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WO2010123102A1 - Promoteur de production de collagène, agent anti-photovieillissement, agent améliorant la rétention d'humidité et composé s'utilisant sur la peau - Google Patents

Promoteur de production de collagène, agent anti-photovieillissement, agent améliorant la rétention d'humidité et composé s'utilisant sur la peau Download PDF

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Publication number
WO2010123102A1
WO2010123102A1 PCT/JP2010/057244 JP2010057244W WO2010123102A1 WO 2010123102 A1 WO2010123102 A1 WO 2010123102A1 JP 2010057244 W JP2010057244 W JP 2010057244W WO 2010123102 A1 WO2010123102 A1 WO 2010123102A1
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Prior art keywords
group
skin
general formula
substituent
collagen production
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PCT/JP2010/057244
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English (en)
Japanese (ja)
Inventor
勲 湯浅
明子 小島
潤 平竹
立友 韓
Original Assignee
Yuasa Isao
Kojima Akiko
Hiratake Jun
Han Liyou
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Application filed by Yuasa Isao, Kojima Akiko, Hiratake Jun, Han Liyou filed Critical Yuasa Isao
Publication of WO2010123102A1 publication Critical patent/WO2010123102A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61P17/16—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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • 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
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

Definitions

  • the present invention is based on gamma-glutamyltranspeptidase (GGT) inhibitory activity, activates collagen-producing ability in dermal fibroblasts of skin, reduces UV damage, and horny water content
  • GTT gamma-glutamyltranspeptidase
  • the present invention relates to a pharmaceutical composition.
  • the skin has a three-layer structure of the epidermis, dermis, and fat layer (subcutaneous tissue).
  • the dermis is a thick layer made of fibrous tissue and elastic tissue, most of which is composed of an extracellular matrix such as collagen. It gives elasticity and strength, and keeps the skin fresh and supple.
  • the production of collagen which is a major component of the extracellular matrix, decreases and the amount of matrix metalloprotease, a collagenolytic enzyme, increases.
  • the decrease, decomposition, and denaturation of collagen in the dermis accelerates, the skin barrier function decreases, the moisturizing function and elasticity are lost, the skin tension and gloss are lost, wrinkles Appears skin aging symptoms such as sagging.
  • GGT ⁇ -glutamyltranspeptidase
  • GGT plays an important role as an enzyme that degrades glutathione, which is a pool of major cysteine (Cys) outside the cell, and supplies Cys necessary for glutathione biosynthesis to the cell. It is thought that there is a physiological effect that controls the amount of glutathione.
  • the present inventors have reported on GGT inhibitor having high activity and high selectivity in Patent Document 5. JP 2007-186471 A JP 2007-302607 A JP 2004-075646 A JP 2006-151860 A WO 2007/066705 A1 Publication Cutrin et al., Kidney International, Vol. 57 (2000), pp. 526-533) Aberkane et al., Biochem. Biophy. Res. Commun. 285, 1162-1167 (2001)
  • the present invention not only promotes collagen production by exerting GGT inhibitory activity, but also contains a compound that can prevent damage due to ultraviolet rays and prevent photoaging, and can prevent and improve aging such as wrinkles and sagging of the skin.
  • a useful collagen production promoter, photoaging inhibitor and moisturizing function improving agent and contains the collagen production promoter, photoaging inhibitor or moisturizing function improving agent, and is caused by skin wrinkles / sagging or UV damage.
  • a composition for a dermatological agent that is effective for photoaging, moisturizing function improvement, and the like, and for effective skin conditioning.
  • the present inventors have made various studies with the main purpose of solving the above problems, and as a result, found that a decrease in glutathione content in fibroblasts is associated with an increase in collagen production.
  • GGT inhibitors (i) reduce the amount of glutathione in fibroblasts and increase collagen production, (ii) prevent skin damage due to ultraviolet rays, and reduce photoaging.
  • the present invention has been completed by discovering that it has a new function such as prevention and improvement, and (iii) the ability to increase the amount of keratin moisture.
  • the collagen production promoter of the present invention comprises a compound that inhibits ⁇ -glutamyl transpeptidase as an active ingredient.
  • the photoaging inhibitor of the present invention comprises a compound that inhibits ⁇ -glutamyltranspeptidase as an active ingredient.
  • the moisturizing function improving agent of the present invention comprises a compound that inhibits ⁇ -glutamyl transpeptidase as an active ingredient.
  • the compound preferably contains a phosphonic acid diester derivative having a leaving group.
  • the compound is represented by the following general formula (1) (wherein at least one of R1 and R2 represents a leaving group, and at least one of R1 and R2 is represented by the following general formula (2) to general formula (6)):
  • R3 is any of an aryl group optionally having substituent (s) and a heterocyclic residue optionally having substituent (s);
  • Each is at least one substituent selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, and an electron withdrawing group
  • R4 It is preferable to include a phosphonic acid diester derivative represented by the following formula: wherein two adjacent substituents among the substituents of ⁇ R8 may be bonded to each other to form a ring.
  • the compound preferably contains
  • the present invention also includes a composition for dermatology containing the collagen production promoter, photoaging inhibitor or moisturizing function improving agent.
  • the composition for skin preparations is for improving wrinkles or skin elasticity.
  • Non-Patent Document 1 is cited as an academic paper that supports this prediction.
  • acivicin a GGT inhibitor
  • Fig. 6 the amount of glutathione increases compared to the control
  • Fig. 1 GGT activity is reduced by acivicin administration (Fig. 1). That is, Non-Patent Document 1 shows that the addition of a GGT inhibitor suppresses the decomposition of glutathione, and as a result, the amount of glutathione increases.
  • Non-Patent Document 2 describes data indicating that even if acivicin is administered to a V79GGT cell line highly expressing human GGT, no significant difference is observed in the amount of intracellular glutathione (Table IV 2). . GGT is inhibited in a concentration-dependent manner by acivicin (Table IV 1). On the other hand, since the amount of glutathione in cells is related to various factors such as biosynthesis, metabolism, and transport in addition to GGT, it is difficult to simply derive the relationship between GGT activity and the amount of glutathione.
  • acivicin which has been frequently used as a GGT inhibitor, widely inhibits enzymes other than GGT and disturbs the biosynthetic system of cells in various ways, the amount of glutathione and GGT in conventional studies using acivicin The relationship remains unclear.
  • the present inventors have independently studied using a GGT-selective inhibitor instead of acivicin. As a result, the first time in the world that a selective GGT inhibitor reduces the amount of glutathione in fibroblasts. discovered. Such knowledge is not disclosed or suggested at all in, for example, Non-Patent Documents 1 and 2 and also in Patent Documents 4 and 5. Based on this novel finding, the present inventors have reduced the amount of intracellular glutathione by the present GGT inhibitor, resulting in promoting collagen production, reducing damage caused by ultraviolet rays, and increasing the amount of keratinous water. The present inventors have found a novel function of a GGT inhibitor such as being capable of being made, and thus completed the present invention. Therefore, it can be said that the present invention is completely new and original, which has been uniquely found by the present inventors.
  • GGT inhibitors can not only promote collagen production but also reduce damage to skin fibroblasts caused by ultraviolet irradiation, as shown in Examples described later.
  • photoaging is aging caused by exposure to ultraviolet rays, and one of the causes is oxidation of in vivo components by reactive oxygen species. Photoaging causes a decrease in the amount of collagen in the skin, which reduces the elasticity of the skin and causes wrinkles. It is known that an increase in collagen resolution is greatly involved in the decrease in collagen.
  • the GGT inhibitor significantly reduced the amount of intracellular reactive oxygen species produced by exposure to ultraviolet rays, and thus it was revealed that it has a preventive effect or an improvement effect on photoaging.
  • the photoaging inhibitor as used in the field of this invention intends the composition which prevents and / or improves photoaging.
  • the GGT inhibitor has a function of increasing the amount of water in the stratum corneum of the skin.
  • the moisturizing function improving agent as used in the field of this invention intends the composition which improves the moisturizing function of skin (skin) and / or prevents that a moisturizing function falls (maintaining a moisturizing function).
  • a phosphonic acid diester derivative group (Patent Document 5) characterized by high enzyme selectivity and irreversible inhibitory activity can also be used.
  • This group of phosphonic acid diester derivatives can be preferably used because of its particularly low biotoxicity.
  • the following phosphonic acid diester derivative groups can be preferably used.
  • R3 is any of an aryl group optionally having substituent (s) and a heterocyclic residue optionally having substituent (s); R4, R5, R6, R7, R8 and R9; Each is at least one substituent selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, and an electron withdrawing group, and R4 To R8, two adjacent substituents may be bonded to each other to form a ring.
  • R12 represents any of an alkyl group which may have a substituent, an aryl group which may have a substituent, and a hydrogen atom
  • R13 represents a hydrogen atom and a general formula (8)
  • n1 is an integer of 0 to 4
  • n2 is any of 0 and 1
  • n3 is an integer of 0 to 4
  • X1 is any of an amide group and an alkenyl group
  • X2 is a carboxy group
  • Any one of the equivalents of a carboxy group represents any one of R14 represents either a hydrogen atom or a lower alkyl group.
  • a phosphonic acid diester derivative is
  • a phosphonic acid diester derivative which is at least one group selected from the group consisting of an alkylsulfanyl group, an arylsulfanyl group, a hydroxy group, a carboxy group, a carbamoyl group, an amino group, a guanidino group, an alkoxy group, and an amide group.
  • Y1 represents one group selected from the group consisting of —R ′, —OR ′, and an electron withdrawing group
  • Y2 is substituted with either a carboxy group or an equivalent of a carboxy group
  • Y1 represents one group selected from the group consisting of —R ′, —OR ′, and an electron withdrawing group
  • Y2 is substituted with either a carboxy group or an equivalent of a carboxy group
  • Y2 represents one group selected from the group consisting of an alkyl group optionally having a double bond, a hydrogen atom, a carboxy group, and an equivalent of a carboxy group, and two adjacent substituents Y1 And Y2 may be bonded to each other to form a ring
  • R ′ represents either a hydrogen atom or an alkyl group optionally having a double bond.
  • R16 represents either a hydrogen atom or a lower alkyl group, and Y1 and Y2 represent the same meaning as described above.
  • M represents an alkali metal
  • R17 represents an alkoxycarbonyl group including an optionally substituted aromatic hydrocarbon group
  • a metal of 2-substituted amino-4-phosphonobutanoic acid salt is a metal of 2-substituted amino-4-phosphonobutanoic acid salt.
  • R18 represents an optionally substituted aromatic hydrocarbon group, and R17 represents the same meaning as described above
  • 2-substituted amino-4-phosphonobutanoic acid ester 2-substituted amino-4-phosphonobutanoic acid ester.
  • Patent Document 5 The detailed production method and various properties of the phosphonic acid diester derivatives shown in the above 1 to 20 are disclosed in Patent Document 5.
  • the description in Patent Document 5 can be incorporated as necessary, and the contents described in Patent Document 5 can be appropriately used in the present invention. That is, the disclosed content of Patent Document 5 is also a part of the present invention, and correction based on the described content of Patent Document 5 is also possible.
  • the phosphonic acid diester derivative exhibits GGT activity when the leaving group is eliminated from the phosphate group. That is, GGT activity improves as the leaving group is easily removed.
  • the ease of leaving of the leaving group is related to the stability of the compound, it is not preferable to use a compound having a leaving group that is easily removed.
  • the compound having an excellent balance between the detachability of the leaving group and the stability include the phosphonic acid diester derivatives 1 to 20 above.
  • R15 represents the general formula (13).
  • (15) is more preferred, and 2-amino-4- ⁇ [3- (carboxymethyl) phenyl] (methyl) phosphono ⁇ butanoic acid is particularly preferred.
  • the phosphonic acid diester derivative may contain not only a simple substance and a mixture but also an optical isomer.
  • an optical isomer For example, in the case of 2-amino-4- ⁇ [3- (carboxymethyl) phenyl] (methyl) phosphono ⁇ butanoic acid used in the examples, since there are two chiral atoms, a total of four types of optical isomerism It is a mixture of bodies.
  • Collagen production promoter, photoaging inhibitor or moisturizing function improving agent by GGT inhibitory activity of the present invention is used for preventing or improving wrinkles and sagging by improving skin firmness and gloss, or for UV damage (photoaging). It can be applied to the skin as a composition for dermatological use for prevention / improvement or maintenance / improvement of the skin moisturizing function. It can also be used as a poultice, cosmetics, bath preparation, and sometimes as a subcutaneous injection. It can be arbitrarily selected according to the purpose.
  • the cosmetic can be widely used as a cosmetic, and can be in the form of creams, ointments, emulsions, solutions, gels, powders, granules, etc., and packs, lotions, powders, sticks, etc. .
  • preparation forms including aqueous solution, solubilization system, emulsification system, powder system, oil liquid system, gel system, ointment system, aerosol system, water-oil two-layer system, water-oil-powder three-layer system, etc. can do.
  • the blending amount of the GGT inhibitor is not particularly limited, and varies depending on the type, properties, quality, and expected effect of the dosage form to be blended. For example, 0.00001 to 50.0% by weight, more preferably 0 0.0005 to 10.0% by weight, more preferably 0.0005 to 1.0% by weight is particularly preferable. In particular, when penetration is promoted by, for example, converting a GGT inhibitor into a liposome, the effect can be expected even with a smaller amount.
  • the above-mentioned dermatological agent generally includes components that are usually used in dermatological agents such as cosmetics and pharmaceuticals, such as whitening agents, moisturizers, antioxidants, oily components, ultraviolet absorbers. , Surfactants, thickeners, alcohols, powder components, colorants, aqueous components, water, various skin nutrients / vitamins, and the like can be appropriately blended as necessary.
  • Drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, arbutin, kojic acid and other whitening agents, glucose, fructose, mannose, sucrose, Sugars such as
  • vegetable oils such as olive oil, avocado oil, palm oil, coconut oil, and hardened castor oil
  • animal oils such as beef tallow and pork fat
  • waxes include beeswax, carnauba wax, whale wax, and lanolin.
  • mineral oil examples include liquid paraffin, petrolatum, paraffin, squalene, squalane and the like.
  • fatty acids in addition to natural fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, and oleic acid, synthetic fatty acids such as isononanoic acid and caproic acid can be used.
  • alcohols natural alcohols such as ethanol and isopropanol, synthetic alcohols such as 2-hexyldecanol, isostearyl alcohol and 2-octyldodecanol, ethylene glycol, polyethylene glycol, 1,3-butylene glycol, glycerin, batyl alcohol, Polyhydric alcohols such as pentaerythritol, sorbitol, mannitol, glucose and sucrose can also be used.
  • esters such as isopropyl myristate, metal soaps such as aluminum stearate, gums and water-soluble polymer compounds such as gum arabic, carrageenan, gelatin, alginic acid and its salt, hyaluronic acid and its salt, chondroitin sulfate, carboxy You may mix
  • Surfactants anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants
  • vitamins amino acids, moisturizers, animals or plants, herbal extracts or extracts, microbial culture metabolites, ⁇ -Hydroxy acids, inorganic pigments, UV absorbers, astringents, bactericides / disinfectants, hair preparations, fragrances, pigments / colorants, other hormones, sequestering agents, pH adjusters, chelating agents, antiseptics Antifungal agent, refreshing agent, stabilizer, emulsifier, animal / plant protein and its degradation product, animal / plant polysaccharide and its degradation product, animal / plant glycoprotein and its degradation product, blood flow promoter, Anti-inflammatory agents / anti-allergic agents, cell activators, keratolytic agents, wound treatment agents, foaming agents, thickeners, oral preparations, deodorants / deodorants, bitterings, seasonings, enzymes, etc. are also available .
  • the present invention also provides a compound that inhibits ⁇ -glutamyl transpeptidase as an active ingredient in a collagen production promoter that promotes collagen production in skin fibroblasts by reducing the amount of glutathione in skin fibroblasts.
  • Collagen production promoters or photoaging inhibitors can be included.
  • the collagen production promoter can be read as a method of promoting collagen production using a GGT inhibitor, or the use of a GGT inhibitor for promoting collagen production.
  • the photoaging inhibitor is a method of preventing and / or improving photoaging using a GGT inhibitor (a method of reducing UV damage), or the use of a GGT inhibitor for preventing and / or improving photoaging.
  • the moisturizing function improving agent is a method for maintaining and / or improving the skin moisturizing function using a GGT inhibitor (a method for preventing the moisturizing function from being lowered), or for maintaining and / or improving the moisturizing function. It can also be read as “use of GGT inhibitor” (use of GGT inhibitor for preventing decrease in moisturizing function).
  • Human normal skin-derived fibroblasts (CCD-1059SK, Dainippon Pharmaceutical Co., Ltd.) were subcultured 3-6 times in DMEM medium containing 10% FBS (fetal bovine serum). Next, the cells were seeded in a TC petri dish (manufactured by Greiner) having a diameter of 35 ⁇ 10 5 cells, added with GGT5a, and cultured for 0 to 10 hours. Thereafter, the cells were collected using 500 ⁇ l of 25 mM Tris-HCl (pH 7.4) solution, and centrifuged at 100,000 ⁇ g for 30 minutes.
  • FBS fetal bovine serum
  • sample Normal human skin-derived fibroblasts (CCD-1059SK, Dainippon Pharmaceutical Co., Ltd.) were subcultured 3-6 times in DMEM medium containing 10% FBS (fetal bovine serum). Next, it is prepared on a culture slide (Culture slide: manufactured by Falcon) so that the number of cells becomes 1 ⁇ 10 6 , cultured for 24 hours in DMEM medium containing 10% FBS, and further fixed on the slide. In order to match the cell cycle, the cells were cultured in DMEM medium alone for 24 hours. Then, it replaced
  • FBS fetal bovine serum
  • the culture slide was washed 3 times with PBS solution for 5 minutes, 4% paraformaldehyde solution was added, and the mixture was allowed to stand at 4 ° C. overnight to fix the sample. After washing 3 times with PBS solution containing 0.1% Triton-X for 5 minutes, endogenous peroxidase was blocked with 3% H 2 O 2 solution for 5 minutes. Subsequently, non-specific reaction was blocked for 5 minutes using 10% normal goat serum. Then, the reaction of the primary antibody was performed for 60 minutes using an anti-rat type 1 collagen antibody (Anti-rat type I collagen antibody (LSL) 200-fold diluted solution).
  • Anti-rat type I collagen antibody LSL
  • the reaction of the secondary antibody was performed for 30 minutes using a biotinylated goat anti-rabbit immunoglobulin antibody (Biotinylated Goat anti-rabbit immunogloblins antibody (DAKO) diluted 400 times). It was. After washing 3 times with PBS solution for 5 minutes, a reaction with an enzyme solution (horseradish peroxidase-labelled streptavidine-biotine complex (DAKO) 400-fold dilution) was performed for 30 minutes. After washing with PBS solution for 3 minutes for 5 minutes, a DAB (3,3-diaminobenzidin tetra-hydrocheloride) solution was reacted for 5 minutes to perform peroxidase color reaction.
  • DAKO Biotinylated Goat anti-rabbit immunogloblins antibody
  • the values in the table are expressed as a ratio of the staining intensity of each sample when the control is 100 (value measured and averaged for 20 cells per slide).
  • Test period / Subjects • Mid-December to late February (8 weeks continuous use, 3 evaluation measurements) ⁇ 1 healthy woman in 20s, 3 healthy women in 30s, 8 healthy women in 40s (12 in total)
  • Test outline Skin lotion formulated with GGT5a (0.0005%) was used twice a day (morning and evening; placebo lotion, GGT5a blended lotion half face each) for 8 weeks, before and after skin condition was measured and compared to evaluate the effect of the GGT inhibitor on the amount of keratinous moisture in the skin.
  • the left and right cheeks were placed in a constant environment after being kept acclimatized in a constant temperature and humidity room (room temperature 20 ° C., relative humidity 50%) for about 20 minutes.
  • the average value of 6 intermediate points excluding 2 points above and below the measured value was taken as the amount of horny moisture at that site.
  • the graph shows the change in the amount of horny water after 4 weeks / 8 weeks of continuous use, where the average of subjects before continuous use is 100.
  • Matricixyl is a known cosmetic ingredient that is a 3% blended sample and has been shown to improve wrinkles due to increased collagen synthesis.
  • the prescription of the lotion used was the same prescription as above except that the concentration of the GGT inhibitor was 10 times 0.005% by weight.
  • the placebo lotion has the same composition except that no GGT inhibitor is blended.
  • Matrixil formulated lotion is also a lotion having the same composition except that 3% of matrixil is blended in place of the GGT inhibitor.
  • Test content Subjects: 10 general women in their 30s to 50s Test period: Mid- May to late August Measurements: 4 times (before 1st, 1st, 2nd, 3rd month) Equipment used: Cutometer (Courage + Khazaka electronic GmbH) Measurement site: cheek (left / right) In addition, all measurements were performed after acclimatizing the skin to room temperature for 20 minutes under constant temperature and humidity (20 ° C., RH 50%) after washing the face.
  • Sample Placebo lotion 1 2. Toner lotion containing Matrixyl (3%) Toner lotion containing GGT inhibitor (0.005%) The subjects used samples after washing their face twice a day in the morning and evening. The test subjects were divided into 2 groups (groups A and B) of 5 people, each applied to the face in the following manner, and then a special moisturizing cream was applied to the entire face.
  • the moisturizing cream is a moisturizing cream prepared for this test and formulated to obtain the minimum moisturizing effect, improving skin elasticity, whitening effect, There are no ingredients with anti-inflammatory effects.
  • FIG. 4 shows the results of examining the change in skin elasticity over time. Relative values are plotted on a graph when each numerical value before continuous use is 100, and the vertical axis represents the average change rate (unit:%) of the elasticity parameter R7 (Ur / Uf; unit: none). The higher the value is, the higher the elasticity of the skin is. As shown in the figure, placebo decreased from one month onward, while those using matrixyl and GGT inhibitor showed a continuous increase in the number from one month onward. Matrixil shows almost no change after 2 to 3 months, but the GGT inhibitor shows a large increase from 2 to 3 months. ⁇ 5.
  • Human normal skin-derived fibroblasts consist of 10% fetal bovine serum (FBS), penicillin (penicillin, 50 units / ml, Meiji Seika) and streptomycin (50 mg / ml). ml, Meiji Seika) was adjusted to a Dulbecco's modified Eagle's medium (DMEM) medium (Nissui Pharmaceutical) so that the number of cells was 1.0 ⁇ 10 5 cells / ml, and adjusted to 37 ° C. and 5% CO 2 . The cells were cultured in an incubator and the medium was changed every two days. When the cells became confluent, the main culture was started, and the medium was replaced with a DMEM medium.
  • DMEM Dulbecco's modified Eagle's medium
  • a GGT inhibitor was added to a concentration of 10 ⁇ M and cultured for 3 hours, followed by ultraviolet irradiation. Thereafter, the intracellular reactive oxygen species production was measured for 1 hour and then subjected to experiments. For measurement of cell viability, the cells were cultured for 24 hours and then subjected to experiments.
  • UV irradiation to human normal skin-derived fibroblasts A UV lamp (TOSHIBA germicidal lamp GL15) was used for UV irradiation. Using a UV-340UV LIGHT METER (Sato Corporation), the height of the UV lamp was adjusted so that the UV intensity was 20 ⁇ W.
  • the petri dish was placed under a UV lamp, the lid was opened, and UV was irradiated for 1 minute.
  • MTT method The methylthiazole tetrazoleum (MTT) method is a method in which living cells are stained with a dye and the relative cell mass is simply measured. The almost dye-free tetrazolium salt taken up into the cell is reduced by mitochondrial oxidoreductase to form an insoluble colored substance (formazan). Since the amount of formazan produced corresponds to the number of living cells, this dye was extracted with an organic solvent and the absorbance was measured.
  • the cells were adjusted to a concentration of 1.0 ⁇ 10 5 cells / ml, seeded 1.0 ⁇ 10 3 cells in a plastic petri dish having a diameter of 35 mm, and each sample was added. After completion of the main culture, 200 ⁇ l of 0.5% MTT solution was added to 1 ml of the medium, and further incubated for 2 hours in a CO 2 incubator. After completely removing the medium with an aspirator or micropipette, 1 ml of 0.04N HCl / isopropanol was added, and reddish purple formazan was dissolved while pipetting. Thereafter, the absorbance was measured at a wavelength of 570 nm using an absorptiometer (UV mini 1240).
  • UV mini 1240 absorptiometer
  • Reactive oxygen species (ROS) production amount was measured by labeling intracellular peroxides with DCFH-DA.
  • the sample was subjected to protein quantification by the Bradford method, and the amount of ROS produced per protein amount was calculated.
  • Two methods were used to measure the amount of reactive oxygen species produced: an absorbance method and a fluorescence microscope method. The measuring method is as follows.
  • FIG. 6 shows the results of examining the effect of a GGT inhibitor on the survival rate of human normal skin-derived fibroblasts under ultraviolet irradiation. As shown in the figure, the survival rate of dermal fibroblasts was reduced by about 20% by irradiation with ultraviolet rays. Moreover, when a GGT inhibitor was added, the tendency which recovered the survival rate fallen by the ultraviolet-ray was recognized.
  • FIG. 7 and FIG. 8 show the results of examining the effect of a GGT inhibitor on the increase in the amount of H 2 O 2 produced by normal human skin-derived fibroblasts under ultraviolet irradiation.
  • the amount of H 2 O 2 produced by normal human skin-derived fibroblasts was higher than that of the non-irradiated group when irradiated with ultraviolet rays.
  • the GGT inhibitor decreased the amount of H 2 O 2 increased by ultraviolet irradiation.
  • composition (wt%) Sorbit 4.0 Glycerin 3.0 Butylene glycol 3.0 Polyethylene glycol 1500 5.0 POE (20) oleyl alcohol ether 0.5 Sucrose fatty acid ester 0.2 Methylcellulose 0.2 GGT inhibitor 0.005 Purified water Amount of 100 [Prescription example: Emulsion] An emulsion having the following formulation was produced by a conventional method.
  • the collagen production promoter of the present invention comprises a GGT inhibitor that reduces the amount of glutathione in fibroblasts as an active ingredient, and is used in skin fibroblasts. It has the effect of significantly promoting collagen production. As a result, the collagen production promoter of the present invention has the effect of significantly promoting collagen production in skin fibroblasts, preventing and improving skin aging, specifically maintaining skin firmness and gloss. Effective in preventing and improving wrinkles and sagging by improvement, or maintaining and improving the moisture retention function of the skin.
  • the photoaging inhibitor of the present invention can also reduce damage to skin cells due to ultraviolet rays.
  • the moisturizing function improving agent of the present invention can improve the moisturizing function of the skin by increasing the amount of keratinous moisture in the skin.
  • composition for dermatological agents containing the collagen production promoter by GGT inhibitory activity of this invention has the effect
  • the composition for dermatological agents containing the photoaging inhibitor by GGT inhibitory activity of this invention reduces the damage by ultraviolet rays, and exhibits an effective effect
  • the composition for dermatological agents containing the moisturizing function improving agent by GGT inhibitory activity of this invention exhibits the effect
  • a collagen production promoter that improves the amount of collagen production by exerting GGT inhibitory activity.
  • the GGT inhibitor also has an effect of reducing damage caused by ultraviolet rays and an effect of increasing the amount of stratum corneum.
  • a dermatological agent suitable for preventing or improving aging such as wrinkles and sagging of the skin, preventing and improving photoaging due to ultraviolet rays, and maintaining and improving the moisture retention function of the skin is provided. It is.

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Abstract

L'invention concerne une préparation destinée à être appliquée sur la peau et qui a pour effet d'activer manifestement la production de collagène dans les fibroblastes cutanés. Une matière active de cette préparation est un inhibiteur de la ?-glutamyl transpeptidase qui réduit la quantité de glutathion dans les fibroblastes cutanés. L'invention concerne aussi une préparation destinée à être appliquée sur la peau, ladite préparation permettant de réduire les dommages dus au rayonnement ultraviolet. L'invention concerne de plus une préparation destinée à être appliquée sur la peau, ladite préparation améliorant la rétention d'humidité.
PCT/JP2010/057244 2009-04-24 2010-04-23 Promoteur de production de collagène, agent anti-photovieillissement, agent améliorant la rétention d'humidité et composé s'utilisant sur la peau WO2010123102A1 (fr)

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WO2015030106A1 (fr) * 2013-09-02 2015-03-05 国立大学法人京都大学 Composé ayant un effet inhibiteur de ggt et inhibiteur d'enzymes de la famille des ggt
WO2018194000A1 (fr) * 2017-04-17 2018-10-25 株式会社ナールスコーポレーション Promoteur de guérison des plaies
CN109715636A (zh) * 2016-09-14 2019-05-03 国立大学法人京都大学 Nahlsgen的光学拆分方法
JP2020033326A (ja) * 2018-08-31 2020-03-05 株式会社ナールスコーポレーション 体臭抑制剤
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same

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JP5787246B2 (ja) * 2010-09-15 2015-09-30 国立大学法人京都大学 角化細胞遊走・増殖促進剤を含む、創傷治癒剤および褥瘡（床ずれ）治療薬
BR112015015857A2 (pt) * 2013-01-28 2017-07-11 Unilever Nv composição tópica e método de melhorar a microcirculação da pele
JP5791216B1 (ja) * 2013-12-03 2015-10-07 博 村上 液状化粧品
JP6294773B2 (ja) * 2014-06-27 2018-03-14 株式会社ナールスコーポレーション 口腔粘膜疾患の予防または治療用経口製剤
JP6457292B2 (ja) * 2015-02-15 2019-01-23 株式会社ナールスコーポレーション 植物の鮮度保持剤組成物、植物の育成促進剤組成物、植物、並びに、植物の製造方法及び植物の処理方法
JP6550656B2 (ja) * 2015-02-23 2019-07-31 株式会社ナールスコーポレーション 炎症性皮膚疾患の予防または治療用製剤
JP6351550B2 (ja) * 2015-06-30 2018-07-04 富士フイルム株式会社 ハリ感評価装置、ハリ感評価方法およびハリ感評価プログラム
JP6778362B2 (ja) * 2015-12-01 2020-11-04 株式会社ナールスコーポレーション グルタチオン産生促進剤
JP6778361B2 (ja) * 2015-12-01 2020-11-04 株式会社ナールスコーポレーション フィラグリン遺伝子発現促進剤
JP7212900B2 (ja) 2017-04-17 2023-01-26 株式会社ナールスコーポレーション 光学活性な２－アミノ－ホスホノアルカン酸、光学活性な２－アミノ－ホスホノアルカン酸塩、及びこれらの水和物

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Cited By (10)

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WO2015030106A1 (fr) * 2013-09-02 2015-03-05 国立大学法人京都大学 Composé ayant un effet inhibiteur de ggt et inhibiteur d'enzymes de la famille des ggt
JPWO2015030106A1 (ja) * 2013-09-02 2017-03-02 国立大学法人京都大学 Ｇｇｔ阻害作用を有する化合物及びｇｇｔファミリー酵素阻害剤
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
CN109715636A (zh) * 2016-09-14 2019-05-03 国立大学法人京都大学 Nahlsgen的光学拆分方法
WO2018194000A1 (fr) * 2017-04-17 2018-10-25 株式会社ナールスコーポレーション Promoteur de guérison des plaies
JPWO2018194000A1 (ja) * 2017-04-17 2020-02-27 株式会社ナールスコーポレーション 創傷修復促進剤
US11090318B2 (en) 2017-04-17 2021-08-17 Nahis Corporation Co., Ltd. Wound healing promoter
JP7177444B2 (ja) 2017-04-17 2022-11-24 株式会社ナールスコーポレーション 創傷修復促進剤
JP2020033326A (ja) * 2018-08-31 2020-03-05 株式会社ナールスコーポレーション 体臭抑制剤
JP7280562B2 (ja) 2018-08-31 2023-05-24 株式会社ナールスコーポレーション 体臭抑制剤

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