Classifications

• • 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
  • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
• • 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
  • A61K8/42—Amides
• • 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
  • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
• • 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
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
  • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
• • 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
  • A61K2800/70—Biological properties of the composition as a whole

Definitions

• composition for external application containing PPARs activator from plant [Technical Field]
• the present invention relates to a skin external application composition which comprises one or more compounds selected from the group consisting of Galbulin (hereinafter, referred to as 'Ga' ) , Methylhalfordinol (hereinafter, referred to as ⁇ Me') / Brevicarine
• x Br' 3- (4 -Methyl-thiazol-2- yl) -7- (3,4, 5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2- yloxy) -chromen-4-one (hereinafter, referred to as x Cr'), 9-
• ⁇ Cn' Dimethyl-3- (3-methoxyphenyl) -psolen-6-yl propionic acid (hereinafter, referred to as 'Pr') and N- (2- (2 , 3 , 4 ' , 5 ' - tetramethoxychalcon-2-yl) -ethyl) -acetamide (hereinafter, referred to as ⁇ Cn') as an active ingredient, wherein the composition promotes the differentiation of keratinocyte in a skin by the activation of PPARs, and thus has anti- inflammatory and anti-aging effects.
• 'Pr' Dimethyl-3- (3-methoxyphenyl) -psolen-6-yl propionic acid
• ⁇ Cn' N- (2- (2 , 3 , 4 ' , 5 ' - tetramethoxychalcon-2-yl) -ethyl) -acetamide
• the PPARs are a group of nuclear hormone receptor and three kinds of isotypes of PPARs, ⁇ , ⁇ , Y have been identified, each of which shows a difference in the tissue where they are present and the function which they attend to.
• PPARs are activated when a certain ligand is bound to them.
• the activated PPARs are combined with a promoter of interest proteins, which promotes the transcription of the proteins, thereby inducing a physiological change of cells.
• Early studies on the function of PPARs were focused on lipid metabolism and various functions of PPARs have been now reported. The reported functions are divided into four groups : The first is the control of metabolism in cells.
• PPARs usually play a role in the metabolism of lipid.
• the major functions of PPARs in lipid metabolism are the control of transport, oxidation and storage of fatty acid (J Biol Chem, 1997, 272:28210-7; Cell MoI Life Sci, 2004, 61:393-416; DiabetS, 2004, 53:1243-52).
• the second is the control of proliferation and differentiation of cells.
• PPARs have important functions in the development and differentiation of placentas, adipocytes, osteoblasts, skins and intestine, but the functions differ according to the kinds of cells and PPARs ( ⁇ , ⁇ and ⁇ ) .
• the epidermis of skin is a specialized tissue where keratinocytes which proliferate and differentiate and peripheral organs such as hair follicle, sebaceous gland, etc. are interconnected. All of the three kinds of PPARs promote the differentiation of keratincytes (Cell Death Differ 2005, J Invest Dermatol, 2004, 123:305-12; J Invest Drematol, 2000, 115:353-60) and also promote the differentiation of sebocytes and the formation of sebum (MoI Genet Metab, 2001, 74:362-9).
• PPARs interact with an immune system, an insuline signal system and a tissue regeneration system.
• PPARs are broadly involved in the immune reactions from the general immune reaction such as the prevention of infection by a foreigner to the severe immune reaction of pathological condition such as an atherosclerosis.
• PEG2 is one among the factors which induce inflammatory reaction and it increases the production of many matrix metalloproteinases (MMPs) including collagenase and stromelysin, but decreases the syntheses of collagen and fibronectin (J Biol Chem, 2006, 281(29) :19849-60) . Further, it was studied that inflammatory mediators such as PEG2 and the activation of NF-kB which is a transcription factor regulating the synthesis of inflammatory cytokines induce the production of MMPs in cells, which promotes the degradation of intercellular matrix (Clin Orthop Relat Res., 2003, S75-85) .
• MMPs matrix metalloproteinases
• MMPs by inflammatory mediators such as PEG2 and activated NF-kB leads to the depletion of collagen and fibronectin in a dermis and skin aging phenomena such as wrinkle production and elasticity reduction can be followed by it.
• ROS Reactive oxygen species
• SOD superoxide dismutase
• PPARs when activated, they inhibit the activities of inflammatory stimulators such as NF-kB and AP-I and, thus, suppress the production of inflammatory cytokines and MMPs (MoI Med., 2006, 12(1-3): 17-24) . This prevents the destruction of collagen which is a major constituent of dermis by MMPs, thus preventing or improving the formation of skin wrinkle. Further, PPARs regulate the expression of enzymes involved in ROS scavenging, uncoupling protein 2, catalase, cupper/zinc SOD, and thus promote the elimination of ROS which stimulates skin aging (J Immunol., 2006 Sep 15, 177 (6) : 3737-45) .
• an object of the present invention is to provide a skin external composition for preventing inflammation and delaying or improving skin aging through the activation of PPAR
• composition of the present invention for anti-inflammation and anti-aging by the activation of PPARs comprises one or more selected from the group consisting of Ga, Me, Br, Cr, Pr and Cn which are represented by the following formula 1 to 6, respectively, as an active ingredient.
• the active ingredients of the present composition are natural compounds derived from plants and they are found out by screening the pure natural chemical library (GPC) (Grenpharma S.A).
• GPC pure natural chemical library
• the plants from which said active ingredients are originated are shown below: Ga: Himantandra baccata; Me: Aegle marmelos, Triphasia trifolia; Br: Carex brevicollis, Carex parva; Cr: Glycine max, Piptanthus nepalensis , Pueraria lobata;
• Pr Sclerotinia sclerotiorum
• the present composition comprises at least one selected from the group consisting of Ga, Me 7 Br, Cr, Pr and Cn as an active ingredient and, thus, can be used as a skin external composition which promotes the differentiation of keratinocytes in skin through the activation of PPARs in keratinocytes of skin and ultimately inhibits inflammation and delays or improves skin aging. It is preferred that said ingredients are comprised in an amount of 0.1 to 10.0 % based on the total weight of the composition, upon the consideration of the kind of formulation and skin safety.
• a new skin external composition which can promote the differentiation of keratinocytes through the activation of PPAR- ⁇ and PPAR- ⁇ and the increase in expression and thus inhibit inflammation and delay or improve skin aging, when the PPARs activators originated from plants are applied to skin.
• FIG. 1 is a graph showing PPAR- ⁇ activation by Ga, Me, Br, Cr, Pr and Cn comprised in the present composition.
• FIG. 2 is a graph showing the activation depending on the concentration of each substance.
• FIG. 3 is a graph showing PPAR- ⁇ activation by each substance .
• FIG. 4 is a graph showing PPAR- ⁇ activation by each substance . [Best Mode]
• Test Example 1 Construction of the system for measuring PPAR-y activation using CV-I cell 1.
• plasmids Four kinds of plasmids were used: the plasmid with PPAR ⁇ , PPAR ⁇ or PPARY gene downstream the universal promoter which is expressed under general culture condition, the plasmid with, as a promoter, PPARs response element
• PPARs and, as a reporter, a firefly luciferase gene reporter downstream the promoter, the plasmid used as a reference in which ⁇ -galactosidase gene is bound to a universal promoter, and the empty plasmid used as a carrier which has no genes to be expressed.
• the genes of ⁇ , ⁇ and ⁇ PPARs only one kind of gene was incorporated into the plasmid.
• CV-I cells were seeded at 5 x 10 4 cells/well in a 24- well plate and cultured for 18 to 24 hours. After reacting said plasmids with DMEM, PEI (polyethylenimine) mixture at a room temperature for 15 minutes, they were sprayed on each well to transfect the cells.
• PEI polyethylenimine
• Test Example 2 Identification of PPAR- ⁇ activators
• the system for measuring PPAR- ⁇ activation constructed according to Test Example 1 was treated with DMSO which is a negative control, Troglitazone (hereinafter, referred to as ⁇ TGZ'), Genistein (hereinafter, referred to as 'G2') and Trans, trans-Farnesol (hereinafter, referred to as 'FOH') which are positive controls, and each test substance at ⁇ concentration as shown in FIG. 1.
• DMSO Troglitazone
• Genistein hereinafter, referred to as 'G2'
• Trans trans-Farnesol
• the activity of PPAR- ⁇ in each test group was compared by measuring the amount of light radiated to luminometer after mixing cell lysate with luciferase substrate (Promega) at a ratio of 4:1. Also, beta- galactosidase activity in each test group was compared by measuring the absorbance at a wavelength of 420 nm after adding to cell lysate 2X ⁇ -galactosidase enzyme assay buffer (Promega) and reacting them at 37°C for 30 minutes.
• the PPAR- ⁇ activity in each test group was calibrated with the beta-galactosidase activity showing the transfection efficiency of each test group and the significance of test results was determined by comparing the mean value of the test group with that of the negative group by two-sample t-test in Minitab program.
• FIG. 1 is a graph showing the PPAR-Y activation by the effective substances of Ga, Me, Br, Cr, Pr and Cn which are identified by the above procedures.
• FIG. 2 is a graph showing the process reaching to saturation condition after PPAR- ⁇ is increasingly activated, when the system for measuring the PPAR- ⁇ activation is treated with each effective substance having a gradually increased concentration.
• Test Example 3 Analysis of specificity of the identified effective substances to PPAR- ⁇ and PPAR- ⁇ To determine that the identified substances can activate PPAR- ⁇ and PPAR- ⁇ , the following experiment was carried out while using the CV-I activation system in Test Example 1. The difference of Test Example 3 from Test Example 1 is that the activity of PPAR- ⁇ was determined by transfecting the cells with the plasmid which can express PPAR- ⁇ and treating them with WY-14643 as a positive control group and that the activity of PPAR- ⁇ was determined by transfecting the cells with the plasmid which can express PPAR- ⁇ and treating them with L-165041 as a positive control group. The concentration for the treatment is shown FIGs . 3 and 4 and the remaining experimental procedures and statistical analysis were carried out as shown in Test Example 2.
• FIG. 3 is a graph showing the effect of PPAR-Y activators on the activation of PPAR- ⁇ , indicating that Me, Br and Cr activate PPAR- ⁇ .
• FIG. 4 is a graph showing the effect of PPAR- ⁇ activators on the activation of PPAR- ⁇ , indicating that the substances identified according to the present invention do not activate PPAR- ⁇ .
• the natural compounds of the present invention which is derived from plants, that is, Ga, Me, Br, Cr, Pr and Cn activate PPAR-Y depending on the concentration of the compounds and, although there is a difference in the degree of the activity, the compounds also can activate PPAR- ⁇ .
• PPARs play an important role: of regulating lipid metabolism in a body, division and differentiation of cells, inflammation, insulin-sensitivity, wound healing, etc. Accordingly, when the active ingredients of the present invention are applied to a skin, they can promote the differentiation of keratinocytes in a skin by the activation of PPAR- ⁇ and PPAR- ⁇ , and thus have anti-inflammatory and anti-aging effect .
• Formulation 1 Nourishing toilet water (milky skin lotion)
• the nourishing toilet water according to the present invention was formulated using the composition shown in Table 1. [Table l]
• Formulation 2 Nourishing cream The nourishing cream according to the present invention was formulated using the composition shown in Table 2. [Table 2]
• the massage cream according to the present invention was formulated using the composition shown in Table 3. [Table 3]
• the skin external composition of the present invention can promote the differentiation of keratinocytes by the activation of PPARs and, thus, inhibit inflammation and improve or delay skin-aging.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
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• Epidemiology (AREA)
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• Gerontology & Geriatric Medicine (AREA)
• Dermatology (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Cosmetics (AREA)

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• 2006
  • 2006-11-30 KR KR1020060119448A patent/KR100806162B1/ko active IP Right Grant
• 2007
  • 2007-10-31 WO PCT/KR2007/005453 patent/WO2008066255A1/en active Application Filing

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