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WO2003053466A1 - Accelerateurs de reparation de la fonction barriere de la peau - Google Patents

Accelerateurs de reparation de la fonction barriere de la peau Download PDF

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Publication number
WO2003053466A1
WO2003053466A1 PCT/JP2002/012945 JP0212945W WO03053466A1 WO 2003053466 A1 WO2003053466 A1 WO 2003053466A1 JP 0212945 W JP0212945 W JP 0212945W WO 03053466 A1 WO03053466 A1 WO 03053466A1
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Prior art keywords
receptor
skin
recovery
function
substance
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PCT/JP2002/012945
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English (en)
Japanese (ja)
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Shigeyoshi Fujiwara
Mitsuhiro Denda
Kaori Inoue
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Shiseido Company, Ltd.
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Priority to JP2003554223A priority Critical patent/JPWO2003053466A1/ja
Publication of WO2003053466A1 publication Critical patent/WO2003053466A1/fr

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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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/7076—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 containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to a skin parer function recovery promoter containing an excitatory cell receptor agonist or an inhibitory cell receptor agonist, and a method for screening a substance having a skin parer function recovery promoting activity.
  • TEWL transepidermal water loss
  • NMF Natural Moisturizing Fac
  • Skin cells like nerve cells, consume energy and create potential differences inside and outside the cell membrane. This potential difference is mainly due to the opening and closing of Ca 2+ , Na + , and CI ion channels by various receptors on the cell surface.
  • Japanese Patent Application Laid-Open No. 2000-290135 discloses a Ca 2+ channel inhibitor or a metal salt having a Ca 2+ channel inhibitory action, for example, manganese salt, strontium Salt, lanthanum salt, cobalt salt, zinc salt, magnesium salt, iron salt, norium salt, jill thiazem and its salt, verapamil and its salt, difedipin and its It is disclosed that salt and the like can restore damaged skin barrier function in a very short time.
  • the present invention provides, in the first aspect, an agent for promoting the recovery of skin pariar function, which comprises an agonist of an excitatory cell receptor or an agonist of an inhibitory cell receptor.
  • the excitatory cell receptor is a glutamate receptor
  • ATP receptor ATP receptor
  • heat-stimulated receptor ATP receptor
  • adrenaline ⁇ 2 receptor ATP receptor
  • the glutamate receptor is an NMD A (N-methyl-D-aspartate) receptor.
  • the NMDA receptor antagonist is MK-801 (dizocilpine) or D-AP5 (D- (1-)-2-amimino 5-phosphonopentanoic acid).
  • the ATP receptor is P2X (capriogenic purino receptor), preferably a P2X3 receptor (modotropic purino receptor subtype 3).
  • the antagonist of the ATP receptor is suramin, PPADS (pyridoxal phosphate-16-azophenyl).
  • TNP-ATP trinitrophone ATP
  • the heat-stimulated receptor is VR-1 (vanilloid receptor subtype 1).
  • the VR-1 antagonist is capsazepine.
  • the antagonist of the adrenerin 32 receptor is ICI-118, 551 ((chi) -1-1_ [2,3-— (dihid mouth_7-methyl-1H— Indene 4- (yl) oxy] — 3 — [(1-methylethyl) amino] -12-butanol).
  • the inhibitory cell receptor is a GABA ( ⁇ -aminobutyric acid) receptor or a glycine receptor.
  • the GA receptor is a type I GAB receptor (a C1-channel-incorporated bicycline-sensitive receptor).
  • the agonist of the type A-GABA receptor is GABA, muscimol or isogpasin.
  • the skin barrier function recovery promoter is an external preparation for skin.
  • the present invention relates to a method for screening a skin-parallel function-recovery activity promoting substance, which comprises suppressing or suppressing the excitatory activity of an excitatory cell receptor.
  • Select a candidate substance that promotes inhibitory activity apply the substance to mammalian skin, and A substance that reduces the transepidermal water loss or a substance that reduces or suppresses the increase in the thickness of the skin subjected to dry stimulation.
  • the selection of a substance that suppresses the excitatory activity of the excitatory cell receptor or promotes the inhibitory activity of the inhibitory cell receptor is performed by selecting a substance that is a calcium ion or sodium ion in the cell. Or, evaluate the effect on chloride ion concentration.
  • the excitatory cell receptor is a glutamate receptor
  • An ATP receptor, a heat-stimulated receptor or an adrenaline j32 receptor, and the inhibitory cell receptor is a ⁇ -aminobutyric acid receptor or a glycine receptor.
  • the present invention relates to a method for screening a substance for promoting skin pariole function recovery activity, which comprises causing a substance which is a candidate for a skin parier function recovery activity promoter to act on a mammalian cell, and thereafter, It is intended to provide a method comprising measuring a chlorine ion concentration and selecting a substance which increases the intracellular chloride ion concentration as a substance promoting the recovery of the skin parer function.
  • human epidermal keratinocytes are used as the cells.
  • the present invention relates to a method of screening a substance for promoting skin pariole function recovery activity, which comprises causing a substance that is a candidate for a skin parier function recovery activity promoter to act on mammalian cells, and then in the cell.
  • Providing a method comprising measuring calcium or sodium ion concentration and selecting a substance which reduces the intracellular calcium or sodium ion concentration as a substance which promotes the recovery of skin barrier function. .
  • human epidermal keratinocytes are used as the cells.
  • the present invention relates to a method for improving skin, comprising: It is intended to provide a method characterized by applying a skin external preparation containing an agonist of an inciting cell receptor or an agonist of an inhibitory cell receptor to promote the recovery of the skin parier function.
  • FIG. 1 is a graph showing the relationship between D-glutamic acid, L-glutamic acid and L-aspartic acid and the recovery of skin parier function.
  • Fig. 2 is a graph showing the relationship between the excitatory receptors antagonist MK-801 and agonist NMDA and the recovery of skin paria function.
  • Fig. 3 shows that MK-801 and NMDA are simultaneously applied to the skin. It is a rough showing skin PARIA function recovery when applied.
  • FIG. 4 is a Draf showing the relationship between the excitatory receptor antagonist D—AP5 and the recovery of skin parier function.
  • FIG. 5 is a graph showing the relationship between the excitatory receptors antagonist MK-801 and agonist NMDA and the thickness of the skin subjected to the dry stimulus.
  • FIG. 6 is a graph showing the relationship between the excitatory receptors antagonist MK-801 and agonist NMDA and intracellular Ca 2+ concentration.
  • FIG. 7 is a graph showing the relationship between the excitatory receptor, an ionotropic ATP receptor P2X3, and skin barrier recovery.
  • Figure 8 shows the function of the skin barrier when suramin, PPADS, and TNP—ATP, the antagonists of the ionotropic ATP receptor excitatory receptor, are applied to the skin. It is a graph which shows recovery.
  • FIG. 9 is a graph showing the relationship between ptsazepine, which is an antagonist of the excitatory receptor VR-1, and cabsaicin, which is an agonist, and the recovery of skin paria function.
  • FIG. 10 is a graph showing the relationship between the antagonist and agonist of each of adrenalin j31 and ⁇ 2 receptors, which are excitatory receptors, and the recovery of the skin barrier function.
  • FIG. 11 is a graph showing the relationship between the type I GAB II receptor, which is an inhibitory receptor, and the recovery of skin parer function.
  • FIG. 12 is a graph showing the recovery of skin parier function when GABA, an inhibitory receptor agonist, and bicuclimetmet bromide, an agonist, are simultaneously applied to the skin.
  • FIG. 13 is a graph showing the relationship between the inhibitory receptor agonist GABA and antagonist BM and the thickness of the skin subjected to the dry stimulus.
  • FIG. 14 shows the inhibitory receptor agonist GABA and 4 is a graph showing the relationship between antagonist BM and intracellular C 1— concentration.
  • FIG. 15 is a graph showing the relationship between glycine receptors, which are excitatory receptors, which are inhibitory receptors, and skin barrier recovery.
  • FIG. 16 is a graph showing the relationship between the influx of chloride ions or calcium ions into cells and the recovery of skin barrier function.
  • FIG. 17 is a histological observation photograph showing the relationship between the influx of chloride ions or calcium ions into cells and the recovery of skin parer function.
  • A is the result of the control with only the acetone treatment (magnification X7,500)
  • B is the result of the C 1 -ionophore treatment (magnification X7,500)
  • D is the enlarged view of (B).
  • C is the result of Ca 2+ ionophore treatment (magnification X7,500)
  • E is an enlarged view of (C) (magnification X75,000).
  • excitatory cell receptor refers to a skin cell, i.e., a cell constituting the stratum corneum, epidermis, basement membrane, dermis, etc.
  • Excitatory receptor Such excitation is caused by the Ca 2+ and Na + ions flowing into the cells by binding of the agonist to the receptor.
  • excitable cell receptors that are currently found in skin cells include, for example, glutamate (NMDA) receptor, ATP receptor, heat-stimulated receptor, and adrenaline] 8 Receptor, acetylcholine • Nicotinic acid-like receptor, serotonin receptor and the like.
  • glutamate (NMDA type) receptor NMDA type receptor
  • ATP receptor ATP receptor
  • heat-stimulated receptor for example, VR-1, or adrenaline
  • the present invention is not limited to the above-mentioned excitatory receptors and the excitatory receptors presently present in skin cells, but extends to other receptors and receptors whose presence is to be found in the future. It is.
  • Antagonists of glutamate (NMDA type) receptor include MK_801, D-AP5, D-AP7, Conantokin T, (R) -CPP and the like. In the present invention, MK-801 or 0-5 is preferred.
  • Antagonists of the ATP receptor include suramin, PPADS, TNP-STP and the like.
  • Antagonists of VR-1 which is a thermal stimulus receptor include cabsazepine and the like.
  • Antagonists of nicotinic acid-like receptors include benzoquinodinum, conde 1 phine, ⁇ ; Antagonists of serotonin receptors include MDL-7222, Y-251300, metoclopramide and the like. It is to be understood that the present invention is not limited to the above-mentioned antagonists or antagonists of excitatory receptors presently present in skin cells, but also to other and future antagonists whose presence is to be found. .
  • the term "inhibitory cell receptor” refers to an inhibitory receptor present on the surface of cells constituting skin cells, for example, keratinocytes, that induces cells from an excited state to a suppressed state. Such suppression is caused by the entry of C1- into cells by binding of the agonist to the receptor.
  • Such suppressor cell receptors that are currently found in skin cells include, for example, GABA receptors, glycine receptors, and the like. It is to be understood that the present invention is not limited to inhibitory receptors present in skin cells at present, but extends to receptors found in the future.
  • GABA receptor agonists include GABA, muscimol, isogpasin, TACA or THIP, and the like.
  • Glycine receptor agonists include glycine, alanine, hypotaurine, serine, taurine and the like. In the present invention, glycine is preferred. It is to be understood that the present invention is not limited to the agonists described above and those of the inhibitory receptors presently present in skin cells, but also extends to other and future agonist receptors.
  • the effect of promoting the recovery of skin parer function can be evaluated by various methods.
  • the effect of tape stripping on the skin of mammals eg, humans, mice, rats, rabbits, etc.
  • the process of restoring the function of the damaged skin barrier to its original state is evaluated quantitatively or qualitatively by evaluating the amount of transepidermal water loss (TEWL) as an index.
  • TEWL transepidermal water loss
  • TEWL transdermal water loss
  • test sample at an appropriate concentration (eg, 1 mM) in an appropriate amount (eg, 100 ⁇ l) on an appropriate substrate, eg, plastic wrap, and affix it to the back of the mammal for an appropriate amount of time. After 5 minutes, remove it.
  • concentration eg, 1 mM
  • amount eg, 100 ⁇ l
  • the amount of water loss Measure TEWL is calculated by subtracting the TEWL value before the removal of the stratum corneum from the measured value at each time.
  • the recovery rate can be determined according to the following equation:
  • promoting the recovery of the skin barrier function means that the transepidermal water loss (TEWL) immediately after the tape stripping of the skin is 0% and the value before the tape stripping is 10%.
  • a value of 0% means that the value of TEWL at each measurement time clearly has a significant difference when compared with the control, and has an effect of promoting the ⁇ EWL recovery rate.
  • the skin is treated with a Cot ton ball impregnated with a 4% aqueous solution of sodium dodecyl sulfate (SDS) to make a judgment. different.
  • the effect of promoting the recovery of skin parrier function can also be determined based on the measurement of skin thickness.
  • a dry stimulus is applied to the skin, the skin tissue is damaged and the skin parrier function is reduced, and as a result, the thickness of the skin increases due to abnormal proliferation of epidermal cells. Therefore, a decrease in the function of skin Paria can be measured by histological observation of skin thickness.
  • Such a histological observation may be performed, for example, as follows. Mammals, preferably hairless mice, are bred in advance in dry conditions, for example in an environment at room temperature and a humidity of 10% or less, until the TEWL reaches a desired level, for example, about 2.5 to 3.5 mg / cni 2 / h.
  • the test substance is dropped on the treated skin, and after that, the skin is cultivated in the above-mentioned environment for an appropriate time to give a dry stimulus, and then the skin of the treated portion is collected, and the skin sample is stained or the like.
  • the thickness of the epidermis is measured by microscopic observation.
  • the agonist of the excitatory cell receptor or the agonist of the suppressive cell receptor according to the present invention significantly promotes the recovery of the skin pariar function, thereby significantly suppressing abnormal epidermal proliferation caused by dry stimulation. However, it can even reduce the thickness of the skin.
  • a method for screening the substance for promoting skin PAR recovery is to select a substance that is a candidate for an agonist of an exciting cell receptor or an agonist of an inhibitory cell receptor, and apply the substance to mammalian skin. This can be achieved by selecting a substance that reduces the transepidermal water loss of the skin.
  • the excitatory receptor binds to the agonist and causes the influx of Ca 2+ and Na + ions into the cell, thereby inducing the cell to an excitable state
  • the receptor binds the agonist to the cell, causing the influx of C 1 -ions into the cell, and inducing the cell from an excited state to a suppressed state.
  • Antagonist an excitatory receptor
  • Antagonist has the opposite effect to agonist, i.e., it causes a decrease in intracellular Ca 2+ and Na + ions, so the candidate substance is intracellular Ca2 + or Na +. It can be selected by evaluating the decrease of the ion and the increase of the C1-ion.
  • candidate substances include an increase in intracellular C 1 -ion, Ca 2+ and It can be selected by evaluating the decrease in Na + ion.
  • the concentration of intracellular Ca 2+ , Na + ions, and CI ions can be measured by conventional methods.
  • a method for screening receptor agonists by assessing calcium ion concentration on the cell surface is described. Specifically, in this application, it is a stimulus receptor on the surface of epithelial cells.
  • VR1 receptor vanilloid receptor subtype 1
  • P2X receptor agonists increase intracellular calcium ion concentration.
  • a method for screening the agonist of the receptor by evaluating the increase in the calcium ion concentration in epithelial cells due to the effect of a test substance is disclosed.
  • a predetermined quinoline derivative is often used as an indicator of cr ion.
  • Such a quinoline derivative is used as an indicator of cr ion based on its decay-causing function of fluorescence due to the presence of a haptogenide ion.
  • Such quinoline derivatives include SPQ (6-Methoxy-N- (3-sulfopropyl) quinolinium 'monohydrate) and MQA E (N-Ethoxycarbonylmethyl-6-methoxyquinodium bromide).
  • DiH—MEQ (6-Methoxy N-ethylquinoline iodide) and the like.
  • DiH-MEQ is available from Molecular Probes as its oxidized form, MEQ (6-Methoxy-1-N-ethylquinoline). Therefore, for example, selection of a test substance that is a candidate for an antagonist of the excitatory cell receptor or an agonist of the inhibitory cell receptor is performed by evaluating the intracellular calcium ion concentration as described below. be able to.
  • epidermal cells for example, epidermal keratinocytes
  • a suitable cell culture medium for example, KGM medium according to a conventional method.
  • the day before the measurement of calcium ion inoculate the cultured cells into a 96-well plate at an appropriate cell concentration (for example, about 2 ⁇ 10 5 cells / well).
  • an appropriate cell concentration for example, about 2 ⁇ 10 5 cells / well.
  • an appropriate buffer for example, BBS (Balanced salt solution) and a calcium-sensitive fluorescent dye, for example, Fluo 3-AM (Dainippon Pharmaceutical) are added to the cultured epidermal keratinocytes (for example, Incubate (for example, at 37 ° C for 60 minutes) under appropriate conditions, and transfer this fluorescent dye into the above cultured keratinocytes. Is taken.
  • Other pigments include calcium-sensitive fluorescent dyes such as Quin 2, Quin 2—AM, Fura_2, Fura-2_AM, Indo—l, Fluo-3, Rhod-2.
  • a calcium-sensitive photoprotein such as E. coli or a reagent used for nuclear magnetic resonance with 19 F such as 5-FBAPTA may be used.
  • the cells are washed, freshly buffered with the same buffer (BBS) is added, and the mixture is allowed to stand (for example, 15 minutes). Thereafter, the buffer is removed from the cultured epidermal keratinocytes, and a test substance dissolved in the same buffer is added to the cells to stimulate the cells. As a control, add the same buffer in which the test substance is not dissolved to the cells.
  • BBS buffered bovine serum
  • Fluorescence is measured in a conventional manner using a fluorescence microplate reader at excitation and emission wavelengths corresponding to the colorants, for example, over time.
  • the intracellular calcium ion concentration can be calculated according to the following equation.
  • F nin Fluorescence value of dye when EDTA is added and Ca 2+ is blocked (minimum fluorescence intensity)
  • F max fluorescence values of the dye in the excess presence of C a 2+ (Yabu ⁇ cell membranes Ri by the surfactant) (the maximum fluorescence intensity)
  • the test substance is expected to be an agonist of an excitatory cell receptor or an agonist of an inhibitory cell receptor.
  • test substance that is a candidate for an agonist of an excitatory cell receptor or an agonist of an inhibitory cell receptor is performed by using, for example, DiH-MEQ as described below. It can also be done by evaluating the concentration.
  • Stimulation of cells with a test substance can be performed in the same manner as described for the evaluation of intracellular calcium concentration.
  • DiH-MEQ (6-Methoxy-N-ethylquinoline iodide), in a suitable physiological buffer (eg PBS) and fill it with 25-50 ⁇ 5 DiH-MEQ.
  • a suitable physiological buffer eg PBS
  • DiH—MEQU can be prepared as described in Molecular Probes, Inc., Molecular Probes Product Information (Revised January 31, 2001) MP06886.
  • DiH-MEQ may be prepared in DMSO (dimethylsulfoxide) into a concentrated stock solution (25-50 mM), and the stock solution may be diluted in physiological buffer.
  • test substance is expected to be a candidate for the agonist of the excitatory cell receptor or the agonist of the inhibitory cell receptor.
  • the substance selected as the agonist of the excitatory cell receptor or the agonist of the inhibitory cell receptor selected in this manner was subjected to the above-mentioned effect of promoting the recovery of skin parier function, thereby reducing the amount of transdermal water loss.
  • Antagonists of excitatory cell receptors and agonists of inhibitory cell receptors can be screened by selecting substances that reduce or suppress the increase in the thickness of the skin subject to the dry stimulus. You can lean.
  • the substance for promoting recovery of the function of the skin paria of the present invention that is, the agonist of the excitatory cell receptor or the agonist of the inhibitory cell receptor is, for example, an ointment, a cream, an emulsion, a lotion, a pack, a bath agent, etc. It can be incorporated into cosmetics, pharmaceuticals, and quasi-drugs, and can be applied to the skin, preferably as an external preparation for skin.
  • the blending amount is not particularly limited, but based on the total amount of these bases, 0.001 mM to: LM, preferably 0.01 to: L 0 0 mM, more preferably 0.1 to: L will be around 0 mM.
  • the effect of promoting the recovery of skin pari function was based on the skin pari function destroyed by applying tape stripping to the skin of hairless mice (Type HR-1, HOSHINO, Japan).
  • the process of recovery to the state was evaluated using the transepidermal water loss (TEWL) as an index, as follows.
  • T EWL transepidermal water loss
  • ME ECO water loss measuring device
  • the value at this time is assumed to be a TE WL recovery rate of 100%.
  • the skin is destroyed by peeling off the stratum corneum of the hairless mouse using cellophane tape. At this time, this operation is repeated until the value of TEWL becomes approximately 800 to 900.
  • the value obtained by subtracting the measurement value before peeling off the stratum corneum from the measurement value after peeling off the stratum corneum is defined as the deepest damage state, that is, the recovery rate of 0%.
  • test sample placed on a plastic wrap at 100 ⁇ m with ImM, affix it to the back, and peel it off after 5 minutes.
  • the recovery rate is calculated according to the following formula:
  • D-, L-glutamic acid and L-aspartic acid are known to be neurotransmitters that bind to glutamate receptors in vivo and exert a neuroexcitatory action.
  • D-glutamic acid promotes the recovery of skin pallia
  • L-glutamic acid and L-aspara Formic acid delayed skin recovery. Therefore, it was suggested that glutamate receptor, which is an excitatory receptor, is involved in the recovery of paria from skin.
  • Antagonist MK-801 promotes skin barrier recovery, while agonist NMDA slows the recovery of the barrier.
  • Antagonist MK-801 an excitatory acid receptor having the effect of promoting the recovery of skin function on skin, on the skin thickness was observed histologically.
  • Hairless mice were bred in advance in an environment at a temperature of 22 to 25 ° C and a humidity of 10% or less.
  • the barrier on the back skin of the hairless mouse was destroyed using acetone until the TEWL became 2.5 to 3.5 mg / cm 2 / h.
  • an aqueous solution of MK_801, NMDA or AMPA ( ⁇ -amino-3-hydroxy-15-methinole-4-isoxazolepropionic acid) in 200 mM was dropped on the skin 200 ⁇ l each, Thereafter, the skin was bred in the above environment for 48 hours to give a dry stimulus, and the skin of the treated portion was collected.
  • ⁇ ⁇ is a ligand specific to the ionotropin glutamate receptor, similar to NMDA.
  • the control is uncoated with any solution.
  • the results are shown in Fig. 5.
  • the results in Fig. 5 show that the application of 8-801 significantly reduces the thickness of the skin compared to the control, and thus the antagonist of the excitatory acid receptor It was demonstrated that ⁇ -801 significantly suppressed the abnormal epidermal proliferation caused by the dry stimulus and improved the skin parrier effect.
  • AMP A like NMDA, is a ligand specific for the ionotropic glutamate receptor, but does not significantly increase skin thickness compared to control. It was shown to behave differently from NMDA.
  • NHEK Normal human epidermal keratinocytes
  • Humedia — KB 2 Humedia — KB 2 (Kurabo Co., Ltd.) containing drocortisone (0.5 ⁇ g / ml), gentamicin (50 ⁇ g / ml) and amphotericin-I B (50 ng / ml)
  • the culture medium of cells grown on force glass was first replaced with a BSS buffer of the following composition: (all in mM) NaCl 150; KC 15; CaCl 2 1.8; MgCl 2 1.2; N_2- Hydroxicetyl piperazine-N 2-ethanesulfonic acid (HEPES) 25; D-glucose 10 (pH 7.4) 0
  • the cells were converted to 5 ⁇ M dye fura-2 acetomethyl methyl ester (fur a-2AM) (molecular
  • the cells were loaded with fura-2 by incubating in BSS for 45 minutes at room temperature (20-22 ° C) at room temperature (Probes). The cells were then washed with BSS buffer and incubated for a further 15 minutes to deesterify the loaded dye.
  • the BSS buffer was removed from the cells, and a test substance (NMDA or MK-801 + NMDA: lmM, respectively) dissolved in the buffer was added to the cells, and the cells were tested for about 30 minutes. The substance was stimulated.
  • a test substance NMDA or MK-801 + NMDA: lmM, respectively
  • the cover glass was mounted on an inverted fluorescence microscope (TMD-130; Nikon) equipped with a 75 W xenon lamp and a band pass filter of 34O and 36OnM, and the measurement was performed at room temperature.
  • the image data was recorded using a high-sensitivity silicon intensifier and target camera (C-2741-08; Hamamatsu Photonitas Co., Ltd.), and a Ca 2+ analysis system (Full Sawa Laboratories Appliance) And prayed for each other.
  • Figure 6 shows the results.
  • NMDA-type glutamate receptor agonist NMDA exerts an effect of significantly increasing the intracellular Ca 2+ concentration. It was also suggested that antagonist MK-801 offset such effects of NMDA, and that MK-801 significantly reduced intracellular Ca 2+ concentration. Therefore, it was demonstrated that the test substance can be identified in vitro as an excitatory receptor agonist or antagonist through measurement of increase and decrease of intracellular Ca 2+ concentration. Was done.
  • thermoreceptor VR-1 Evaluation of the relationship between thermoreceptor VR-1 and recovery of skin paria function
  • a mixed aqueous solution of Samoterol hemi-fumarate and betataxol hydrochloride hemihydrate (ImM each) was applied to the skin of hairless mice as described in the above test method, and a TEWL test was performed.
  • procaterol hydrochloride (Tocris) aqueous solution (ImM), which is an agonist of the drenerin ⁇ 2 receptor
  • IC 1-118,551 (Tocris) aqueous solution (1 mM)
  • a mixed aqueous solution (1 mM each) of ICI-118 and 551 with hydrochloric acid and potassium hydroxide was applied to the epidermis of hairless mice as described in the above test method, and a TEWL test was performed.
  • GABA receptor is an inhibitory neuronal receptor and has a C1-channel.
  • Bicucliline-sensitive A-type GABA
  • G-protein coupled B-type GABA
  • C-type GAB A C-type GAB A
  • Hairless mice were bred in advance in an environment at a temperature of 22 to 25 ° C and a humidity of 10% or less.
  • the barrier on the back skin of the hairless mouse was ruptured using acetone until the TEWL became 2.5 to 3.5 mg / cm 2 / h.
  • a 1 mM aqueous solution of GABA, a mixed aqueous solution of GABA and BM (ImM each), or water was added dropwise to the skin at 200 ⁇ each, and then raised for 48 hours in the above environment. After applying the dry stimulus, the skin of the treated area was collected.
  • GABA GABA receptor agonist
  • BM BM
  • C 1 -imaging was performed by dissolving DiH—MEQ (Molekiura Iprobe) in PBS to prepare a 25-50 solution of 0111—1 ⁇ £ Q.
  • DiH-MEQ was prepared as described in Molecular Probes Product Information (Revised January 31, 2001) MP06886 from Molecular Probes' MEQ force. If necessary, prepare DiH-MEQ into a concentrated stock solution (25-50 mM) using DMSO (dimethylsulfoxide), and transfer the stock solution to physiological buffer. May be diluted.
  • the cells are incubated with the DiH-MEQ-filled solution for 5 minutes, then GABA or GABA + BM (1 mM aqueous solution each) is added to the cells, and the cells are incubated for about 5 minutes. Incubation.
  • This example demonstrates the relationship between the influx of various ions into cells and the recovery of skin paria function.
  • C 1 -ionophore chloride ionophore 1 (Fluka, Switzerland) or Ca 2 + ionophore (ionomycin) (Wako Pure Chemical Industries, Ltd.) was used as described in the above test method and the skin of hairless mice And subjected to a TEWL test.
  • Figure 16 shows the results.
  • C 1 -ionophore is a compound that promotes the influx of chloride ions into cells.
  • the skin parrier function was significantly restored in the skin of mice treated with C 1 -ionophore as compared to the case where only control (water) was applied. Therefore, it was clarified that the influx of chloride ions into cells restored the function of the skin barrier, and by measuring the increase or decrease of intracellular C1-concentration, the substance that promotes the recovery of skin function was in vitro. It has been confirmed that ro can be screened.
  • hairless mice were raised in advance in an environment at a temperature of 22 to 25 ° C and a humidity of 10% or less, as in Example 8, until the TEWL reached 2.5 to 3.5 mg / cm 2 / h. and Yabu ⁇ the path Ria one hairless mouse dorsal skin with seton, then CI - droplet 1 mu Micromax aqueous or C a 2 + Ionofoa of 1 mu Micromax aqueous solution to 2 0 0 ⁇ 1 skin respective Ionofoa After that, the animals were bred for 48 hours in the above environment to give a dry stimulus, and then the skin of the treated portion was collected.
  • FIG. 17 (A) shows the result of the control with only the acetate treatment (magnification X7,500), (B) shows the result of the C 1 -ionophore treatment (magnification X7, 500), and (D) shows the result. (B) Magnified view (magnification X75,000), (C) Ca2 + ionophore treatment result (magnification X7,500), (E) Magnified view of (C) (magnification ⁇ 75,000) Is shown.
  • the stratum corneum that prevents the loss of water from living organisms in mammals.
  • the stratum corneum is constantly renewed, and in healthy skin these structures continue to form without interruption.
  • the lamellar granules containing lipids are formed in the granular layer, and lipids inside the lamellar granules are released extracellularly by exocytosis as the cells become keratinized, forming a layered structure of lipids in the intercellular space (Mitsuhiro Denda) , "Skin" Vol. 41, No. 5, pp. 518-523, October 1999).
  • the lipid layer is a major component of the stratum corneum, which is responsible for the function of the skin paria. The thicker the lipid layer, the higher the parier function.
  • FIG. 18 shows (A) the control in which only acetone was treated in FIG.
  • the agonist of the excitatory cell receptor and the agonist of the inhibitory cell receptor are effective in promoting the recovery of the skin parrier function. According to the present invention, there is provided a novel and effective skin barrier function recovery promoter.

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Abstract

L'invention concerne des accélérateurs de réparation de la fonction barrière de la peau contenant un antagoniste de récepteurs de cellules d'excitation ou un agoniste de récepteurs de cellules régulatrices, ainsi qu'un procédé de criblage d'une substance ayant pour effet d'accélérer la réparation de la fonction barrière de la peau.
PCT/JP2002/012945 2001-12-13 2002-12-11 Accelerateurs de reparation de la fonction barriere de la peau WO2003053466A1 (fr)

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Cited By (6)

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JP2003342195A (ja) * 2002-05-28 2003-12-03 Shiseido Co Ltd 不全角化抑制剤、毛穴縮小剤及び皮膚外用剤
WO2008046788A1 (fr) * 2006-10-18 2008-04-24 Unilever Plc Compositions cutanées bénéfiques contenant un antagoniste du récepteur vanilloïde
WO2008114732A1 (fr) * 2007-03-16 2008-09-25 Shiseido Company Ltd. Agent de prévention et de modification des rides
JP2014185141A (ja) * 2013-02-22 2014-10-02 Mikimoto Pharmaceut Co Ltd インボルクリン産生促進剤、皮膚角化促進剤
CN116617199A (zh) * 2023-06-20 2023-08-22 华熙生物科技股份有限公司 γ-氨基丁酸在预防和/或改善由热刺激导致的相关细胞改变的用途及实现该用途的方法
CN117442598A (zh) * 2023-12-25 2024-01-26 天津嘉氏堂科技有限公司 硝酸酯类化合物在制备改善敏感肌表皮屏障产品中的应用

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003342195A (ja) * 2002-05-28 2003-12-03 Shiseido Co Ltd 不全角化抑制剤、毛穴縮小剤及び皮膚外用剤
WO2003099327A1 (fr) * 2002-05-28 2003-12-04 Shiseido Company, Ltd. Inhibiteur de la parakeratose, agent de resserrement des pores et preparation de la peau aux fins d'utilisation externe
WO2008046788A1 (fr) * 2006-10-18 2008-04-24 Unilever Plc Compositions cutanées bénéfiques contenant un antagoniste du récepteur vanilloïde
WO2008114732A1 (fr) * 2007-03-16 2008-09-25 Shiseido Company Ltd. Agent de prévention et de modification des rides
US8173705B2 (en) 2007-03-16 2012-05-08 Shiseido Company Ltd. Agent for alleviating wrinkles
JP5501758B2 (ja) * 2007-03-16 2014-05-28 株式会社 資生堂 しわ防止・改善剤
KR101560840B1 (ko) 2007-03-16 2015-10-15 가부시키가이샤 시세이도 주름 방지·개선제
JP2014185141A (ja) * 2013-02-22 2014-10-02 Mikimoto Pharmaceut Co Ltd インボルクリン産生促進剤、皮膚角化促進剤
CN116617199A (zh) * 2023-06-20 2023-08-22 华熙生物科技股份有限公司 γ-氨基丁酸在预防和/或改善由热刺激导致的相关细胞改变的用途及实现该用途的方法
CN117442598A (zh) * 2023-12-25 2024-01-26 天津嘉氏堂科技有限公司 硝酸酯类化合物在制备改善敏感肌表皮屏障产品中的应用
CN117442598B (zh) * 2023-12-25 2024-03-12 天津嘉氏堂科技有限公司 硝酸酯类化合物在制备改善敏感肌表皮屏障产品中的应用

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