparation for skin containing the present agent can be provided.
  • Nicotinic acid amide (CAS No. 98-92-0) is an amide compound of nicotinic acid, and is known to have effects such as promoting blood circulation, improving rough skin, and whitening. However, it has now been found by the inventors for the first time that nicotinamide can modulate the M1/M2 balance, eg induce or activate M2 or M2-like macrophages. Nicotinamide or a pharmaceutically acceptable salt used in the present invention may be an extract from a natural product or a product synthesized by a known method. For example, specifically, those listed in the 17th revision of the Japanese Pharmacopoeia can be used.
  • Pharmaceutically acceptable salts are inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, e.g. acetates, tartrates, citrates, fumarates, maleic acid salts, organic acid salts such as toluenesulfonates and methanesulfonates; metal salts such as sodium salts, potassium salts, calcium salts, aluminum salts such as triethylamine salts, guanidine salts, ammonium salts, hydrazine salts, and quinine salts; , salts with bases such as cinchonine salts, and the like.
  • inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, e.g. acetates, tartrates, citrates, fumarates, maleic acid salts, organic acid salts such as toluenesul
  • the agent of the present invention may be used in combination with any substance known to adjust/improve the M1/M2 balance, such as the substances described in Patent Documents 4 to 7.
  • the route of administration can also be arbitrarily selected, for example, transdermal administration, oral administration, subcutaneous administration, transmucosal administration, intramuscular administration, etc., and can be administered to a specific site on the skin to prevent and/or improve dermal pigmentation.
  • Transdermal administration may be preferred.
  • transdermal administration may be preferred so that the epidermis and dermis can be reached through the skin.
  • adjustment/improvement of the M1/M2 balance may be, for example, induction of differentiation into M2 macrophages, or any other M1/M2 balance adjustment/improvement method.
  • the agent or composition that can be used in the present invention adjusts/improves the M1/M2 balance, thereby suppressing photoaging and/or dermal pigmentation.
  • the M1/M2 balance adjusting/improving agent, anti-photoaging agent, anti-pigmentation agent, and anti-dermal pigmentation agent of the present invention (hereinafter collectively referred to as "the agent of the present invention") is the above Any one of the active ingredients may be contained alone, or two or more may be contained in any combination and ratio.
  • the agent of the present invention can also be a composition in which the above active ingredients are combined with one or more other ingredients such as excipients, carriers and/or diluents.
  • the composition and form of the composition are arbitrary, and may be appropriately selected according to conditions such as the active ingredient and application.
  • the composition can be produced by a conventional method in a formulation in which other ingredients such as excipients, carriers and/or diluents are appropriately combined according to the dosage form.
  • the agent of the present invention can be used for humans and animals by being blended into cosmetics or the like, or can be administered to humans and animals as a pharmaceutical formulation. In addition, it may be added to various foods, drinks, and feeds to be ingested by humans and animals.
  • the blending amount (dry mass) of the plant body or its extract depends on the type, purpose, form, method of use, etc. , can be determined accordingly. For example, 0.00001% to 50% of nicotinic acid amide or a pharmaceutically acceptable salt and/or a cinnamon extract (on a dry weight basis in the case of extracts or herbal medicines) can be blended in the total amount of the cosmetic.
  • ingredients that are usually used in external skin preparations such as cosmetics, pharmaceuticals, and quasi-drugs, such as antioxidants, oils, and UV protection agents, to the extent that they do not impair the effects of the present invention.
  • surfactants, thickeners, alcohols, powder components, coloring materials, aqueous components, water, various skin nutrients and the like can be appropriately blended as necessary.
  • the external preparation for skin of the present invention can be applied as cosmetics, quasi-drugs, etc., which are applied to the outer skin, particularly preferably as cosmetics, and its dosage form is not limited as long as it can be applied to the skin.
  • Arbitrary formulations such as solution system, solubilization system, emulsification system, powder dispersion system, water-oil two-layer system, water-oil-powder three-layer system, ointment, lotion, gel, and aerosol are applicable.
  • agent of the present invention When the agent of the present invention is used as cosmetics, lotion, emulsion, foundation, lipstick, lip balm, cleansing cream, massage cream, mask, hand cream, hand powder, body shampoo, body lotion, body cream, bath cosmetics, etc. You may use it as a form.
  • the forms that the agents and compositions of the present invention can take are not limited to the dosage forms and forms described above.
  • the agent or composition of the present invention may be used in combination with the device or method of the present invention or other devices or methods.
  • the subject to which the method, device, agent and composition of the present invention are applied is a subject in which skin photoaging and / or pigmentation (e.g., dermal pigmentation) is objectively or subjectively observed, even if it is a subject with pigmentation. It can also be a subject that one wishes to prevent. For example, it may be a subject determined to have an M1/M2 balance. In one embodiment, the subject may be determined to have a high degree of pigmentation (for example, degree of dermal pigmentation) using the M1/M2 balance in the skin as an index.
  • skin photoaging and / or pigmentation e.g., dermal pigmentation
  • it may be a subject determined to have an M1/M2 balance.
  • the subject may be determined to have a high degree of pigmentation (for example, degree of dermal pigmentation) using the M1/M2 balance in the skin as an index.
  • the subject may be concerned with phenotypes specific to photoaging of the skin, such as spots, wrinkles, sagging, etc., or epidermis and pigmentation, such as spots, dullness, bruises, tattoo marks, etc. may be a target of concern. Spots, wrinkles, sagging, dullness, bruises, tattoo marks, etc. can be determined by visual judgment or using known indices.
  • Cosmetic treatments include, but are not particularly limited to, any treatment that is believed to be effective in inhibiting photoaging and/or pigmentation, such as applying cosmetics containing the agent of the present invention or other ingredients.
  • Cosmetics refers to cosmetics that are applied to the skin, such as lotions, milky lotions, serums, creams, foundations, etc., but not limited to these, and is not intended to directly improve skin conditions. However, it is intended to include anything that is applied to the skin, including, for example, sunscreens and the like.
  • the cosmetic treatment may be applying physical stimuli to the skin, such as stretching stimuli, pressing stimuli, massages, and the like.
  • a cosmetic treatment may be a one-time treatment or an ongoing treatment over a period of days to weeks. The cosmetic treatment may be performed privately, or may be performed at a beauty salon, a cosmetics store, a beauty salon, or the like.
  • THP-1 M0, M1 and M2 Differentiation Induction THP-1 M0, M1 and M2 Differentiation Induction
  • THP-1 a human-derived cell line
  • RPMI1640 Nakalai
  • 1 mM Na Pyruvate Nakalai
  • 2 mM L-glutamine Nakalai
  • FBS FBS
  • 100 nM PMA abcam
  • the mRNA of each differentiated or undifferentiated cell is extracted, and realtime PCR is performed by TaqMan Gene expression assay using IL-1beta, TNF-alpha, and IL-10 probes (Applied Biosystems). , the expression level was quantified (Fig. 1c upper panel). Furthermore, using a CD86 antibody (R&D) and a CD206 antibody (BD), PCR was performed in the same manner to quantify the expression level (Fig. 1c, lower figure). Each value was corrected with the expression level of GAPDH mRNA.
  • macrophages differentiated by the above method produce inflammatory cytokines (IL-1beta, TNF-alpha) characteristic of M1 and anti-inflammatory cytokines (IL-10) characteristic of M2, respectively. It was shown to produce Furthermore, these differentiation-induced macrophages showed increased expression of CD86 and CD206, surface markers of M1 and M2 macrophages, respectively. These results confirmed that differentiation induction was successful. Therefore, M1 and M2 macrophages differentiated by the above method and undifferentiated M0 macrophages were used in the following experiments.
  • IL-1beta inflammatory cytokines
  • IL-10 anti-inflammatory cytokines
  • Experiment 2 Search for M1 suppressor/M2 inducer (1) Various M1/M2 markers were used to search for agents that could prevent and/or improve photoaging and/or dermal pigmentation by adjusting or improving the M1/M2 balance, and cakushinin had a strong M2-inducing effect. was found.
  • the extract used here (without hydrolysis or with hydrolysis) was prepared with reference to Japanese Patent No. 4781842 (Patent Document 9) and International Publication No. 2012/0571243 (Patent Document 10). and was prepared by the following procedure. It should be noted that the procedures for preparing the extracts of Chinese cinnamon that can be used in the present invention are not limited to those described below.
  • the THP-1 cells were used in the undifferentiated state of M0 and cultured overnight at 37°C. After that, 3 ppm of unhydrolyzed (without alkali treatment) hakushinin (control) dissolved in a solvent (DMSO), or 0.3 ppm, 1 ppm, or 3 ppm of hakushinin hydrolyzate was added, and the mixture was heated at 37°C. cultured overnight. Cells were harvested and RNA was extracted, the expression levels of CD86, CCR7, TNF-alpha, CD206, CD163, IL-10 and GAPDH were quantified by real-time PCR, and the expression level of each gene was divided by the expression level of GAPDH. bottom.
  • the hakushinin hydrolyzate concentration-dependently reduced the expression levels of the CD86 gene and TNF- ⁇ gene, and increased the expression levels of the CD206 gene and IL-10 gene. From this, it was found that the Hakushinin hydrolyzate has the effect of suppressing M1 induction and promoting M2 induction (Fig. 2).
  • the ratio of M1 increases due to photoaging, and the higher the ratio of M2, the higher the amount of skin collagen and the higher the pigment phagocytosis (Patent Document 11). It is suggested that the pigmentation inhibitory effect is high in the dermis.
  • Experiment 4 Intracellular activity of macrophages
  • the flux analyzer is a device that enables noninvasive and highly sensitive temporal measurement of the state of glycolysis, which is the main energy metabolism pathway of cells, and aerobic respiration by mitochondria.
  • Oligomycin ATP synthase inhibitor
  • FCCP uncoupler
  • rotenone mitochondriachondrial complex I inhibitor
  • antimycin A mitochondriachondrial complex III inhibitor
  • ECAR extracellular acidification rate
  • mitochondrial respiratory activity was high in the order of M2 macrophages, M0 macrophages, and M1 macrophages (Fig. 4).
  • M0, M1, and M2 differentiated from THP-1 were prepared in the same manner as in Experiment 1, and Hakushinin extract (Hakushinin hydrolyzate) (0.3 ppm, 1 ppm) prepared in the same manner as in Experiment 2 was added to M0. or 3 ppm) was added. After 48 hours of incubation, oxygen consumption rate (OCR) was measured with a flux analyzer. Each measured value was corrected by the cell number obtained by counting the cell nuclei stained by adding Hoechst (Fig. 5).
  • OCR oxygen consumption rate
  • Hakushinin extract is known to contain unsaturated fatty acids such as linolenic acid and juniperonic acid, which are ⁇ 3 fatty acids, and linoleic acid, which is ⁇ 6 fatty acid. It has been reported that unsaturated fatty acids (EPA, DHA) act on M1 inflammation-related genes to suppress inflammation (Non-Patent Document 8 (Cell Metab. 2017 Feb 7; 25(2): 412-427). ). Therefore, we investigated the effect of unsaturated fatty acids contained in the extract of Hakushinin on the intracellular activity of macrophages.
  • unsaturated fatty acids such as linolenic acid and juniperonic acid, which are ⁇ 3 fatty acids, and linoleic acid, which is ⁇ 6 fatty acid. It has been reported that unsaturated fatty acids (EPA, DHA) act on M1 inflammation-related genes to suppress inflammation (Non-Patent Document 8 (Cell Metab. 2017 Feb 7; 25(2): 412-4
  • M0 Basal OCR and mitochondrial respiration values were investigated when the incubation time was changed to 24 hours after the addition of the cinnamon extract or unsaturated fatty acids.
  • the experimental method was the same as the method described in Experiment 6, except that the incubation time after the addition of the cinnamon extract or the unsaturated fatty acid was changed to 24 hours.
  • M0 differentiated from THP-1 by the same method as in Experiment 1 was further induced to differentiate into M1. Changes in activity were analyzed using a flux analyzer (Fig. 9).
  • Mitochondrial respiration of macrophages during M1 differentiation was significantly increased by the extract of Hakushinin, but not by the unsaturated fatty acids contained in the extract of Hakushinin alone. It was suggested that there is a possibility that it is a specific effect due to the mixture of various components contained.
  • Experiment 9 Search for M1 suppressor/M2 inducer (2) As shown in Experiment 4 above, repair-type M2 macrophages have higher mitochondrial respiration than undifferentiated M0 macrophages and inflammatory M1 macrophages, and obtain energy through mitochondrial respiration. Inflammatory M1 macrophages depend on glycolysis for energy. Therefore, when searching for substances capable of inducing M2 or M2-like macrophages using intracellular activities (mitochondrial respiration and glycolysis) as indices, it was found that nicotinamide can significantly increase the mitochondrial activity of macrophages. (Fig. 11).
  • M0 was prepared by differentiation induction from THP-1, and nicotinamide (0 mM (control), 0.6 mM or 3.0 mM) was added to M0. After 24 hours of incubation, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured with a flux analyzer. Each count value was corrected by the cell number obtained by counting the cell nuclei stained by adding Hoechst.
  • OCR oxygen consumption rate
  • ECAR extracellular acidification rate
  • nicotinamide is a substance that can increase the oxygen consumption rate (OCR) that is characteristic of M0 macrophages and M2 or M2-like macrophages.
  • the oxygen consumption rate (OCR value) and the extracellular acidification rate (ECAR value) were measured using a flux analyzer 24 hours after the addition of nicotinamide. was measured.
  • the oxygen consumption rate (OCR value) and the extracellular acidification rate (ECAR value) were measured using a flux analyzer 24 hours after the addition of nicotinamide. was measured.
  • M0 was prepared by differentiation induction from THP-1, and Hakushinin extract (prepared in the same manner as in Experiment 2. 10 ppm), nicotinic acid amide (0.1 mM) or Hakushinin extract was added to M0. A mixture (10 ppm) and nicotinamide (0.1 mM) was added. After 24 hours of incubation, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured with a flux analyzer. Each count value was corrected by the cell number obtained by counting the cell nuclei stained by adding Hoechst.
  • OCR oxygen consumption rate
  • ECAR extracellular acidification rate
  • a succinicin extract prepared in the same manner as in Experiment 2. 10 ppm), nicotinic acid amide (0.1 mM), or a succinicin extract (10 ppm).
  • Oxygen consumption rate (OCR value) and extracellular acidification rate (ECAR value) were measured using a flux analyzer 24 hours after addition of nicotinamide (0.1 mM) mixture (mix).
  • nicotinamide and succinicin extract induce or activate M2 or M2-like macrophages, and as a result, modulate or improve the balance of M1/M2, thereby preventing photoaging and/or dermal pigmentation. It was suggested that it can be prevented and/or improved.

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Abstract

La présente invention concerne : un inducteur ou un activateur de macrophages M2 ou de type M2, comprenant en tant que principe actif du nicotinamide ou un sel pharmaceutiquement acceptable correspondant ; et un procédé pour induire ou activer des macrophages M2 ou de type M2 qui utilise ledit inducteur ou activateur.
PCT/JP2022/036772 2021-10-14 2022-09-30 Inducteur ou activateur de macrophages m2 ou de type m2, procédé pour induire ou activer des macrophages m2 ou de type m2, composition pour prévenir et/ou améliorer la pigmentation dermique et procédé pour prévenir et/ou améliorer la pigmentation dermique WO2023063118A1 (fr)

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Citations (7)

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Publication number Priority date Publication date Assignee Title
JPH0320207A (ja) * 1989-05-05 1991-01-29 Unilever Nv 皮膚化粧用組成物
JP2007176810A (ja) * 2005-12-27 2007-07-12 Kanebo Seiyaku Kk 美白用皮膚外用組成物
JP2007223944A (ja) * 2006-02-23 2007-09-06 Shiseido Co Ltd 植物性美白剤の製造方法、植物性美白剤および美白用皮膚外用剤
WO2012057123A1 (fr) * 2010-10-27 2012-05-03 株式会社 資生堂 Agent favorisant la production de collagène, agent favorisant la production d'hyaluronane, agent favorisant la prolifération de fibroblastes et agent antirides
JP2012519735A (ja) * 2010-07-22 2012-08-30 ザ プロクター アンド ギャンブル カンパニー 角化細胞のｐａｒ２活性化を阻害するための組成物及び方法
WO2020213743A1 (fr) * 2019-04-19 2020-10-22 株式会社 資生堂 Méthode et dispositif de prévention et/ou d'atténuation du photovieillissement et/ou de la pigmentation dermique, agent inhibiteur de photovieillissement et/ou de pigmentation dermique, méthode de criblage d'un agent inhibiteur de photovieillissement et/ou de pigmentation dermique, méthode d'évaluation d'un traitement cosmétique inhibiteur de photovieillissement et/ou de pigmentation dermique, et méthode d'évaluation du photovieillissement et/ou de la pigmentation dermique
JP2020183377A (ja) * 2019-04-26 2020-11-12 株式会社コーセー Ｓｖｃｔ発現促進剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0320207A (ja) * 1989-05-05 1991-01-29 Unilever Nv 皮膚化粧用組成物
JP2007176810A (ja) * 2005-12-27 2007-07-12 Kanebo Seiyaku Kk 美白用皮膚外用組成物
JP2007223944A (ja) * 2006-02-23 2007-09-06 Shiseido Co Ltd 植物性美白剤の製造方法、植物性美白剤および美白用皮膚外用剤
JP2012519735A (ja) * 2010-07-22 2012-08-30 ザ プロクター アンド ギャンブル カンパニー 角化細胞のｐａｒ２活性化を阻害するための組成物及び方法
WO2012057123A1 (fr) * 2010-10-27 2012-05-03 株式会社 資生堂 Agent favorisant la production de collagène, agent favorisant la production d'hyaluronane, agent favorisant la prolifération de fibroblastes et agent antirides
WO2020213743A1 (fr) * 2019-04-19 2020-10-22 株式会社 資生堂 Méthode et dispositif de prévention et/ou d'atténuation du photovieillissement et/ou de la pigmentation dermique, agent inhibiteur de photovieillissement et/ou de pigmentation dermique, méthode de criblage d'un agent inhibiteur de photovieillissement et/ou de pigmentation dermique, méthode d'évaluation d'un traitement cosmétique inhibiteur de photovieillissement et/ou de pigmentation dermique, et méthode d'évaluation du photovieillissement et/ou de la pigmentation dermique
JP2020183377A (ja) * 2019-04-26 2020-11-12 株式会社コーセー Ｓｖｃｔ発現促進剤

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