JP4175740B2 - Melanin production inhibitor - Google Patents
Melanin production inhibitor Download PDFInfo
- Publication number
- JP4175740B2 JP4175740B2 JP15602899A JP15602899A JP4175740B2 JP 4175740 B2 JP4175740 B2 JP 4175740B2 JP 15602899 A JP15602899 A JP 15602899A JP 15602899 A JP15602899 A JP 15602899A JP 4175740 B2 JP4175740 B2 JP 4175740B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- melanin production
- parts
- present
- skin
- 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.)
- Expired - Fee Related
Links
- 230000008099 melanin synthesis Effects 0.000 title claims description 29
- 239000003112 inhibitor Substances 0.000 title claims description 12
- 210000003491 skin Anatomy 0.000 description 22
- YZHICMXANUYYLB-UHFFFAOYSA-N OC1=C(C)C=C2C(C(C)C)CC=C(C)C2=C1 Chemical compound OC1=C(C)C=C2C(C(C)C)CC=C(C)C2=C1 YZHICMXANUYYLB-UHFFFAOYSA-N 0.000 description 18
- 239000002537 cosmetic Substances 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- -1 alkali metal salts Chemical class 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000006210 lotion Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000002087 whitening effect Effects 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 241000208983 Arnica Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000003425 Tyrosinase Human genes 0.000 description 2
- 108060008724 Tyrosinase Proteins 0.000 description 2
- 239000003788 bath preparation Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical group 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000004200 microcrystalline wax Substances 0.000 description 2
- 235000019808 microcrystalline wax Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010040829 Skin discolouration Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- OSJHTLOGFHGOEK-UHFFFAOYSA-N [2,2-dimethyl-3-(6-methylheptanoyloxy)propyl] 6-methylheptanoate Chemical compound CC(C)CCCCC(=O)OCC(C)(C)COC(=O)CCCCC(C)C OSJHTLOGFHGOEK-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960000271 arbutin Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000013040 bath agent Substances 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229940119170 jojoba wax Drugs 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 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
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Landscapes
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、化粧料などに好適な皮膚外用剤に関する。
【０００２】
【従来の技術】
色白の美しい肌は、古来より全人が希望してきたことであり、この様な肌を得るために数々の努力が為されてきた。この中で、色の白さ、言い換えれば色の黒さの原因が、メラノサイトで生成されるメラニンであることが明らかにされた。このメラニンの量の多少により、肌の色が黒くなったり白くなったりすることも解明された。このメラニンの生合成には、チロシナーゼやチロシナーゼ関連蛋白質群と呼ばれる蛋白が関与していることも既に知られていることである。又、この様な酵素等の働きを阻害し色白を具現化するための素材や化粧料が開発され、かなりの程度は色を白くすることが可能になってきた。しかしながら、色黒とメラニンの生合成の関係についてこれらからでは説明しきれない因子が残っており、又、色黒について、その種類によってメラニンの生合成の関係因子が異なっていることもおぼろげながら知られるようになってきた。しかしながら、従来より、比較的効果が高いとされているメラニン産生抑制剤であっても、その効果が発現しない人が存在することも既に良く知られていることである。この理由としては、メラニン産生に関与する因子が多く、これの差違によって、メラニン産生抑制剤が効果を発揮したりしなかったりするものであると考えられている。この様な因子とメラニン産生のメカニズムは解明されきっているとは言えず、従って、種々の種類の新規のメラニン産生抑制剤を探し出すことが望まれているのが現状と言わざるを得ない。
【０００３】
一方、後記一般式（Ｉ）に表される化合物は、既に文献公知の化合物であるが、これらを皮膚外用剤に含有させることも、これらの化合物がメラニン産生抑制作用を有していることも全く知られていなかった。
【０００４】
【発明が解決しようとする課題】
本発明は、新規のメラニン産生抑制剤を見いだし、メラニン産生抑制作用を有する化粧料などの皮膚外用剤を提供することを課題とする。
【０００５】
【課題の解決手段】
この様な状況に鑑み、本発明者らは新規のメラニン産生抑制剤を求め鋭意研究を重ねた結果、後記式（Ｉ）に表される７−ヒドロキシ−３，４−ジヒドロカダリン、その７−アシル化物、又は７−アルキル化物に、その様な作用を見いだした。更に、皮膚外用剤への応用研究を重ねた結果、かかる化合物を含有する皮膚外用剤が、メラニン産生抑制作用に起因する美白効果を有していることを見いだし、発明を完成させるに至った。以下、本発明について実施の形態を中心に詳細に説明を加える。
【０００６】
【化３】
【０００７】
【発明の実施の形態】
（１）本発明のメラニン産生抑制剤
本発明のメラニン産生抑制剤は、上記式（Ｉ）に表される７−ヒドロキシ−３，４−ジヒドロカダリン、その７−アシル化物、又は７−アルキル化物からなる。該化合物は様々な類縁体や立体異性体が存在するが、７−ヒドロキシ−３，４−ジヒドロカダリンが特に好ましい。これは、優れたメラニン産生抑制作用を有するからである。この立体構造は化学構造式２に示されるものが最も一般的であるので好ましい。この様な構造を有する化合物は、天然物として植物体などに多く含まれているので、植物体の抽出物を精製して得ることもできる。例えば、一般式（Ｉ）に表される化合物であれば、アルニカ等のキク科ウサギギク属の植物体中に多く含まれていることを、本発明者らは見いだしている。これらの植物体にメタノールなどの溶媒を加え、室温であれば数日、沸点付近の温度であれば数時間浸漬し、濾過した後濃縮し、シリカゲルカラムクロマトグラフィー等の方法で精製すれば得ることが出来る。又、比較的簡単な化学構造であるため、化学合成によっても製造することができる。本発明では、これら何れの方法で製造された一般式（Ｉ）に表される化合物であってもメラニン産生抑制剤として使用できる。これらの化合物は何れも優れた安全性とメラニン産生抑制作用とを有する。又、これらの中にはフェノール性水酸基を有し塩を形成するものがあるが、この様な塩を用いることも、本発明の技術的範囲に属する。塩としては、生理的に許容されるものであれば、特段の限定無く使用することができ、例えば、ナトリウムやカリウム等のアルカリ金属塩、カルシウムやマグネシウムなどのアルカリ土類金属塩、アンモニウム塩、有機アミン塩、リジンやアルギニンなどの塩基性アミノ酸塩等が好適に例示できる。又、この様な水酸基を有する一般式（Ｉ）に表される化合物を常法に従って処理すると、アセチル化物等のアシル化物やメチル化物などのアルキル化物を得ることができる。これらも、塩同様に本発明の技術的範囲に属する。即ち、アシル化であれば、ピリジン等の塩基を溶媒にアシルハライドを反応させればよいし、アルキル化であればアルカリ存在下アルキルハライドを反応させればよい。
【０００８】
＜製造例１＞
キク科アルニカの植物体５００ｇに１００％メタノールを５ｌ加えて、３時間加熱還流し、冷却後減圧濃縮し、水５ｌとｎ−ヘキサン５ｌを加え、液液抽出を行い、ｎ−ヘキサン層を取り、濃縮した後、シリカゲルカラムクロマトグラフィー（溶出溶媒；ノルマルヘキサン：酢酸エチル＝１００：０→５０：５０）で精製し、ｎ−ヘキサンから再結晶して、７−ヒドロキシ−３，４−ジヒドロカダリン（化学構造式１）を得た。このものの立体は化学構造式２であるものと、ＮＭＲの測定結果より推定された。
【０００９】
【化４】
【００１０】
【化５】
【００１１】
（２）本発明の好適に適用される皮膚外用剤
本発明皮膚外用剤は、上記式（Ｉ）に表される７−ヒドロキシ−３，４−ジヒドロカダリン、その７−アシル化物、又は７−アルキル化物を含有することを特徴とする。上記式（Ｉ）に表される７−ヒドロキシ−３，４−ジヒドロカダリンは優れた安全性とメラニン産生抑制作用を有しているため、本発明の皮膚外用剤は化粧料として好適であり、中でも美白用の化粧料として特に好適である。ここで、本発明で言う皮膚外用剤とは、皮膚上に投与する形態の組成物の総称であって、皮膚外用医薬組成物、医薬部外品、化粧料、皮膚洗浄料、浴用剤などを総括して意味する言葉である。皮膚外用剤において、一般式（Ｉ）に表される７−ヒドロキシ−３，４−ジヒドロカダリン、その７−アシル化物、又は７−アルキル化物の好ましい含有量は、総量で０．０１〜１０重量％であり、更に好ましくは更に好ましくは０．０５〜１重量％である。一般式（Ｉ）に表される化合物で、本発明の皮膚外用剤に特に好ましく含有されるものは、７−ヒドロキシ−３，４−ジヒドロカダリン（化学構造式１）である。
【００１２】
本発明では、上記必須成分以外に、通常皮膚外用剤で使用される、任意成分を含有することが出来る。かかる任意成分としては、ワセリンやマイクロクリスタリンワックス等のような炭化水素類、ホホバ油やゲイロウ等のエステル類、牛脂、オリーブ油等のトリグリセライド類、セタノール、オレイルアルコール等の高級アルコール類、ステアリン酸、オレイン酸等の脂肪酸、グリセリンや１，３−ブタンジオール等の多価アルコール類、非イオン界面活性剤、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、エタノール、カーボポール等の増粘剤、防腐剤、紫外線吸収剤、抗酸化剤、色素、粉体類等が好ましく例示できる。勿論、既にメラニン産生抑制作用が知られている、ビタミンＣとその誘導体、ハイドロキノンとその誘導体、レゾルシノールとその誘導体等を含有することも可能である。本発明の皮膚外用剤は上記必須成分と任意成分とを常法に従って処理することにより得ることが出来る。
【００１３】
【実施例】
以下に、実施例を挙げて、本発明について更に詳細に説明を加えるが、本発明がこれら実施例にのみ限定を受けないことは言うまでもない。
【００１４】
＜実施例１＞
メラニン産生抑制作用
上記化合物１について、メラニン産生抑制作用をマウスメラノーマＢ−１６細胞を用いて、メラニン産生抑制作用を調べた。即ち、プラスチック培養フラスコ（２５ｃｍ２）内の１０％ＦＢＳ加ＭＥＭ培地に９×１０４個のマウスメラノーマＢ−１６細胞を播種し、５％炭酸ガス加気流中３７℃で培養した。播種２４時間後、最終濃度１×１０−３（Ｗ／Ｖ）％となるように、上記メラニン産生抑制剤をＤＭＳＯに溶解させて加え、更に２日間培養した。この際、ＤＭＳＯは最終濃度で０．２％を越えないように注意した。培養終了後、培地を除き、燐酸緩衝生理食塩水液で洗浄後、トリプシン処理し細胞を剥離させ、遠心分離により細胞を回収し、細胞数より細胞毒性を、細胞の色よりメラニン産生抑制作用を判定した。判定基準は細胞数が、＋＋：検体無添加（対照）に比し著しく少ない、＋：対照に比し明らかに少ない、±：対照に比しやや少ない、−：対照に比し同程度であり、メラニン産生抑制作用は、＋＋：対照に比し著しく白い、＋：対照に比し明らかに白い、±：対照に比しやや白い、−：対照同程度に黒いであった。結果を表１に示す。これより、本発明のメラニン産生抑制剤は細胞毒性が低いにもかかわらずメラニン産生抑制作用に優れることがわかる。
【００１５】
【表１】
＜実施例２＞
以下に示す処方に従って、本発明の化粧料を作成した。即ち、処方成分を室温で撹拌溶解し、本発明の化粧料である化粧水を得た。
７−ヒドロキシ−３，４−ジヒドロカダリン １ 重量部
ポリオキシエチレン（６０）硬化ヒマシ油 ０．５重量部
エタノール １０ 重量部
グリセリン ５ 重量部
水 ８３．５重量部
【００１７】
＜実施例３＞
以下に示す処方に従って、本発明の化粧料を作成した。即ち、処方成分を室温で撹拌溶解し、本発明の化粧料である化粧水を得た。
７−ヒドロキシ−３，４−ジヒドロカダリン ０．１重量部
ポリオキシエチレン（６０）硬化ヒマシ油 ０．５重量部
エタノール １０ 重量部
グリセリン ５ 重量部
水 ８４．４重量部
【００１８】
＜実施例４＞
以下に示す処方に従って、本発明の化粧料を作成した。即ち、処方成分を室温で撹拌溶解し、本発明の化粧料である化粧水を得た。
７−ヒドロキシ−３，４−ジヒドロカダリン ０．０１重量部
ポリオキシエチレン（６０）硬化ヒマシ油 ０．５重量部
エタノール １０ 重量部
グリセリン ５ 重量部
水 ８４．３９重量部
【００１９】
＜実施例５＞
以下に示す処方に従って、本発明のクリームを作成した。即ち、イの成分を良く混練りした後、８０℃に加熱し、ロ、ハを予め８０℃に予熱しておき、イにロを加え希釈し、これにハを徐々に加え乳化し、撹拌冷却しクリームを得た。
イ
トリグリセリンジイソステアレート ５ 重量部
マルチトール７０％水溶液 ５ 重量部
グリセリン ３ 重量部
１，３−ブタンジオール ５ 重量部
７−アセチルオキシ−３，４−ジヒドロカダリン ０．７重量部
メチルパラベン ０．２重量部
ブチルパラベン ０．１重量部
ロ
流動パラフィン １５ 重量部
マイクロクリスタリンワックス ３ 重量部
ネオペンチルグリコールジイソオクタネート ５ 重量部
カルナウバワックス ２ 重量部
ハ
水 ５６ 重量部
【００２０】
＜実施例６＞
上記実施例２〜５の各化粧料を被験者１名の上腕内側部の１ｃｍ×１ｃｍの部位に塗布した後、１時間後にふき取り、予め測定した最小紅斑照射量の２倍の線量の紫外線（線源ＢＬＢランプ及びＳＥランプ）を照射し、照射後１週間に黒化度を＋＋：対照に比し著しく白い、＋：対照に比し明らかに白い、±：対照に比しやや白いの基準で判定した。尚、対照はサンプルを投与せずに紫外線照射のみを行った。結果を表２に示す。これより本発明の皮膚外用剤である化粧料は、美白作用の内、肌が黒くなるのを予防する作用に優れることがわかる。
【００２１】
【表２】
＜実施例７＞
上記実施例３の化粧水を用いて、実使用試験を行い美白効果を確かめた。即ち、色黒に悩むパネラー１群１０名、４群計４０名を用い、実施例３の化粧水、実施例３の化粧水の化学構造式１の化合物をビタミンＣナトリウム塩に置換した比較例１、実施例３の化粧水の化学構造式１の化合物をアルブチンに置換した比較例２、実施例３の化粧水の化学構造式１の化合物を水に置換した対照例の４群で、朝晩１日２回、２カ月連続使用してもらい、色黒の改善の印象を＋＋：すばらしい改善、＋：明らかな改善、±：やや改善、−：改善せずのランクに分けてアンケートで答えてもらった。結果を表３に出現例数として示す。これより、本発明の化粧料は美白作用に優れることがわかる。
【００２３】
【表３】
＜実施例８＞
下記に示す処方に従って、色素異常症の治療用の軟膏を作成した。即ち、処方成分を良く混練りし、軟膏を得た。
白色ワセリン ９０ 重量部
７−ヒドロキシ−３，４−ジヒドロカダリン １０ 重量部
【００２５】
＜実施例９＞
下記に示す処方に従って、美白用の浴用剤を作成した。即ち、処方成分を良くヘンシェルミキサーで混合した後、０．９ｍｍ丸穴スクリーンを装着したパルベラーザーで粉砕し、浴用剤を得た。
硫酸ナトリウム ９０ 重量部
７−ヒドロキシ−３，４−ジヒドロカダリン １０ 重量部
【００２６】
【発明の効果】
本発明によれば、新規のメラニン産生抑制作用を有する化粧料などの皮膚外用剤を提供することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a skin external preparation suitable for cosmetics and the like.
[0002]
[Prior art]
Fair-skinned beautiful skin has been desired by all since ancient times, and many efforts have been made to obtain such skin. In this, it was clarified that the cause of the whiteness of color, in other words, the blackness of color, is melanin produced in melanocytes. It has also been clarified that the skin color becomes black or white depending on the amount of melanin. It is already known that proteins called tyrosinase and tyrosinase-related proteins are involved in the biosynthesis of melanin. In addition, materials and cosmetics have been developed to inhibit the action of such enzymes and the like to realize fairness, and it has become possible to whiten the color to a considerable extent. However, there are still unexplained factors regarding the relationship between the color black and melanin biosynthesis, and the factors related to the biosynthesis of melanin differ depending on the type of color black. It has become known. However, it is already well known that there are people who do not exhibit the effects of melanin production inhibitors that have been considered to have a relatively high effect. The reason for this is that there are many factors involved in melanin production, and it is considered that the melanin production inhibitor may or may not be effective due to the difference. It cannot be said that such factors and the mechanism of melanin production have been elucidated. Therefore, it is necessary to say that it is desired to search for various kinds of novel melanin production inhibitors.
[0003]
On the other hand, the compounds represented by the general formula (I) to be described later are compounds already known in the literature. However, these compounds may be contained in an external preparation for skin, or these compounds may have a melanin production inhibitory action. It was not known at all.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to find a novel melanin production inhibitor and to provide a skin external preparation such as a cosmetic having a melanin production inhibitory action.
[0005]
[Means for solving problems]
In view of such circumstances, the present inventors have result of extensive studies seeking new melanin production inhibitors, represented in the after-mentioned formula (I) 7- hydroxy-3,4 Jihidorokada Li down, its 7 -Such an action was found in acylated product or 7-alkylated product. Furthermore, as a result of repeated application studies to external preparations for skin, it was found that an external preparation for skin containing such a compound has a whitening effect due to an inhibitory action on melanin production, and has completed the invention. Hereinafter, the present invention will be described in detail with a focus on embodiments.
[0006]
[Chemical 3]
[0007]
DETAILED DESCRIPTION OF THE INVENTION
(1) Melanin production inhibitor of the present invention The melanin production inhibitor of the present invention is a 7-hydroxy-3,4-dihydrocadalin represented by the above formula (I), a 7-acylated product thereof, or a 7-alkyl. Consists of chemicals . The compound has various analogs and stereoisomers , and 7-hydroxy-3,4-dihydrocadalin is particularly preferable. This is because it has an excellent melanin production inhibitory action. As this three-dimensional structure, the one represented by the chemical structural formula 2 is the most common, which is preferable. Since many compounds having such a structure are contained in plants as natural products, they can be obtained by purifying extracts of plants. For example, the present inventors have found that a large amount of the compound represented by the general formula (I) is contained in plants of the genus Rabbitaceae such as Arnica. It can be obtained by adding a solvent such as methanol to these plants, immersing them for several days at room temperature, immersing for several hours at temperatures near the boiling point, filtering, concentrating, and purifying by a method such as silica gel column chromatography. I can do it. Moreover, since it has a relatively simple chemical structure, it can also be produced by chemical synthesis. In the present invention, the compound represented by the general formula (I) produced by any of these methods can be used as a melanin production inhibitor. These compounds all have excellent safety and melanin production-suppressing action. Some of them have a phenolic hydroxyl group to form a salt, and it is also within the technical scope of the present invention to use such a salt. As the salt, any physiologically acceptable salt can be used without any particular limitation. For example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, Suitable examples include organic amine salts, basic amino acid salts such as lysine and arginine. Further, when such a compound represented by the general formula (I) having a hydroxyl group is treated according to a conventional method, an acylated product such as an acetylated product or an alkylated product such as a methylated product can be obtained. These belong to the technical scope of the present invention as well as the salt. That is, for acylation, an acyl halide may be reacted with a base such as pyridine as a solvent, and for alkylation, an alkyl halide may be reacted in the presence of an alkali.
[0008]
<Production Example 1>
Add 5 liters of 100% methanol to 500 g of Arnica plant, heat and reflux for 3 hours, cool and concentrate under reduced pressure, add 5 liters of water and 5 liters of n-hexane, perform liquid-liquid extraction, and remove the n-hexane layer. After concentration, the residue was purified by silica gel column chromatography (elution solvent; normal hexane: ethyl acetate = 100: 0 → 50: 50), recrystallized from n-hexane, and purified by 7-hydroxy-3,4-dihydrocarbonate. Darin (chemical structural formula 1) was obtained. The solid of this product was estimated from the NMR measurement result as having the chemical structural formula 2.
[0009]
[Formula 4]
[0010]
[Chemical formula 5]
[0011]
(2) suitably applied external preparation for skin present invention The skin external preparation of the present invention is 7-hydroxy-3,4-dihydro-mosquito Darrin represented the above formula (I), its 7-acylated or 7, -An alkylated product is contained. Since the 7-hydroxy-3,4-dihydrocadalin represented by the above formula (I) has excellent safety and melanin production inhibitory action, the skin external preparation of the present invention is suitable as a cosmetic. Especially, it is particularly suitable as a cosmetic for whitening. Here, the external preparation for skin referred to in the present invention is a general term for a composition in a form to be administered on the skin, and includes an external pharmaceutical composition for skin, quasi-drug, cosmetic, skin cleansing agent, bath preparation and the like. These are words that collectively mean. In the skin external agent of the general formula (I) in represented by 7-hydroxy-3,4-dihydro-mosquito Darin, the 7-acylated, or preferred content of 7-alkylated product is the total amount from 0.01 to 10 % By weight, more preferably 0.05 to 1% by weight. The compound represented by the general formula (I) and particularly preferably contained in the external preparation for skin of the present invention is 7-hydroxy-3,4-dihydrocadalin (chemical structural formula 1).
[0012]
In this invention, in addition to the said essential component, the arbitrary component normally used with a skin external preparation can be contained. Such optional components include hydrocarbons such as petrolatum and microcrystalline wax, esters such as jojoba oil and gallow, triglycerides such as beef tallow and olive oil, higher alcohols such as cetanol and oleyl alcohol, stearic acid, olein Fatty acids such as acids, polyhydric alcohols such as glycerin and 1,3-butanediol, nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, thickeners such as ethanol and carbopol Preservatives, ultraviolet absorbers, antioxidants, pigments, powders and the like can be preferably exemplified. Of course, it is also possible to contain vitamin C and its derivatives, hydroquinone and its derivatives, resorcinol and its derivatives, which are already known to inhibit melanin production. The skin external preparation of this invention can be obtained by processing the said essential component and arbitrary components in accordance with a conventional method.
[0013]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to these examples.
[0014]
<Example 1>
Melanin Production Inhibitory Action With respect to Compound 1, the melanin production inhibitory action was examined using mouse melanoma B-16 cells. That is, seeded with 10% FBS pressurized MEM medium 9 × 10 4 cells of mouse melanoma B-16 cells in plastic culture flasks (25 cm 2), and cultured at 37 ° C. in a 5% carbon dioxide gas pressurized stream. 24 hours after sowing, the melanin production inhibitor was dissolved in DMSO and added to a final concentration of 1 × 10 −3 (W / V)%, and further cultured for 2 days. At this time, care was taken not to exceed 0.2% of DMSO at the final concentration. After completion of the culture, remove the medium, wash with phosphate buffered saline, trypsinize, peel off the cells, collect the cells by centrifugation, cytotoxicity from the number of cells, and melanin production inhibitory action from the color of the cells. Judged. Criterion is the number of cells, ++: sample significantly less than the no addition (control), +: control obviously less than in, ±: slightly less than the control, -: be comparable relative to the control The melanin production inhibitory action was ++: markedly white compared to the control, +: clearly white compared to the control, ±: slightly white compared to the control, −: black as much as the control. The results are shown in Table 1. From this, it can be seen that the melanin production inhibitor of the present invention is excellent in the melanin production inhibitory action even though the cytotoxicity is low.
[0015]
[Table 1]
<Example 2>
The cosmetic of the present invention was prepared according to the formulation shown below. That is, the prescription ingredients were stirred and dissolved at room temperature to obtain a lotion that is the cosmetic of the present invention.
7-hydroxy-3,4-dihydrocadalin 1 part by weight polyoxyethylene (60) hydrogenated castor oil 0.5 part by weight ethanol 10 parts by weight glycerin 5 parts by weight water 83.5 parts by weight
<Example 3>
The cosmetic of the present invention was prepared according to the formulation shown below. That is, the prescription ingredients were stirred and dissolved at room temperature to obtain a lotion that is the cosmetic of the present invention.
7-hydroxy-3,4-dihydrocadalin 0.1 part by weight polyoxyethylene (60) hydrogenated castor oil 0.5 part by weight ethanol 10 parts by weight glycerin 5 parts by weight water 84.4 parts by weight
<Example 4>
The cosmetic of the present invention was prepared according to the formulation shown below. That is, the prescription ingredients were stirred and dissolved at room temperature to obtain a lotion that is the cosmetic of the present invention.
7-hydroxy-3,4-dihydrocadalin 0.01 parts by weight polyoxyethylene (60) hydrogenated castor oil 0.5 parts by weight ethanol 10 parts by weight glycerin 5 parts by weight water 84.39 parts by weight
<Example 5>
The cream of the present invention was prepared according to the formulation shown below. That is, after knead | mixing the component of (a) well, it heats to 80 degreeC, preheats (b) and (c) beforehand to 80 degreeC, dilute by adding (b) to (a), and gradually add and emulsify this, and stir. Cooled to obtain a cream.
Itriglycerin diisostearate 5 parts by weight Maltitol 70% aqueous solution 5 parts by weight Glycerin 3 parts by weight 1,3-butanediol 5 parts by weight 7-acetyloxy-3,4-dihydrocadalin 0.7 parts by weight methylparaben 0. 2 parts by weight butyl paraben 0.1 part by weight liquid paraffin 15 parts by weight microcrystalline wax 3 parts by weight neopentyl glycol diisooctanoate 5 parts by weight carnauba wax 2 parts by weight C water 56 parts by weight
<Example 6>
After applying each cosmetic of Examples 2 to 5 to a 1 cm × 1 cm site on the inner side of the upper arm of one subject, it was wiped off after 1 hour, and ultraviolet rays (line) twice the minimum erythema dose measured in advance. Source: BLB lamp and SE lamp), and the degree of blackening within one week after irradiation is ++: markedly white compared to the control, +: clearly white compared to the control, ±: slightly white compared to the control Judged. As a control, only the ultraviolet irradiation was performed without administering the sample. The results are shown in Table 2. From this, it can be seen that the cosmetic which is an external preparation for skin according to the present invention is excellent in the effect of preventing the skin from becoming dark in the whitening effect.
[0021]
[Table 2]
<Example 7>
Using the lotion of Example 3 above, an actual use test was conducted to confirm the whitening effect. That is, the comparative example which substituted the compound of Chemical Formula 1 of the lotion of Example 3 and the lotion of Example 3 with vitamin C sodium salt using the panel 1 group 10 persons and 4 groups total 40 persons who suffer from darkness. 1. Comparative group 2 in which the compound of formula 1 of the lotion of Example 3 was substituted with arbutin, and 4 groups of control examples in which the compound of formula 1 of the lotion of Example 3 was substituted with water. Use twice a day for two consecutive months, and give impressions of improvement in darkness ++: Great improvement, +: Clear improvement, ±: Slight improvement,-: No improvement received. The results are shown in Table 3 as the number of appearance examples. This shows that the cosmetic of the present invention is excellent in whitening action.
[0023]
[Table 3]
<Example 8>
An ointment for treating dyschromia was prepared according to the prescription shown below. That is, the formulation components were well kneaded to obtain an ointment.
White petrolatum 90 parts by weight 7-hydroxy-3,4-dihydrocadalin 10 parts by weight
<Example 9>
A whitening bath agent was prepared according to the formulation shown below. That is, the prescription ingredients were well mixed with a Henschel mixer and then pulverized with a pulverizer equipped with a 0.9 mm round hole screen to obtain a bath preparation.
Sodium sulfate 90 parts by weight 7-hydroxy-3,4-dihydrocadalin 10 parts by weight
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, skin external preparations, such as cosmetics which have a novel melanin production inhibitory effect, can be provided.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15602899A JP4175740B2 (en) | 1999-06-03 | 1999-06-03 | Melanin production inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15602899A JP4175740B2 (en) | 1999-06-03 | 1999-06-03 | Melanin production inhibitor |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2000344619A JP2000344619A (en) | 2000-12-12 |
| JP2000344619A5 JP2000344619A5 (en) | 2004-10-28 |
| JP4175740B2 true JP4175740B2 (en) | 2008-11-05 |
Family
ID=15618742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15602899A Expired - Fee Related JP4175740B2 (en) | 1999-06-03 | 1999-06-03 | Melanin production inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4175740B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002020276A (en) * | 2000-07-06 | 2002-01-23 | Kansai Tlo Kk | Anti-inflammatory and analgesic |
-
1999
- 1999-06-03 JP JP15602899A patent/JP4175740B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000344619A (en) | 2000-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2012001467A (en) | Skin external preparation | |
| JPH0930946A (en) | Beautifying and whitening dermal preparation for external use | |
| JPH10279428A (en) | Cosmetics | |
| JP3584489B2 (en) | External preparation for skin | |
| JPH0925209A (en) | Skin preparation for external use | |
| JP4175740B2 (en) | Melanin production inhibitor | |
| JPH0925212A (en) | Skin preparation for external use | |
| JPH0925214A (en) | Skin preparation for external use | |
| JP3869949B2 (en) | Skin external preparation suitable for whitening | |
| JP3869558B2 (en) | Skin external preparation suitable for whitening | |
| JP2001335472A (en) | Tyrosinase activity inhibitor and cosmetic | |
| JP4235602B2 (en) | Melanin production inhibitor and topical skin preparation | |
| JPH09241154A (en) | Preparation for external use for skin | |
| JP3967471B2 (en) | Skin external preparation suitable for whitening | |
| JPH0930945A (en) | Dermal preparation for external use | |
| JP3650147B2 (en) | Melanin production inhibitor and topical skin preparation | |
| JPH08301758A (en) | Skin preparation for external use | |
| JP2000247874A (en) | Preparation for external use for skin suitable for bleaching | |
| JP4762477B2 (en) | Topical skin preparation | |
| JPH07277941A (en) | External preparation for skin | |
| JPH0930948A (en) | Beautifying and whitening dermal preparation for external use | |
| JPH11139931A (en) | Preparation for external use for skin whitening | |
| KR20050085266A (en) | Dendrite elongation inhibitor for melanocyte and skin preparation for external use containing the same | |
| JPH0920635A (en) | Whitening skin preparation for external use | |
| JP3354031B2 (en) | External preparation for skin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20041122 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20041207 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050207 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20050308 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050428 |
|
| A911 | Transfer of reconsideration by examiner before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20050623 |
|
| A912 | Removal of reconsideration by examiner before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20060721 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080624 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20080819 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140829 Year of fee payment: 6 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |