JPH0459714A - Tyrosinase activity inhibitor - Google Patents
Tyrosinase activity inhibitorInfo
- Publication number
- JPH0459714A JPH0459714A JP2169637A JP16963790A JPH0459714A JP H0459714 A JPH0459714 A JP H0459714A JP 2169637 A JP2169637 A JP 2169637A JP 16963790 A JP16963790 A JP 16963790A JP H0459714 A JPH0459714 A JP H0459714A
- Authority
- JP
- Japan
- Prior art keywords
- lactoferrin
- tyrosinase activity
- apolactoferrin
- milk
- iron
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000694 effects Effects 0.000 title claims description 38
- 102000003425 Tyrosinase Human genes 0.000 title claims description 32
- 108060008724 Tyrosinase Proteins 0.000 title claims description 32
- 239000003112 inhibitor Substances 0.000 title claims description 19
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 claims abstract description 40
- 235000021242 lactoferrin Nutrition 0.000 claims abstract description 36
- 108010063045 Lactoferrin Proteins 0.000 claims abstract description 33
- 102000010445 Lactoferrin Human genes 0.000 claims abstract description 33
- 229940078795 lactoferrin Drugs 0.000 claims abstract description 33
- 108010038047 apolactoferrin Proteins 0.000 claims abstract description 15
- 235000013336 milk Nutrition 0.000 claims abstract description 11
- 239000008267 milk Substances 0.000 claims abstract description 11
- 210000004080 milk Anatomy 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 241000124008 Mammalia Species 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 230000001055 chewing effect Effects 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 24
- 229910052742 iron Inorganic materials 0.000 abstract description 12
- 239000002537 cosmetic Substances 0.000 abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052802 copper Inorganic materials 0.000 abstract description 8
- 239000010949 copper Substances 0.000 abstract description 8
- 239000008213 purified water Substances 0.000 abstract description 8
- 235000013305 food Nutrition 0.000 abstract description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000011701 zinc Substances 0.000 abstract description 6
- 229910052725 zinc Inorganic materials 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 3
- 230000002087 whitening effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003995 emulsifying agent Substances 0.000 abstract description 2
- 238000004255 ion exchange chromatography Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 4
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000001804 emulsifying effect Effects 0.000 abstract 1
- 239000000796 flavoring agent Substances 0.000 abstract 1
- 235000019634 flavors Nutrition 0.000 abstract 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 abstract 1
- 238000007493 shaping process Methods 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 13
- 238000012360 testing method Methods 0.000 description 9
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229910000365 copper sulfate Inorganic materials 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910001431 copper ion Inorganic materials 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229910000358 iron sulfate Inorganic materials 0.000 description 2
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000008133 Iron-Binding Proteins Human genes 0.000 description 1
- 108010035210 Iron-Binding Proteins Proteins 0.000 description 1
- 244000141359 Malus pumila Species 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 101100194706 Mus musculus Arhgap32 gene Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 241000223259 Trichoderma Species 0.000 description 1
- 241000121220 Tricholoma matsutake Species 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 101100194707 Xenopus laevis arhgap32 gene Proteins 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 235000021016 apples Nutrition 0.000 description 1
- 229960000271 arbutin Drugs 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000021152 breakfast Nutrition 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000003022 colostrum Anatomy 0.000 description 1
- 235000021277 colostrum Nutrition 0.000 description 1
- MIHINWMALJZIBX-UHFFFAOYSA-N cyclohexa-2,4-dien-1-ol Chemical class OC1CC=CC=C1 MIHINWMALJZIBX-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- RNZCSKGULNFAMC-UHFFFAOYSA-L zinc;hydrogen sulfate;hydroxide Chemical compound O.[Zn+2].[O-]S([O-])(=O)=O RNZCSKGULNFAMC-UHFFFAOYSA-L 0.000 description 1
- SFVVQRJOGUKCEG-OPQSFPLASA-N β-MSH Chemical compound C1C[C@@H](O)[C@H]2C(COC(=O)[C@@](O)([C@@H](C)O)C(C)C)=CCN21 SFVVQRJOGUKCEG-OPQSFPLASA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、哺乳類の乳汁から分離したラクトフェリン、
アポラクトフェリン、金属飽和ラクトフェリン、及びこ
れらの任意の混合物からなる群より選択されるラクトフ
ェリンを有効成分として含有することを特徴とするチロ
シナーゼ活性阻害剤に関する。[Detailed Description of the Invention] [Industrial Application Field] The present invention provides lactoferrin isolated from mammalian milk,
The present invention relates to a tyrosinase activity inhibitor containing as an active ingredient a lactoferrin selected from the group consisting of apolactoferrin, metal-saturated lactoferrin, and any mixture thereof.
［技術の背景及び従来技術の説明１
ラクトフエリンは、涙、唾液、抹消面、乳汁等に含まれ
ている天然の鉄結合性蛋白質であり、大腸菌、カンジダ
菌、クロストリジウム菌等の有害微生物に対して抗菌作
用を示すことか知られているか［ジャーナル・オブ・ペ
ディアトリクス（Ｊｏｕｒｎａｌ Ｏｆ Ｐｅｄｉａｔ
ｒｉｃｓ）、第９４巻、第１ページ、１９７９年］、ラ
クトフェリンかチロシナーゼ活性阻害剤果を有すること
は従来知られていない。[Technical Background and Description of Prior Art 1 Lactoferrin is a natural iron-binding protein contained in tears, saliva, peritoneal fluid, milk, etc., and is effective against harmful microorganisms such as Escherichia coli, Candida, and Clostridium. Is it known to exhibit antibacterial activity [Journal of Pediatrics]
rics), Volume 94, Page 1, 1979], it has not been previously known that lactoferrin has the effect of inhibiting tyrosinase activity.
チロシナーゼは、チロシン、その他の１価フェノール類
及び相当するオルソ−２価フェノール類の分子状酸素に
よる酸化を触媒する酵素であり、キノコ、ジャガイモ、
リンゴ等多くの植物及び動物組織に広く存在し、植物に
おいては切傷部分の黒変現象に関与し、動物においては
組織、特に皮膚表皮細胞のメラニン色素の形成に関与し
ていることが知られている（化学大辞典編集委員会編、
化学大辞典、第５巻、第９７６ページ、共立出版、昭和
３５年）。アジラン病において皮膚粘膜に黒褐色のメラ
ニン色素沈着を生するのは、チロシナーゼ活性を促進す
るメラノトロピンと拮抗する副腎皮質ホルモンの分泌減
少に起因することも知られている（化学大辞典編集委員
全編、化学大辞典、第１巻、第６５ページ、共立出版、
昭和３５年）。Tyrosinase is an enzyme that catalyzes the oxidation of tyrosine, other monohydric phenols, and the corresponding ortho-dihydric phenols with molecular oxygen.
It is widely present in many plant and animal tissues, such as apples, and is known to be involved in the blackening phenomenon of cut areas in plants, and in the formation of melanin pigment in tissues, especially skin epidermal cells, in animals. (edited by the Chemistry Encyclopedia Editorial Committee,
Encyclopedia of Chemistry, Volume 5, Page 976, Kyoritsu Publishing, 1960). It is also known that the dark brown melanin pigmentation on the skin mucosa in Ajilan's disease is due to the decreased secretion of melanotropin, which promotes tyrosinase activity, and adrenal cortical hormone, which competes with it. Encyclopedia of Chemistry, Volume 1, Page 65, Kyoritsu Publishing,
(Showa 35).
更にチロシナーゼは、食品の鮮度低下にも関与している
ともいわれている。Furthermore, tyrosinase is said to be involved in reducing the freshness of foods.
上述のようＩコ従来知られている食品、化粧品又は医薬
品分野において、チロシナーゼによる望ましくない作用
を防止し、予防し又は治療するためのチロシナーゼ活性
阻害剤の開発か強く望まれていた。特に化粧品業界では
、メラニン色素の生成を有効に抑制し、美白効果を付与
した化粧品又は皮膚外用剤の研究か活発であり、チロシ
ナーゼ活性阻害剤を配合した製品が次々と開発されてい
る。As mentioned above, there has been a strong desire for the development of tyrosinase activity inhibitors for preventing, preventing or treating undesirable effects caused by tyrosinase in the conventionally known food, cosmetic or pharmaceutical fields. In particular, in the cosmetics industry, research is active into cosmetics or external skin preparations that effectively suppress the production of melanin pigment and impart a whitening effect, and products containing tyrosinase activity inhibitors are being developed one after another.
チロシナーゼ活性阻害剤としては、システィン、ヒタミ
ンＣ（三島豊等、基礎皮膚科学、第２５８ページ、朝食
書店、昭和４８年）、コウジ酸（日経産業新聞、昭和６
３年５月２４日）、アルブチン（富田健〜、第２０回Ｆ
Ｊセミナー予稿集、第２１ペーソ、フレグランスンヤー
ナル社、平成２年３月１４日）、トリコデルマ属に属す
る微生物の産生物（特開平２−１４５１８９号公報）等
が知られている。Examples of tyrosinase activity inhibitors include cysteine, hitamine C (Yutaka Mishima et al., Basic Dermatology, p. 258, Breakfast Shoten, 1972), kojic acid (Nikkei Sangyo Shimbun, 1978).
May 24, 2013), Arbutin (Ken Tomita ~, 20th F
J Seminar Proceedings, No. 21, Fragrance Sun Yarnal Co., March 14, 1990), and products of microorganisms belonging to the genus Trichoderma (Japanese Patent Application Laid-Open No. 145189/1999).
しかしなから、従来のチロシナーゼ活性阻害剤よ、製品
中で不安定であったり、メラニン色素を合成するメラノ
サイト細胞への作用か強すぎたり、原料の入手か困難で
あるため極めて高価であったり、いずれも欠点かあり、
安全で美白効果にすくれた化粧品又は皮膚外用剤として
満足できるものではなかった。However, conventional tyrosinase activity inhibitors are unstable in products, have too strong effects on melanocytes that synthesize melanin pigment, and are extremely expensive because raw materials are difficult to obtain. Both have their drawbacks,
It was not satisfactory as a cosmetic product or external skin preparation that was safe and had a whitening effect.
［発明か解決しようとする課題］
本発明者等は、従来の化粧品等に認められた前記の欠点
を克服するのみならず、食品及び医薬品にも使用か可能
な安全、かつ安定なチロシナーゼ活性阻害剤について鋭
意研究した結果、哺乳類の乳汁中に存在するラクトフェ
リン、該ラクトフェリンに化学的処理を施したアポラク
トフェリン、金属飽和ラクトフェリン、又はこれらの任
意の混合物に、顕著なチロシナーゼ活性阻害剤作用のあ
ることを見出たし、本発明を完成した。[Problem to be solved by the invention] The present inventors have devised a safe and stable tyrosinase activity inhibitor that not only overcomes the above-mentioned drawbacks observed in conventional cosmetics, but also can be used in foods and pharmaceuticals. As a result of intensive research on lactoferrin, it was found that lactoferrin present in mammalian milk, apo-lactoferrin obtained by chemically treating lactoferrin, metal-saturated lactoferrin, or any mixture thereof has a significant tyrosinase activity inhibitory effect. They discovered this and completed the present invention.
［課題を解決するための手段］
本発明において使用するラクトフェリンは、市販品、哺
乳類（例えは、人、牛、羊、山羊、馬等）の初乳、移行
乳、窩孔、末期孔等又はこれらの処理物である脱脂乳、
ホユー等（以下これらをまとめて乳等と記載する）から
常法（例えば、イオン交換クロマトグラフィー）により
分離したラクトフェリン、それらから常法により鉄を除
去したアポラクトフェリン、それらを常法により鉄、銅
、亜鉛、マンガン等の金属をキレートさせた金属飽和ラ
クトフェリン（以下これらをまとめてＬＦと記載する）
である。[Means for Solving the Problems] The lactoferrin used in the present invention is a commercially available product, colostrum of mammals (e.g., humans, cows, sheep, goats, horses, etc.), transitional milk, pores, terminal pores, etc. Skim milk, which is a processed product of these,
Lactoferrin separated from whey etc. (hereinafter collectively referred to as milk etc.) by a conventional method (e.g. ion exchange chromatography), apolactoferrin from which iron is removed by a conventional method, iron and copper separated by a conventional method. , metal-saturated lactoferrin chelated with metals such as zinc and manganese (hereinafter collectively referred to as LF)
It is.
本発明のチロシナーゼ活性阻害剤は、ＬＦそのものであ
っても良いが、ＬＦの有効量を成分として含有している
ＬＦ配配合老若くは組成物であっても良い。例えば精製
水にＬＦを溶解し、必要に応じ適宜乳化剤、賦形剤、香
料などの食品、化粧品、医薬部外品又は医薬品またはそ
れらの成分として許容されている各種成分のひとつ以上
と混合いて乳化あるいは分散することかできる。ＬＦの
荷効量は、少なくとも０５％、望ましくはチロシナーゼ
活性阻害剤果か５０％以上を示す１．０％〜２．０％、
である。The tyrosinase activity inhibitor of the present invention may be LF itself, or may be an LF-containing composition containing an effective amount of LF as a component. For example, LF is dissolved in purified water and emulsified by mixing it with one or more of foods, cosmetics, quasi-drugs, or pharmaceuticals, such as emulsifiers, excipients, and fragrances, or various ingredients that are permitted as ingredients thereof. Or it can be distributed. The effective amount of LF is at least 0.5%, preferably 1.0% to 2.0%, showing a tyrosinase activity inhibitor effect of 50% or more.
It is.
次に試験例を示して本発明を詳述する。Next, the present invention will be explained in detail by showing test examples.
（試験例）
この試験は、各種ＬＦのチロシナーゼ活性阻害効果を調
へるために行われた。(Test Example) This test was conducted to examine the tyrosinase activity inhibiting effects of various LFs.
（１）試料の調整
１）アポラクトフェリン
乳等から分離したままの市販のＬＦ（ベルギのオレオフ
ィナ社製。以下間し）［以下の記載において１乳等から
分離したままの」なる文言は、ラクトフェリンを乳等か
ら分離したのみであって、脱鉄、金属飽和等の化学的処
理を行っていないこと（即ちアポラクトフェリン、金属
飽和ラクトフェリンでないことを意味する１ ９０ｇを
精製水２１００ｍ＋２に溶解し、１０％クエン酸水溶液
を添加してｐ）（を２．５に調整し、室温で１時間反応
させた。(1) Preparation of sample 1) Apolactoferrin Commercially available LF (manufactured by Oleofina, Belgium) as separated from milk, etc. [In the following description, the phrase "as isolated from milk, etc." is only separated from milk, etc., and has not undergone any chemical treatment such as iron removal or metal saturation (that is, it is not apolactoferrin or metal-saturated lactoferrin). % citric acid aqueous solution was added to adjust p)( to 2.5, and the reaction was carried out at room temperature for 1 hour.
この反応生成物を限外濾過し、そのケーキを凍結乾燥し
てアポラクトフェリン約８７ｇを調製した。The reaction product was ultrafiltered and the cake was freeze-dried to prepare about 87 g of apolactoferrin.
２）ラクトフェリン亜鉛
前記ｌ）のアポラクトフェリン３０ｇを０．０５Ｍリン
酸緩衝液（ｐＨ７−６）７００ｍＱに溶解し、これを２
．６ｍＭクエン酸含有２゜６ｍＭ硫酸亜鉛水酸液２８５
ｍ＋２と、室温において１５分間反応させた。2) Lactoferrin zinc Dissolve 30 g of apo-lactoferrin from l) above in 700 mQ of 0.05 M phosphate buffer (pH 7-6), and add 2
．． 2°6mM zinc sulfate hydroxide solution containing 6mM citric acid 285
m+2 for 15 minutes at room temperature.
この反応生成物を限界濾過し、そのケーキを凍結乾燥し
てラクトフェリン亜鉛約２５ｇを調製した。The reaction product was ultrafiltered and the cake was freeze-dried to prepare about 25 g of zinc lactoferrin.
３）ラクトフェリン銅
前記２）において、２．５ｍＭクエン酸含有２．６ｍＭ
硫酸亜鉛水溶液の代わりに、２゜６ｍＭクエン酸含有２
．６ｍＭ硫酸銅水溶液を使用したこと以外は２）と同様
にしてラクトフェリン銅約２４ｇを調製した。3) Lactoferrin copper 2.6mM containing 2.5mM citric acid in 2) above
Instead of zinc sulfate aqueous solution, 2.6mM citric acid containing 2
．． Approximately 24 g of copper lactoferrin was prepared in the same manner as in 2) except that a 6 mM copper sulfate aqueous solution was used.
４）ラクトフェリン鉄
市販のＬＰ（オレオフィナ社製）３０ｇを精製水７００
ｍ１２に溶解し、これを２．６’ｍＭ硫酸鉄水溶液２８
５ｍ＋２と室温において２４時間反応させた。この反応
生成物を限外濾過し、そのケーキを凍結乾燥してラクト
フェリン鉄約２６ｇを調製した。4) Lactoferrin iron 30g of commercially available LP (manufactured by Oreofina) and 700 g of purified water
m12 and add this to a 2.6'mM iron sulfate aqueous solution 28
5m+2 for 24 hours at room temperature. The reaction product was ultrafiltered and the cake was freeze-dried to prepare about 26 g of iron lactoferrin.
（３）試験方法
■）チロシナーゼ活性阻害効果の測定
ａ）各種溶液の調製
■基質溶液の調製
試薬特級のし一チロシン（和光紬薬工業社製）を０．１
Ｍリン酸緩衝液に０．０４５％（Ｗ／Ｖ）の濃度で溶解
した。(3) Test method ■) Measurement of tyrosinase activity inhibition effect a) Preparation of various solutions ■ Preparation of substrate solution Reagent Special grade Noshiichi tyrosine (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) at 0.1
It was dissolved in M phosphate buffer at a concentration of 0.045% (W/V).
■酵素溶液の調製
マツシュルーム由来のチロシナーゼ（シグマ社製。３．
０００単位／ ｍ ｇ ）を０．１Ｍリン酸緩衝液（ｐ
Ｈ７，０）にＯ，１％（Ｗ；／ Ｖ ）の濃度で溶解し
た。■Preparation of enzyme solution Tyrosinase derived from pine mushroom (manufactured by Sigma. 3.
000 units/mg) in 0.1 M phosphate buffer (p
It was dissolved in H7,0) at a concentration of O,1% (W;/V).
■銅イオン溶液の調製
試薬特級の硫酸銅（和光紬薬工業社製）を精製水に１％
（Ｗ／Ｖ）の濃度で溶解した。■Preparation of copper ion solution Add 1% reagent special grade copper sulfate (manufactured by Wako Tsumugi Kogyo Co., Ltd.) to purified water.
(W/V).
■試料溶液の調製
前期（１）において調製した各試料を表１に示した各濃
度でＯ，１ＭＩＪン酸暖衝液（ｐＨ７゜０）に溶解した
。(2) Preparation of sample solutions Each of the samples prepared in the first step (1) was dissolved in O, 1MIJ acid buffer solution (pH 7.0) at each concentration shown in Table 1.
ｂ）酸素反応
予め３７°Ｃに加温した基質溶液０．９ｍＱ、試料溶液
１．０ｍρ、銅イオン溶液０．０２ｍρを試験管に採取
し、同温度に加温した酵素溶液０゜０８ｍ４を添加し、
（全量２．０ｒｒｌ） 、３７°Ｃで３分間反応させた
。次いで３０％酢酸溶液２ｍＱを添加して反応を停止き
せ、分光光度計で波長６４０ｎｍでの吸殉度を測定した
。（この吸光値をＢとする）。対照として試料溶液の代
わりにＯ，１Ｍリン酸緩衝液１．０ｍｆｆを添加して同
様に吸光度を測定した（この吸光値をＡとする）。尚、
試験溶液が白濁している場合は、酵素溶液の代わりに０
．１Ｍリン酸緩衝液０゜０８ｍＱを添加して同様に吸光
度を測定しくこの吸光値をＣとする）、反応液の濁り部
分に由来する吸光度を除去した。測定された各吸光値か
らチロシナーゼ活性阻害率（％）を次式により算出した
。b) Oxygen reaction 0.9 mQ of the substrate solution, 1.0 mρ of the sample solution, and 0.02 mρ of the copper ion solution preheated to 37°C are collected in a test tube, and 0°08 m4 of the enzyme solution heated to the same temperature is added. death,
(Total volume: 2.0 rrl) and reacted at 37°C for 3 minutes. Next, 2 mQ of 30% acetic acid solution was added to stop the reaction, and the absorbance intensity at a wavelength of 640 nm was measured using a spectrophotometer. (This absorbance value is designated as B). As a control, 1.0 mff of O, 1M phosphate buffer was added instead of the sample solution, and the absorbance was measured in the same manner (this absorbance value was designated as A). still,
If the test solution is cloudy, use 0 instead of the enzyme solution.
．． 0.08 mQ of 1M phosphate buffer was added and the absorbance was measured in the same manner (this absorbance value was designated as C) to remove the absorbance originating from the turbid part of the reaction solution. Tyrosinase activity inhibition rate (%) was calculated from each measured absorbance value using the following formula.
阻害率（％）＝ｌＯＯ［１−（Ｂ−Ｃ）／Ａ］（３）試
験結果
この試験の結果は表１に示すとおりであった。Inhibition rate (%) = lOO[1-(B-C)/A] (3) Test results The results of this test were as shown in Table 1.
（注）チロシナーゼ活性阻害率（％）
表１から明らかなようにラクトフェリン、ラクトフェリ
ンに結合している鉄を除去したアポラクトフェリン、ア
ポラクトフェリンに亜鉛、□銅、鉄をそれぞれ結合させ
たラクトフェリン亜鉛、ラクトフェリン銅、ラクトフェ
リン鉄は、いずれも０１１％の添加で約ｌＯ％のチロシ
ナーゼ活性阻害効果を示した。阻害効果は添加量が増大
するにつれて向上し、１％の添加で約５０％、２％の添
加で約８０％の阻害率を示した。なお、これらのラクト
フェリン類の間には阻害率に有意な差は認められなかっ
た。(Note) Tyrosinase activity inhibition rate (%) As is clear from Table 1, lactoferrin, apolactoferrin from which the iron bound to lactoferrin has been removed, lactoferrin from which zinc, □ copper, and iron are bound to apolactoferrin, zinc, and lactoferrin Copper and lactoferrin iron both exhibited an inhibitory effect on tyrosinase activity of about 10% when added at 0.11%. The inhibitory effect improved as the amount added increased, and the inhibition rate was about 50% with 1% addition and about 80% with 2% addition. Note that no significant difference in inhibition rate was observed between these lactoferrins.
次に実施例を示して本発明を更に詳述する。Next, the present invention will be explained in further detail by showing examples.
実施例Ｉ
市販のＬＦ（オレオフィナ社製）２７０ｇを精製水６３
００ｍｆｆに溶解した後、１０％クエン酸水溶液を添加
してそのｐＨを２．５に調整し、室温において１時間反
応させた。この反応生成物を限外濾過し、そのケーキを
凍結乾燥してアポラクトフェリン約２６０ｇを得た。こ
のアポラクトフェリン２００ ｇ、グリシン（和光紬薬
工業社製）７００ｇ及びリゾチーム（和光紬薬工業）１
００ｇを均一に混合し、食品の鮮度保持用のチロシナー
活性阻害剤約１０００ｇを得た。Example I 270 g of commercially available LF (manufactured by Oleofina) was mixed with 63 g of purified water.
After dissolving in 00 mff, a 10% aqueous citric acid solution was added to adjust the pH to 2.5, and the mixture was reacted at room temperature for 1 hour. The reaction product was ultrafiltered and the cake was freeze-dried to obtain about 260 g of apolactoferrin. 200 g of this apolactoferrin, 700 g of glycine (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) and 1 gram of lysozyme (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.)
00g were mixed uniformly to obtain about 1000g of a tyrosiner activity inhibitor for preserving the freshness of foods.
得られた食品の鮮度保持用のチロシナーゼ活性阻害剤を
１０％の濃度で水に溶解し、チロ／ナゼ活性阻害率を試
験例と同一の方法で測定した結果、８２％であった。The obtained tyrosinase activity inhibitor for preserving food freshness was dissolved in water at a concentration of 10%, and the inhibition rate of tyrosinase activity was measured in the same manner as in the test example, and the result was 82%.
実施例２
実施例１で得たアポラクトフェリン６０ｇを０゜０５Ｍ
リン酸暖衝液（ｐＨ７，６）１４００ｍｃに溶解し、こ
れを２．６ｍＭクエン酸含有２．６ｍＭ硫酸銅水溶液５
７０ｍ（ｌと、室温において１５分間反応させた。この
反応生成物を限外濾過し、そのケーキを凍結乾燥してラ
クトフェリン銅約５０ｇを調製した。Example 2 60g of apolactoferrin obtained in Example 1 was added to 0°05M
Dissolved in 1400mc of phosphoric acid warm solution (pH 7,6), and added 2.6mM copper sulfate aqueous solution containing 2.6mM citric acid.
The reaction product was ultrafiltered and the cake was freeze-dried to prepare about 50 g of copper lactoferrin.
このラクトフェリン銅４０ｇ、 プロピレングリコール
（和光紬薬工業社製）２００ｇ、オレイルアルコール（
和光紬薬工業社製）２ｇ、エタノール（和光紬薬工業社
製）１００ｇ及び精製水１６５８ｇを均一に混合し、化
粧品用チロシナーゼ活性阻害剤約２０００ｇを得た。40 g of this lactoferrin copper, 200 g of propylene glycol (manufactured by Wako Tsumugi Kogyo Co., Ltd.), and oleyl alcohol (
(manufactured by Wako Tsumugi Kogyo Co., Ltd.), 100 g of ethanol (manufactured by Wako Tsumugi Kogyo Co., Ltd.), and 1,658 g of purified water were uniformly mixed to obtain about 2,000 g of a tyrosinase activity inhibitor for cosmetics.
得られた化粧品用チロシナーゼ活性阻害剤のチロシナー
ゼ活性阻害率を試験例と同一の方法で測定した結果、見
掛けの阻害率は５１％であったが、濃度換算を行った実
際の阻害率は８１％であった。The tyrosinase activity inhibition rate of the obtained cosmetic tyrosinase activity inhibitor was measured using the same method as in the test example, and the apparent inhibition rate was 51%, but the actual inhibition rate when converted to concentration was 81%. Met.
実施例３
市販のＬＦ（オレオフィナ社製）９０ｇを精製水２１０
０ｍＱに溶解し、これを２．６ｍ（２硫酸鉄水溶液７５
５ｍＱと室温において２４時間反応させた。この反応生
成物を限外濾過し、そのケーキを凍結乾燥してラクトフ
ェリン鉄約７８ｇを調製しｌ二。このラクトフェリン鉄
６０ｇ１ ヒアルロン酸ナトリウム（和光紬薬工業社製
）２ｇ、グリセリン（和光紬薬工業社製）２０ｇ及び精
製水１９１８ｇを均一に混合し、化粧品用チロシナーゼ
活性阻害剤約２０００ｇを得た。Example 3 90 g of commercially available LF (manufactured by Oleofina) was mixed with 210 g of purified water.
Dissolve in 0 mQ, add 2.6 m (2 iron sulfate aqueous solution 75
It was reacted with 5mQ at room temperature for 24 hours. The reaction product was ultrafiltered, and the cake was freeze-dried to prepare about 78 g of iron lactoferrin. 60 g of this lactoferrin iron, 2 g of sodium hyaluronate (manufactured by Wako Tsumugi Kogyo Co., Ltd.), 20 g of glycerin (manufactured by Wako Tsumugi Kogyo Co., Ltd.) and 1918 g of purified water were uniformly mixed to obtain about 2000 g of a tyrosinase activity inhibitor for cosmetics.
得られた化粧品用チロシナーゼ活性阻害剤のチロシナー
ゼ活性阻害率を試験例と同一の方法で測定した結果、見
掛けの阻害率は７５％であったが、濃度換算を行った実
際の阻害率は９０％であった。The tyrosinase activity inhibition rate of the obtained cosmetic tyrosinase activity inhibitor was measured using the same method as the test example, and the apparent inhibition rate was 75%, but the actual inhibition rate when converted to concentration was 90%. Met.
［発明の効果］ 本発明によって奏せられる効果は次のとおりである。[Effect of the invention] The effects achieved by the present invention are as follows.
（１）本発明のチロシナーゼ活性阻害剤は各種製品に添
加しても安定であり、すぐれた作用か得られる。(1) The tyrosinase activity inhibitor of the present invention is stable even when added to various products, and provides excellent effects.
（２）本発明のチロ／カーゼ活性阻害剤は液状又は粉末
状のいずれの状態も使用できるので、用途か広範である
。(2) The tyro/case activity inhibitor of the present invention can be used in either liquid or powder form, so it has a wide range of uses.
Claims (2)
ラクトフェリン、金属飽和ラクトフェリン、及びこれら
の任意の混合物からなる群より選択されるラクトフェリ
ンを有効成分として含有することを特徴とするチロシナ
ーゼ活性阻害剤。(1) A tyrosinase activity inhibitor containing as an active ingredient lactoferrin selected from the group consisting of lactoferrin isolated from the milk of chewing mammals, apolactoferrin, metal-saturated lactoferrin, and any mixture thereof.
含有されている請求項（１）記載のチロシナーゼ活性阻
害剤。(2) The tyrosinase activity inhibitor according to claim (1), wherein the active ingredient is contained in a concentration of at least 0.5% (by weight).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2169637A JP2702590B2 (en) | 1990-06-26 | 1990-06-26 | Tyrosinase activity inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2169637A JP2702590B2 (en) | 1990-06-26 | 1990-06-26 | Tyrosinase activity inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0459714A true JPH0459714A (en) | 1992-02-26 |
| JP2702590B2 JP2702590B2 (en) | 1998-01-21 |
Family
ID=15890188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2169637A Expired - Lifetime JP2702590B2 (en) | 1990-06-26 | 1990-06-26 | Tyrosinase activity inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2702590B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032847A1 (en) * | 2006-09-11 | 2008-03-20 | Up Well Co. Ltd. | External preparation for skin |
| JP2008532513A (en) * | 2005-03-08 | 2008-08-21 | フォンテラ コ−オペレイティブ グループ リミティド | High-pressure treatment of metal ion lactoferrin |
| JP2008290975A (en) * | 2007-05-25 | 2008-12-04 | Snow Brand Milk Prod Co Ltd | Skin whitening agent |
-
1990
- 1990-06-26 JP JP2169637A patent/JP2702590B2/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008532513A (en) * | 2005-03-08 | 2008-08-21 | フォンテラ コ−オペレイティブ グループ リミティド | High-pressure treatment of metal ion lactoferrin |
| WO2008032847A1 (en) * | 2006-09-11 | 2008-03-20 | Up Well Co. Ltd. | External preparation for skin |
| JPWO2008032847A1 (en) * | 2006-09-11 | 2010-01-28 | 株式会社アップウェル | Topical skin preparation |
| JP2008290975A (en) * | 2007-05-25 | 2008-12-04 | Snow Brand Milk Prod Co Ltd | Skin whitening agent |
| WO2008146710A1 (en) * | 2007-05-25 | 2008-12-04 | Snow Brand Milk Products Co., Ltd. | Skin whitening agent |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2702590B2 (en) | 1998-01-21 |
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