JP2017066167A - ミトコンドリア機能改善剤、及び製造方法 - Google Patents
ミトコンドリア機能改善剤、及び製造方法 Download PDFInfo
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- JP2017066167A JP2017066167A JP2017008866A JP2017008866A JP2017066167A JP 2017066167 A JP2017066167 A JP 2017066167A JP 2017008866 A JP2017008866 A JP 2017008866A JP 2017008866 A JP2017008866 A JP 2017008866A JP 2017066167 A JP2017066167 A JP 2017066167A
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- Prior art keywords
- acid
- extract
- sodium
- group
- oil
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- 230000004898 mitochondrial function Effects 0.000 title claims abstract description 47
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 24
- ZMJBYMUCKBYSCP-UHFFFAOYSA-N Hydroxycitric acid Chemical class OC(=O)C(O)C(O)(C(O)=O)CC(O)=O ZMJBYMUCKBYSCP-UHFFFAOYSA-N 0.000 claims abstract description 85
- 150000003839 salts Chemical class 0.000 claims abstract description 70
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 65
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- -1 alkali metal salt Chemical class 0.000 claims description 365
- 239000003795 chemical substances by application Substances 0.000 claims description 84
- 125000004432 carbon atom Chemical group C* 0.000 claims description 65
- 229940089491 hydroxycitric acid Drugs 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 37
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- 238000000034 method Methods 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 229910052783 alkali metal Inorganic materials 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
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- 239000001257 hydrogen Substances 0.000 claims description 3
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- 125000001183 hydrocarbyl group Chemical group 0.000 claims 12
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000013535 sea water Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VIDTVPHHDGRGAF-UHFFFAOYSA-N selenium sulfide Chemical compound [Se]=S VIDTVPHHDGRGAF-UHFFFAOYSA-N 0.000 description 1
- 229960005265 selenium sulfide Drugs 0.000 description 1
- 229940124513 senna glycoside Drugs 0.000 description 1
- VRMHCMWQHAXTOR-CMOCDZPBSA-N sesamin Natural products C1=C2OCOC2=CC([C@@H]2OC[C@@]3(C)[C@H](C=4C=C5OCOC5=CC=4)OC[C@]32C)=C1 VRMHCMWQHAXTOR-CMOCDZPBSA-N 0.000 description 1
- 229950008379 siccanin Drugs 0.000 description 1
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- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
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- 229910021647 smectite Inorganic materials 0.000 description 1
- LLELVHKMCSBMCX-UHFFFAOYSA-M sodium 1-[(4-chloro-5-methyl-2-sulfophenyl)diazenyl]naphthalen-2-olate Chemical compound [Na+].Cc1cc(N=Nc2c(O)ccc3ccccc23)c(cc1Cl)S([O-])(=O)=O LLELVHKMCSBMCX-UHFFFAOYSA-M 0.000 description 1
- LGZQSRCLLIPAEE-UHFFFAOYSA-M sodium 1-[(4-sulfonaphthalen-1-yl)diazenyl]naphthalen-2-olate Chemical compound [Na+].C1=CC=C2C(N=NC3=C4C=CC=CC4=CC=C3O)=CC=C(S([O-])(=O)=O)C2=C1 LGZQSRCLLIPAEE-UHFFFAOYSA-M 0.000 description 1
- OEVOERXYCSHDAU-UHFFFAOYSA-M sodium 4-(2,6-dichloro-3-methylbenzoyl)-2,5-dimethylpyrazol-3-olate Chemical compound ClC1=C(C=CC(=C1C(=O)C=1C(=NN(C=1[O-])C)C)Cl)C.[Na+] OEVOERXYCSHDAU-UHFFFAOYSA-M 0.000 description 1
- AZLXCBPKSXFMET-UHFFFAOYSA-M sodium 4-[(4-sulfophenyl)diazenyl]naphthalen-1-olate Chemical compound [Na+].C12=CC=CC=C2C(O)=CC=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 AZLXCBPKSXFMET-UHFFFAOYSA-M 0.000 description 1
- JAOZKJMVYIWLKU-UHFFFAOYSA-N sodium 7-hydroxy-8-[(4-sulfonaphthalen-1-yl)diazenyl]naphthalene-1,3-disulfonic acid Chemical compound C1=CC=C2C(=C1)C(=CC=C2S(=O)(=O)O)N=NC3=C(C=CC4=CC(=CC(=C43)S(=O)(=O)O)S(=O)(=O)O)O.[Na+] JAOZKJMVYIWLKU-UHFFFAOYSA-N 0.000 description 1
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- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
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- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- JWBPVFVNISJVEM-UHFFFAOYSA-M sodium caffeine benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1.CN1C(=O)N(C)C(=O)C2=C1N=CN2C JWBPVFVNISJVEM-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
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- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- PXLIDIMHPNPGMH-UHFFFAOYSA-N sodium chromate Chemical compound [Na+].[Na+].[O-][Cr]([O-])(=O)=O PXLIDIMHPNPGMH-UHFFFAOYSA-N 0.000 description 1
- 229940096501 sodium cocoamphoacetate Drugs 0.000 description 1
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- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- MSFGZHUJTJBYFA-UHFFFAOYSA-M sodium dichloroisocyanurate Chemical compound [Na+].ClN1C(=O)[N-]C(=O)N(Cl)C1=O MSFGZHUJTJBYFA-UHFFFAOYSA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- SIGUVTURIMRFDD-UHFFFAOYSA-M sodium dioxidophosphanium Chemical compound [Na+].[O-][PH2]=O SIGUVTURIMRFDD-UHFFFAOYSA-M 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940080264 sodium dodecylbenzenesulfonate Drugs 0.000 description 1
- RZFBEFUNINJXRQ-UHFFFAOYSA-M sodium ethyl xanthate Chemical compound [Na+].CCOC([S-])=S RZFBEFUNINJXRQ-UHFFFAOYSA-M 0.000 description 1
- 239000000264 sodium ferrocyanide Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- GCLGEJMYGQKIIW-UHFFFAOYSA-H sodium hexametaphosphate Chemical compound [Na]OP1(=O)OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])O1 GCLGEJMYGQKIIW-UHFFFAOYSA-H 0.000 description 1
- 235000019982 sodium hexametaphosphate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000015281 sodium iodate Nutrition 0.000 description 1
- 239000011697 sodium iodate Substances 0.000 description 1
- 229940032753 sodium iodate Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- NGSFWBMYFKHRBD-UHFFFAOYSA-M sodium lactate Chemical compound [Na+].CC(O)C([O-])=O NGSFWBMYFKHRBD-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- 229940045944 sodium lauroyl glutamate Drugs 0.000 description 1
- WPUMTJGUQUYPIV-UHFFFAOYSA-L sodium malate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)CC([O-])=O WPUMTJGUQUYPIV-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000019983 sodium metaphosphate Nutrition 0.000 description 1
- 235000019795 sodium metasilicate Nutrition 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- 229940077092 sodium myristoyl glutamate Drugs 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 229940068459 sodium pantothenate Drugs 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 239000012418 sodium perborate tetrahydrate Substances 0.000 description 1
- 229940045872 sodium percarbonate Drugs 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- GOZDTZWAMGHLDY-UHFFFAOYSA-L sodium picosulfate Chemical compound [Na+].[Na+].C1=CC(OS(=O)(=O)[O-])=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OS([O-])(=O)=O)C=C1 GOZDTZWAMGHLDY-UHFFFAOYSA-L 0.000 description 1
- 229960005077 sodium picosulfate Drugs 0.000 description 1
- 235000019830 sodium polyphosphate Nutrition 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-N sodium polysulfide Chemical compound [Na+].S HYHCSLBZRBJJCH-UHFFFAOYSA-N 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- VZWGHDYJGOMEKT-UHFFFAOYSA-J sodium pyrophosphate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O VZWGHDYJGOMEKT-UHFFFAOYSA-J 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 235000018716 sodium selenate Nutrition 0.000 description 1
- 239000011655 sodium selenate Substances 0.000 description 1
- 229960001881 sodium selenate Drugs 0.000 description 1
- VPQBLCVGUWPDHV-UHFFFAOYSA-N sodium selenide Chemical compound [Na+].[Na+].[Se-2] VPQBLCVGUWPDHV-UHFFFAOYSA-N 0.000 description 1
- 229940079864 sodium stannate Drugs 0.000 description 1
- 229940045898 sodium stearoyl glutamate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 229940079101 sodium sulfide Drugs 0.000 description 1
- ZGHLCBJZQLNUAZ-UHFFFAOYSA-N sodium sulfide nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[Na+].[S-2] ZGHLCBJZQLNUAZ-UHFFFAOYSA-N 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 229940046307 sodium thioglycolate Drugs 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- RCVIHORGZULVTN-YGJXXQMASA-M sodium;(1r,4as,10ar)-1,4a-dimethyl-7-propan-2-yl-6-sulfo-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylate Chemical compound [Na+].OC(=O)[C@@](C)([C@@H]1CC2)CCC[C@]1(C)C1=C2C=C(C(C)C)C(S([O-])(=O)=O)=C1 RCVIHORGZULVTN-YGJXXQMASA-M 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- IWIUXJGIDSGWDN-UQKRIMTDSA-M sodium;(2s)-2-(dodecanoylamino)pentanedioate;hydron Chemical compound [Na+].CCCCCCCCCCCC(=O)N[C@H](C([O-])=O)CCC(O)=O IWIUXJGIDSGWDN-UQKRIMTDSA-M 0.000 description 1
- FCBUGCHAVCFTHW-NTISSMGPSA-N sodium;(2s)-2-(tetradecanoylamino)pentanedioic acid Chemical compound [Na].CCCCCCCCCCCCCC(=O)N[C@H](C(O)=O)CCC(O)=O FCBUGCHAVCFTHW-NTISSMGPSA-N 0.000 description 1
- KDHFCTLPQJQDQI-BDQAORGHSA-M sodium;(4s)-4-amino-5-octadecanoyloxy-5-oxopentanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC(=O)[C@@H](N)CCC([O-])=O KDHFCTLPQJQDQI-BDQAORGHSA-M 0.000 description 1
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- RFOHRSIAXQACDB-UHFFFAOYSA-M sodium;2-(2,4-dichlorophenoxy)acetate Chemical compound [Na+].[O-]C(=O)COC1=CC=C(Cl)C=C1Cl RFOHRSIAXQACDB-UHFFFAOYSA-M 0.000 description 1
- STAPBGVGYWCRTF-UHFFFAOYSA-M sodium;2-(4-chloro-2-methylphenoxy)acetate Chemical compound [Na+].CC1=CC(Cl)=CC=C1OCC([O-])=O STAPBGVGYWCRTF-UHFFFAOYSA-M 0.000 description 1
- BGXXYHIWOXFRLF-UHFFFAOYSA-M sodium;2-(imidazol-1-ylmethyl)-4,5-dihydro-1-benzothiophene-6-carboxylate Chemical compound [Na+].C=1C=2CCC(C(=O)[O-])=CC=2SC=1CN1C=CN=C1 BGXXYHIWOXFRLF-UHFFFAOYSA-M 0.000 description 1
- GOJYXPWOUJYXJC-UHFFFAOYSA-M sodium;2-[1-(2-hydroxyethyl)-2-undecyl-4,5-dihydroimidazol-1-ium-1-yl]acetate;hydroxide Chemical compound [OH-].[Na+].CCCCCCCCCCCC1=NCC[N+]1(CCO)CC([O-])=O GOJYXPWOUJYXJC-UHFFFAOYSA-M 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- SONHXMAHPHADTF-UHFFFAOYSA-M sodium;2-methylprop-2-enoate Chemical compound [Na+].CC(=C)C([O-])=O SONHXMAHPHADTF-UHFFFAOYSA-M 0.000 description 1
- RWVGQQGBQSJDQV-UHFFFAOYSA-M sodium;3-[[4-[(e)-[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-n-ethyl-3-methylanilino]methyl]benzenesulfonate Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C(=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C)C=2C(=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C)C=C1 RWVGQQGBQSJDQV-UHFFFAOYSA-M 0.000 description 1
- WCIMWHNSWLLELS-UHFFFAOYSA-M sodium;3-acetamido-2,4,6-triiodo-5-(methylcarbamoyl)benzoate Chemical compound [Na+].CNC(=O)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I WCIMWHNSWLLELS-UHFFFAOYSA-M 0.000 description 1
- IBDSNZLUHYKHQP-UHFFFAOYSA-N sodium;3-oxidodioxaborirane;tetrahydrate Chemical compound O.O.O.O.[Na+].[O-]B1OO1 IBDSNZLUHYKHQP-UHFFFAOYSA-N 0.000 description 1
- HHZQLQREDATOBM-CODXZCKSSA-N sodium;4-[2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]-4-oxobutanoic acid Chemical compound [Na+].O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC(O)=O)[C@@H]4[C@@H]3CCC2=C1 HHZQLQREDATOBM-CODXZCKSSA-N 0.000 description 1
- MJFZIDUBUNIFLZ-UHFFFAOYSA-M sodium;4-aminobenzenesulfonate;dihydrate Chemical compound O.O.[Na+].NC1=CC=C(S([O-])(=O)=O)C=C1 MJFZIDUBUNIFLZ-UHFFFAOYSA-M 0.000 description 1
- BNHGKKNINBGEQL-UHFFFAOYSA-M sodium;5-ethyl-5-(3-methylbutyl)pyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].CC(C)CCC1(CC)C(=O)NC(=O)[N-]C1=O BNHGKKNINBGEQL-UHFFFAOYSA-M 0.000 description 1
- QYTMJGNCASLBCG-UHFFFAOYSA-M sodium;5-ethyl-8-oxofuro[3,2-b][1,8]naphthyridine-7-carboxylate Chemical compound [Na+].N1=C2N(CC)C=C(C([O-])=O)C(=O)C2=CC2=C1C=CO2 QYTMJGNCASLBCG-UHFFFAOYSA-M 0.000 description 1
- AFWAHDXCIBPFNW-UHFFFAOYSA-J sodium;antimony(3+);2,3-dihydroxybutanedioate Chemical compound [Na+].[Sb+3].[O-]C(=O)C(O)C(O)C([O-])=O.[O-]C(=O)C(O)C(O)C([O-])=O AFWAHDXCIBPFNW-UHFFFAOYSA-J 0.000 description 1
- AGHLUVOCTHWMJV-UHFFFAOYSA-J sodium;gold(3+);2-sulfanylbutanedioate Chemical compound [Na+].[Au+3].[O-]C(=O)CC(S)C([O-])=O.[O-]C(=O)CC(S)C([O-])=O AGHLUVOCTHWMJV-UHFFFAOYSA-J 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- KKVTYAVXTDIPAP-UHFFFAOYSA-M sodium;methanesulfonate Chemical compound [Na+].CS([O-])(=O)=O KKVTYAVXTDIPAP-UHFFFAOYSA-M 0.000 description 1
- UOOVFPYJUPSROO-UHFFFAOYSA-M sodium;naphthalene-1-sulfinate Chemical compound [Na+].C1=CC=C2C(S(=O)[O-])=CC=CC2=C1 UOOVFPYJUPSROO-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-UHFFFAOYSA-M sodium;octadec-9-enoate Chemical compound [Na+].CCCCCCCCC=CCCCCCCCC([O-])=O BCKXLBQYZLBQEK-UHFFFAOYSA-M 0.000 description 1
- MWNQXXOSWHCCOZ-UHFFFAOYSA-L sodium;oxido carbonate Chemical compound [Na+].[O-]OC([O-])=O MWNQXXOSWHCCOZ-UHFFFAOYSA-L 0.000 description 1
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Abstract
【解決手段】下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有するミトコンドリア機能改善剤(ただし、皮膚外用剤を除く);式(I)中、R1及びR2は、それぞれ独立に水素原子、又は下記式(Ia)で示される群から選択されるいずれかの基を表し(但し、R1及びR2が同時に水素原子になることはない。)、X1〜X3は、それぞれ独立に窒素又は酸素原子を表し、R3,R4,R5,R3’,R4',R5'は、それぞれ独立に水素原子等を表す。式(Ia)中、R6〜R8はそれぞれ独立に炭素数1〜30の鎖状炭化水素基等を表す。
[化1]
【選択図】なし
Description
老化した細胞や紫外線などのストレスによりダメージを受けた細胞において、ミトコンドリアの機能を改善することにより、細胞の賦活化が出来ると考えられる。これまで、ミトコンドリア機能改善剤としてはスフィンゴミエリンや抗酸化物質としてグルタチオンなどが報告されているが(特許文献1、非特許文献4)、その効果はまだ十分ではない。
[1]下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有するミトコンドリア機能改善剤(ただし、皮膚外用剤を除く);
[2]下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有する、ミトコンドリア機能低下が関連する疾患の予防又は治療に用いられるミトコンドリア機能改善剤;
炭素数14〜22の、カルボン酸、アシルクロライド、若しくはアルキルニトリル、又は、アシル基の炭素数14〜22の、カルボン酸無水物、若しくはカルボン酸エステルと、前記第一工程で得られた化合物とを反応させ、前記第一工程で得られた化合物の水酸基をエステル化する第二工程と、
前記第二工程で得られた化合物のエステル結合部位のうち、第一工程で形成されたエステル結合部位の一部または全部を切断する第三工程とを有する方法により製造する前記[1]〜[7]のいずれか一つに記載の剤の製造方法。
下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有する線維芽細胞のミトコンドリア機能改善による線維芽細胞賦活化剤;
また、本発明の老化防止用組成物によれば、シワ、タルミの形成等をはじめとする細胞や皮膚組織の老化の防止又は改善に有用である。
<ヒドロキシクエン酸誘導体又はその塩>
本発明のミトコンドリア機能改善剤は、下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有する。
これらのうち、上記式(Ia)で示される群から選択されるいずれかの基は、炭素数8〜24、好ましくは炭素数14〜22の基であることが望ましい。
R6、R7、R8としては、後に記載のR3,R4,R5,R3',R4',R5'として具体的に示される基を例示できる。
分子中の水酸基が修飾された誘導体の例としては、具体的には、上記式(I)中のR1及び/又はR2が、ヘキサノイル基、2−メチルペンタノイル基、3−メチルペンタノイル基、4−メチルペンタノイル基、2−エチルブタノイル基、ヘプタノイル基、2−メチルヘキサノイル基、3−メチルヘキサノイル基、4−メチルヘキサノイル基、2−エチルペンタノイル基、3−エチルペンタノイル基、オクタノイル基、2−メチルヘプタノイル基、3−メチルヘプタノイル基、4−メチルヘプタノイル基、5−メチルヘプタノイル基、6−メチルヘプタノイル基、2−エチルヘキサノイル基、3−エチルヘキサノイル基、4−エチルヘキサノイル基、2−プロピルペンタノイル基、ノナノイル基、デカノイル基、ウンデカノイル基、10−ウンデセノイル基、ドデカノイル基、トリデカノイル基、テトラデカノイル基、ペンタデカノイル基、ヘキサデカノイル基、9−ヘキサデセノイル基、
ヘプタデカノイル基、オクタデカノイル基、イソステアリル基、シス−9−オクタデセノイル基、11−オクタデセノイル基、シス,シス−9,12−オクタデカジエノイル基、9,12,15−オクタデカトリエノイル基、6,9,12−オクタデカトリエノイル基、9,11,13−オクタデカトリエノイル基、ノナデカノイル基、2,6,10,14−テトラメチルベンタデカノイル基、イコサノイル基、8,11−イコサジエノイル基、5,8,11−イコサトリエノイル基、5,8,11,14−イコサテトラエノイル基、3,7,11,15−テトラメチルヘキサデカノイル基、ヘンイコサノイル基、ドコサノイル基のいずれかである化合物が挙げられる。
X1〜X3のいずれかが窒素原子の場合は−CONRmRm'(mおよびm’は、X1〜X3に対応して3,4,5のいずれか同じ数を表す。)は置換又は無置換のアミド基を表し、またX1〜X3のいずれかが酸素原子の場合は−COORm(mは、X1〜X3に対応して3,4,5のいずれかの数を表す。)は、カルボキシル基又はエステル基を表す。
また、分子中のカルボキシル基が修飾された誘導体の例としては、既に述べた分子中の水酸基が修飾された誘導体のカルボキシル基部位の少なくとも1つが、置換又は無置換のアミド基、又はエステル基となっている化合物が挙げられる。
R2が水素原子であり、R3〜R5がそれぞれ独立に水素原子又は分岐もしくは不飽和結合を有していてもよい、炭素数1〜30の鎖状炭化水素基であり(但し、R3〜R5が同時に水素原子となることはない。)、且つX1〜X3がすべて酸素原子である下記式(IIb)に示す化合物が好ましい例として挙げられる。
これらの場合、すなわち本発明のミトコンドリア機能改善剤に係るヒドロキシクエン酸誘導体が、下記式(IIa)に示す化合物又は下記式(IIb)に示す化合物である場合、R1は上記式(Ia)で示される群から選択されるいずれかの基を表し、上記式(Ia)で示される基のなかでは、上記式(Ia‐1)で示される基であることが好ましい。さらに式(Ia)において、R6は、分岐、不飽和結合もしくは置換基を有していてもよい、炭素数7〜23の鎖状炭化水素基であることが好ましく、炭素数10〜22の鎖状炭化水素基であることが好ましく、炭素数13〜21の鎖状炭化水素基であることがより好ましく、炭素数13〜18の鎖状炭化水素基であることがさらに好ましい。
鎖状炭化水素基としては鎖状飽和炭化水素基であることが好ましく、置換基を有さないことがより好ましい。R6は、置換基を有さない炭素数7〜23の鎖状飽和炭化水素基であることが好ましく、置換基を有さない炭素数10〜22の鎖状飽和炭化水素基であることが好ましく、置換基を有さない炭素数13〜21の鎖状飽和炭化水素基であることがより好ましく、置換基を有さない炭素数13〜18の鎖状飽和炭化水素基であることがさらに好ましい。
鎖状炭化水素基としては、直鎖状飽和炭化水素基であることが好ましく、置換基を有さないことがより好ましい。R6は、置換基を有さない炭素数7〜23の直鎖状飽和炭化水素基であることが好ましく、置換基を有さない炭素数10〜22の直鎖状飽和炭化水素基であることが好ましく、置換基を有さない炭素数13〜21の直鎖状飽和炭化水素基であることがより好ましく、置換基を有さない炭素数13〜18の直鎖状飽和炭化水素基であることがさらに好ましい。
R1としては、炭素数14〜22のアシル基が望ましい。
アルカリ金属塩としては、ナトリウム塩、カリウム塩等が挙げられ、アルカリ土類金属塩としては、カルシウム塩等が挙げられる。
前記ヒドロキシクエン酸誘導体又はその塩の投与量は、ヒドロキシクエン酸誘導体又はその塩の血中濃度又は培養液中濃度によって定めてもよい。例えば、前記ヒドロキシクエン酸誘導体又はその塩の血中濃度又は培養液中濃度(モル比)としては、例えば、0.001μM〜100μM程度とすることが好ましく、0.005μM〜50μM程度とすることがより好ましく、0.005μM〜20μM程度とすることがさらに好ましい。
次に、本発明のミトコンドリア機能改善剤に係るヒドロキシクエン酸誘導体又はその塩の製造方法について説明する。
本発明のミトコンドリア機能改善剤に係るヒドロキシクエン酸誘導体又はその塩の製造方法には特に制限はなく、ヒドロキシクエン酸及び/又はそのアルカリ金属塩及び/又はそのアルカリ土類金属塩と、カルボン酸誘導体又はリン酸誘導体又はスルホン酸誘導体とを、適当な溶媒中で反応させることによって製造することが可能である。
(1)ヒドロキシクエン酸の水酸基を直接エステル化する方法、
(2)ヒドロキシクエン酸のカルボキシル基をエステル化してから、水酸基をエステル化し、前者のエステル結合部位を切断してカルボキシル基に戻す方法、
(3)ヒドロキシクエン酸のカルボキシル基をエステル化してから、水酸基をエステル化する方法、
(4)ヒドロキシクエン酸の水酸基をエステル化してから、カルボキシル基をエステル化する方法、
(5)ヒドロキシクエン酸のカルボキシル基をアミド化してから、水酸基をエステル化する方法、
(6)ヒドロキシクエン酸のカルボキシル基をアミド化してから、水酸基をエステル化し、前者のアミド結合部位を切断してカルボキシル基に戻す方法、
(7)ヒドロキシクエン酸の水酸基をエステル化してから、カルボキシル基をアミド化する方法等を挙げることができる。
これらの製造方法では試薬の使用量を適当に調節し、ヒドロキシクエン酸の2位の水酸基と3位の水酸基の反応性の違いを利用して、2位の水酸基のみを修飾することも可能である。
反応濃度はとくに限定はないが、0.0001mol/dm3〜10mol/dm3の範囲が好ましく、0.1mol/dm3〜1mol/dm3の範囲がさらに好ましい。
また、このようなpH調節を行うことにより、ヒドロキシクエン酸誘導体の塩を容易に製造することができる。たとえば、pH調整剤としてNaOHを用いれば、ヒドロキシクエン酸誘導体のNa塩を得ることができる。
脂肪族カルボン酸誘導体と前記第一工程で得られた化合物とを反応させ、前記第一工程で得られた化合物の水酸基をエステル化する第二工程と、
前記第二工程で得られた化合物のエステル結合部位のうち、第一工程で形成されたエステル結合部位の一部または全部を切断する第三工程とを有することを特徴とするヒドロキシクエン酸誘導体又はその塩を製造する方法により製造されたものであってもよい。
本発明の老化防止用組成物は、
下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有する老化防止用組成物;
陽イオン性界面活性剤では、ベヘントリモニウムクロリド、ステアルトリモニウムクロリド、セトリモニウムクロリド、ラウリルトリモニウムクロリド等のアルキルトリメチルアンモニウムクロリド;ステアリルトリモニウムブロミド等のアルキルトリメチルアンモニウムブロミド;ジステアリルジモニウムクロリド、ジココジモニウムクロリド等のジアルキルジメチルアンモニウムクロリド;ステアラミドプロピルジメチルアミン、ステアラミドエチルジエチルアミン等の脂肪酸アミドアミン及びその塩;ステアロキシプロピルジメチルアミン等のアルキルエーテルアミン及びその塩または四級塩;エチル硫酸長鎖分岐脂肪酸(12〜31)アミノプロピルエチルジメチルアンモニウム、エチル硫酸ラノリン脂肪酸アミノプロピルエチルジメチルアンモニウム等の脂肪酸アミド型四級アンモニウム塩;ポリオキシエチレンアルキルアミン及びその塩または四級塩;アルキルアミン塩;脂肪酸アミドグアニジウム塩;アルキルエーテルアンモニウム塩;アルキルトリアルキレングリコールアンモニウム塩;ベンザルコニウム塩;ベンゼトニウム塩;塩化セチルピリジニウム等のピリジニウム塩;イミダゾリニウム塩;アルキルイソキノリニウム塩;ジアルキルモリホニウム塩;ポリアミン脂肪酸誘導体;アミノプロピルジメチコン及びアモジメチコン等のアミノ変性シリコーン、カチオン変性シリコーン、カチオン変性及びポリエーテル変性シリコーン、アミノ変性及びポリエーテル変性シリコーン等のシリコーン系陽イオン性界面活性剤等;ラウリルベタイン(ラウリルジメチルアミノ酢酸ベタイン)等のN−アルキル−N,N−ジメチルアミノ酸ベタイン;コカミドプロピルベタイン、ラウラミドプロピルベタイン等の脂肪酸アミドアルキル−N,N−ジメチルアミノ酸ベタイン;ココアンホ酢酸ナトリウム、ラウロアンホ酢酸ナトリウム等のイミダゾリン型ベタイン;アルキルジメチルタウリン等のアルキルスルホベタイン;アルキルジメチルアミノエタノール硫酸エステル等の硫酸型ベタイン;アルキルジメチルアミノエタノールリン酸エステル等のリン酸型ベタイン;ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、スフィンゴミエリン等のスフィンゴリン脂質、リゾレシチン、水素添加大豆リン脂質、部分水素添加大豆リン脂質、水素添加卵黄リン脂質、部分水素添加卵黄リン脂質、水酸化レシチン等のリン脂質類;シリコーン系両性界面活性剤等の両性界面活性剤;ポリビニルアルコール、アルギン酸ナトリウム、デンプン誘導体、トラガントガム、アクリル酸・メタアクリル酸アルキル共重合体;シリコーン系各種界面活性剤等の高分子界面活性剤が挙げられる。
酸化クロム、
水酸化クロム、チタン酸コバルト等の無機緑色系顔料;群青、紺青等の無機青色系顔料;酸化チタンコーテッドマイカ、酸化チタンコーテッドオキシ塩化ビスマス、酸化チタンコーテッドタルク、着色酸化チタンコーテッドマイカ、オキシ塩化ビスマス、魚鱗箔等のパール顔料;アルミニウムパウダー、カッパーパウダー、金等の金属粉末顔料;表面処理無機及び金属粉末顔料;赤色201号、赤色202号、赤色204号、赤色205号、赤色220号、赤色226号、赤色228号、赤色405号、橙色203号、橙色204号、黄色205号、黄色401号、青色404号、赤色3号、赤色104号、赤色106号、赤色227号、赤色230号、赤色401号、赤色505号、橙色205号、黄色4号、黄色5号、黄色202号、黄色203号、緑色3号、青色1号等のジルコニウム、バリウム又はアルミニウムレーキ等の有機顔料;表面処理有機顔料;アスタキサンチン、アリザリン等のアントラキノン類、アントシアニジン、β−カロチン、カテナール、カプサンチン、カルコン、カルサミン、クエルセチン、クロシン、クロロフィル、クルクミン、コチニール、シコニン等のナフトキノン類、ビキシン、フラボン類、ベタシアニジン、ヘナ、ヘモグロビン、リコピン、リボフラビン、ルチン等の天然色素・染料;p−フェニレンジアミン、トルエン−2,5−ジアミン、o−,m−,若しくはp−アミノフェノール、m−フェニレンジアミン、5−アミノ−2−メチルフェノール、レゾルシン、1−ナフトール、2,6−ジアミノピリジン等及びその塩等の酸化染料中間体及びカップラー;インドリン等の自動酸化型染料;ジヒドロキシアセトンが挙げられる。
カリウムミョウバン、酸化カリウム、臭化カリウム、ヨウ化カリウム、硝酸カリウム、硫酸カリウム、硫化カリウム、酢酸カリウム、臭素酸カリウム、塩化カリウム、亜硝酸カリウム、亜硫酸カリウム、ヒ酸カリウム、ヨウ素酸カリウム、水素化カリウム、カリウムt−ブトキシド、炭酸カリウム、塩素酸カリウム、シアン酸カリウム、シアン化カリウム、フッ化カリウム、シュウ酸カリウム、ケイ酸カリウム、亜ヒ酸カリウム、スズ酸カリウム、クロム酸カリウム、水酸化カリウム、リン酸カリウム、ソルビン酸カリウム、重硫酸カリウム、セレン酸カリウム、過硫酸カリウム、ロダン化カリウム、ロサルタンカリウム、亜セレン酸カリウム、亜テルル酸カリウム、ワルファリンカリウム、過ヨウ素酸カリウム、グルコン酸カリウム、カンレノ酸カリウム、過塩素酸カリウム、チオ硫酸カリウム、重クロム酸カリウム、ホウフッ化カリウム、二クロム酸カリウム、モリブデン酸カリウム、ピロ亜硫酸カリウム、アスパラギン酸カリウム、ペミロラストカリウム、次亜塩素酸カリウム、チオシアン酸カリウム、クラブラン酸カリウム、硫酸カリウムアルミニウム、硫シアン化カリウム、水酸化ホウ素カリウム、次亜リン酸カリウム、メタリン酸カリウム、過マンガン酸カリウム、ピロリン酸カリウム、フェリシアン化カリウム、フェロシアン化カリウム、ケイフッ化カリウム、硫酸水素カリウム、メタバナジン酸カリウム、キサントゲン酸カリウム、シュウ酸水素カリウム、クロラゼプ酸二カリウム、セレノシアン酸カリウム、シュウ酸二カリウム、フルオロケイ酸カリウム、スズ酸カリウム三水和物、炭酸水素カリウム、ペルオキソ二硫酸カリウム、硫酸アルミニウムカリウム、ピロリン酸四カリウム、ベンジルペニシリンカリウム、カリウム(メチルスルフィニル)メタニド、リン酸二水素カリウム、リン酸水素二カリウム、グリチルリチン酸二カリウム、テトラフルオロホウ酸カリウム、グアヤコールスルホン酸カリウム、ヘキサフルオロケイ酸カリウム、硫酸カリウムアルミニウム十二水和物、ジチオ炭酸o−エチルカリウム、ヘキサシアノ鉄(III)カリウム、フェノキシメチルペニシリンカリウム、(2E,4E)−2,4−ヘキサジエン酸カリウムなどのカリウム化合物、酸化ルビジウム、臭化ルビジウム、ヨウ化ルビジウム、硫酸ルビジウム、塩化ルビジウム、フッ化ルビジウム、酢酸ルビジウム、硫酸水素ルビジウム、炭酸ジルビジウムなどのルビジウム化合物、セシウムシアニド、酸化セシウム、臭化セシウム、ヨウ化セシウム、硝酸セシウム、硫酸セシウム、塩化セシウム、炭酸セシウム、フッ化セシウム、炭酸ジセシウム、シュウ酸ジセシウム、硫酸二セシウム、L−酒石酸ジセシウム、水酸化セシウム一水和物、トリフルオロ酢酸セシウム、2,3−ジヒドロキシブタン二酸1−セシウム、2,3−ジヒドロキシブタン二酸水素1−セシウムなどがのセシウム化合物、酸化ベリリウム、臭化ベリリウム、炭化ベリリウム、ヨウ化ベリリウム、硝酸ベリリウム、窒化ベリリウム、硫化ベリリウム、塩化ベリリウム、フッ化ベリリウム、ケイ酸ベリリウム、ジステアリン酸ベリリウム、硫酸ベリリウム四水塩、アセチルアセトンベリリウム塩などのベリリウム化合物、酸化マグネシウム、マグネシウムオロテート、アリールマグネシウム、酢酸マグネシウム、ホウ化マグネシウム、臭化マグネシウム、炭化マグネシウム、ヨウ化マグネシウム、硝酸マグネシウム、窒化マグネシウム、硫酸マグネシウム、硫化マグネシウム、マグネシウム(粉末)、塩化マグネシウム、炭酸マグネシウム、塩素酸マグネシウム、クエン酸マグネシウム、フッ化マグネシウム、ケイ酸マグネシウム、ケイ化マグネシウム、水酸化マグネシウム、リン化マグネシウム、オロチン酸マグネシウム、硝酸マグネシウム(II)、ステアリン酸マグネシウム、過塩素酸マグネシウム、ミリスチン酸マグネシウム、シュウ酸マグネシウム、炭酸水素マグネシウム、ケイフッ化マグネシウム、フルオロケイ酸マグネシウム、臭化フェニルマグネシウム、硝酸マグネシウム六水和物、フタロシアニンマグネシウム、酢酸マグネシウム四水和物、安息香酸マグネシウム三水和物、炭酸カルシウムマグネシウム、クロム酸マグネシウム五水和物、ヘキサフルオロケイ酸マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウムビスマス、水酸化アルミニウムマグネシウム炭酸塩水和物などのマグネシウム化合物、カルシウムカーバイド、酸化カルシウム、臭化カルシウム、炭化カルシウム、カルシウムシアナミド、ヨウ化カルシウム、乳酸カルシウム、硝酸カルシウム、窒化カルシウム、硫酸カルシウム、硫化カルシウム、酢酸カルシウム、塩化カルシウム、亜硝酸カルシウム、亜硫酸カルシウム、ヒ酸カルシウム、水素化カルシウム、砒酸カルシウム、ヨウ素酸カルシウム、炭酸カルシウム、塩素酸カルシウム、フッ化カルシウム、シュウ酸カルシウム、過酸化カルシウム、ケイ酸カルシウム、ケイ化カルシウム、シアン化カルシウム、亜ヒ酸カルシウム、ヘパリンカルシウム、亜塩素酸カルシウム、クロム酸カルシウム、水酸化カルシウム、リン酸カルシウム、リン化カルシウム、ホリナートカルシウム、グルコン酸カルシウム、ステアリン酸カルシウム、アスパラギン酸カルシウム、次亜塩素酸カルシウム、ホスホマイシンカルシウム、メタケイ酸カルシウム、チオシアン酸カルシウム、次亜リン酸カルシウム、パントテン酸カルシウム、過マンガン酸カルシウム、フェノプロフェンカルシウム、塩化カルシウム二水和物、炭酸カルシウムマグネシウム、ポリカルボフィルカルシウム、ムピロシンカルシウム水和物、リン酸水素カルシウム、グリセロリン酸カルシウム、ジヨードステアリン酸カルシウム、沈降炭酸カルシウム、エデト酸二ナトリウムカルシウム、アトルバスタチンカルシウム水和物、(+)−パントテン酸カルシウム、パラアミノサリチル酸カルシウム、コハク酸トコフェロールカルシウム、ポリスチレンスルホン酸カルシウム、(+)−パントテン酸カルシウム塩(2:1)、アルミノパラアミノサリチル酸カルシウム、3−ヒドロキシ−4−[(4−メチル−2−スルホフェニル)アゾ]−2−ナフタレンカルボン酸カルシウム塩などのカルシウム化合物、酸化バリウム、アジ化バリウム、酢酸バリウム、臭化バリウム、ヨウ化バリウム、硝酸バリウム、窒化バリウム、硫酸バリウム、硫化バリウム、ギ酸バリウム、乳酸バリウム、塩化バリウム、亜硫酸バリウム、炭酸バリウム、塩素酸バリウム、フッ化バリウム、過酸化バリウム、シアン化バリウム、クロム酸バリウム、水酸化バリウム、チタン酸バリウム、セレン酸バリウム、リン酸バリウム、硝酸バリウム(II)、亜セレン酸バリウム、マンガン酸バリウム、シュウ酸バリウム、ステアリン酸バリウム、過塩素酸バリウム、チオ硫酸バリウム、次亜塩素酸バリウム、過マンガン酸バリウム、クロラニル酸バリウム、塩化バリウム二水和物、二酢酸バリウム、臭化バリウム二水和物、ジプロピオン酸バリウム、塩素酸バリウム一水和物、水酸化バリウム八水和物、チオシアン酸バリウム二水和物、チオ硫酸バリウム一水和物、アセチルアセトンバリウム二水和物などのバリウム化合物が挙げられる。
本発明の老化防止用組成物が化粧料である場合、さらに、既存の化粧品原料を一般的な濃度で添加することもできる。たとえば、化粧品原料基準第二版注解、日本公定書教会編、1984(薬事日報社)、化粧品原料基準外成分規格、厚生省薬務局審査課監修、1993(薬事日報社)、化粧品原料基準外成分規格追補、厚生省薬務局審査課監修、1993(薬事日報社)、化粧品種別許可基準、厚生省薬務局審査課監修、1993(薬事日報社)、化粧品種別配合成分規格、厚生省薬務局審査課監修、1997(薬事日報社)、および化粧品原料辞典、平成3年(日光ケミカルズ)等に記載されている全ての化粧品原料を使用することができる。
本発明の老化防止用組成物のpHは、6〜9であることが好ましく、pH7〜8.5であるとさらに好ましい。pHがこの範囲内であると、ヒドロキシクエン酸誘導体の安定性が良好で、製剤安定性もより良好となる。なお該pHは、約25℃における値である。
本発明に係るヒドロキシクエン酸誘導体を含む製剤は、処方例として下記(表1)に示す処方に沿って、製剤化を行うことができる。
処方例1 クリーム
成分Aを85℃に加温、混合後、ホモミキサーにかけながら、成分Bを85℃に加温、混合したものを徐々に添加した。60℃まで放冷し、その後冷却し、30℃まで攪拌した。
処方例1において、ヒドロキシクエン酸誘導体を精製水に置き換えた処方3を従来のクリームとした。
ヒト皮膚由来線維芽細胞NB1−RGB細胞におけるミトコンドリア機能改善効果を、ミトコンドリア膜電位を指標に下記の条件にて測定した。
コンフルエントな状態のNB1−RGB細胞に600 μM 過酸化水素水を含む10 %ウシ胎児血清を含むD M E M 培地にて1 時間培養する操作を4日間行うことで、人工的に酸化的老化を誘導した細胞を老化細胞とした。この老化細胞と未処理の正常細胞を、4000個/cm2の播種密度で準備し10 %ウシ胎児血清を含むDMEM培地にて24時間培養した。10 %ウシ胎児血清を含むDMEM培地に、試料として、終濃度0μM(コントロール)、又は10μMとなるように50%エタノールに溶かした本発明に係るヒドロキシクエン酸誘導体添加して48 時間培養した。蛍光物質5,5’,6,6’−tetrachloro−1,1’,3,3’−tetraethylbenzimidazoilcarbocyanine iodide(JC−1)は、膜電位が高いほどミトコンドリアに多く取り込まれ、生細胞では赤色の蛍光を発し、膜電位が低いとミトコンドリアに取り込まれず、アポトーシスによる死細胞では緑色の蛍光を発する。このCayman社が提供するJC-1 Mitochondrial Membrane Potential Assay Kitを用い、JC−1を培地に10%濃度で添加し、15分間培養した後、400gで5分間遠心した。さらに、キット添付のアッセイ溶液に培地を置換した後、400gで5分間遠心することを2回繰り返した。新たな、キット添付のアッセイ溶液に置換後、励起520 〜 570 nm /蛍光570 〜 610 nmで生細胞を,励起485 nm /蛍光535 nmで死細胞の蛍光強度を測定した。
表2に示す結果を参照すると、表2に示す本発明に係るヒドロキシクエン酸誘導体の添加によって、アポトーシスを起こした死細胞由来の蛍光強度(相対値)が低下したことから、過酸化水素による酸化ストレスで人工的に老化を誘導した繊維芽細胞において増加するアポトーシスに対する抑制作用が確認された。
ここでは、老化により下がるミトコンドリア膜電位の回復効果をみており、膜電位差が大きいほどミトコンドリアでのエネルギー産生量が多く細胞の状態が健康であるといえることから、この値を「ミトコンドリア機能改善効果」とした。
エラスチンは、主にコラーゲン同士を結びつける働きを持つ繊維状のたんぱく質で、皮膚の真皮や血管、靭帯などに存在し、肌にハリや弾力を与えることが知られている。このエラスチンの産生に対するヒドロキシクエン酸誘導体の効果を以下の方法で検証した。
実験例1で作製した老化細胞と未処理の正常細胞を、4000個/cm2の播種密度で準備し10%ウシ胎児血清を含むDMEM培地にて24時間培養した。10% ウシ胎児血清を含むDMEM培地に、終濃度0μM(コントロール)、0.01μM、又は0.1μMとなるように50%エタノールに溶かした本発明に係るヒドロキシクエン酸誘導体を添加して48 時間培養した。その後細胞を回収し、Biocolor社製のエラスチン測定キットにてエラスチンを抽出し、抽出液の波長513nmの吸光度を測定した。
処方例1のクリームにある処方AおよびBと比較例1の処方Cを用いて、各々女性20人(35〜55才)の肌に試料を1日2回(朝、夕)連続2ケ月間塗布した。判定は使用開始前と2ヶ月連続塗布後の試験部位の評価点との差が2 点以上の場合を「有効」、1点の場合を「やや有効」、0点の場合を「無効」とし、「有効」または「やや有効」となった被験者の人数を「改善効果」とした。それぞれ老化防止効果の典型的な官能指標と考えられる皮膚の湿潤性、平滑性、弾力性の各項目に対して、「皮膚の潤い」、「皮膚の滑らかさ」、「皮膚のハリ」について表5にあるそれぞれの項目に回答した人数で、効果を判定した。
Claims (9)
- 下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有するミトコンドリア機能改善剤(ただし、皮膚外用剤を除く);
- 下記式(I)で示されるヒドロキシクエン酸誘導体又はその塩を有効成分として含有する、ミトコンドリア機能低下が関連する疾患の予防又は治療に用いられるミトコンドリア機能改善剤;
- 前記式(Ia)中、R6が、分岐もしくは不飽和結合を有していてもよい、炭素数7〜23の鎖状炭化水素基であり、R7及びR8が、それぞれ独立に、水素原子、又は分岐もしくは不飽和結合を有していてもよい、炭素数8〜24の鎖状炭化水素基である請求項1又は2に記載の剤。
- 前記式(I)中、X1〜X3がすべて酸素原子であり、R3〜R5が、それぞれ独立に水素原子、又は分岐もしくは不飽和結合を有していてもよい、炭素数1〜30の鎖状炭化水素基であり、且つ、前記式(Ia)中、R6が、分岐もしくは不飽和結合を有していてもよい、炭素数7〜23の鎖状炭化水素基であり、R7及びR8が、それぞれ独立に、水素原子、又は分岐もしくは不飽和結合を有していてもよい、炭素数8〜24の鎖状炭化水素基である請求項1又は2に記載の剤。
- 前記式(I)中、R2が水素原子であり、X1〜X3がすべて酸素原子であり、R3〜R5がすべて水素原子であり、且つ、前記式(Ia)中、R6が、分岐もしくは不飽和結合を有していてもよい、炭素数13〜21の鎖状炭化水素基である請求項1又は2に記載の剤。
- 前記式(I)中、R2が水素原子であり、X1〜X3がすべて酸素原子であり、R3〜R5がそれぞれ独立に水素原子、又は分岐もしくは不飽和結合を有していてもよい、炭素数1〜30の鎖状炭化水素基であり(但し、R3〜R5が同時に水素原子となることはない。)、且つ、前記式(Ia)中、R6は、分岐もしくは不飽和結合を有していてもよい、炭素数13〜21の鎖状炭化水素基である請求項1又は2に記載の剤。
- 前記ヒドロキシクエン酸誘導体又はその塩を、ヒドロキシクエン酸及び/又はそのアルカリ金属塩及び/又はそのアルカリ土類金属塩と、炭素数14〜22の、カルボン酸、アシルクロライド、若しくはアルキルニトリル、又は、アシル基の炭素数14〜22の、カルボン酸無水物、若しくはカルボン酸エステルと、を溶媒中で反応させることによって製造することを含む請求項1〜7のいずれか一項に記載の剤の製造方法。
- 前記ヒドロキシクエン酸誘導体又はその塩を、ヒドロキシクエン酸及び/又はそのアルカリ金属塩及び/又はそのアルカリ土類金属塩を溶媒中でアルコールと反応させ、ヒドロキシクエン酸(トリ)エステルを製造する第一工程と、
炭素数14〜22の、カルボン酸、アシルクロライド、若しくはアルキルニトリル、又は、アシル基の炭素数14〜22の、カルボン酸無水物、若しくはカルボン酸エステルと、前記第一工程で得られた化合物とを反応させ、前記第一工程で得られた化合物の水酸基をエステル化する第二工程と、
前記第二工程で得られた化合物のエステル結合部位のうち、第一工程で形成されたエステル結合部位の一部または全部を切断する第三工程とを有する方法により製造する請求項1〜7のいずれか一項に記載の剤の製造方法。
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