CN103402524A - 用于改善认知功能的组合剂 - Google Patents
用于改善认知功能的组合剂 Download PDFInfo
- Publication number
- CN103402524A CN103402524A CN2011800687085A CN201180068708A CN103402524A CN 103402524 A CN103402524 A CN 103402524A CN 2011800687085 A CN2011800687085 A CN 2011800687085A CN 201180068708 A CN201180068708 A CN 201180068708A CN 103402524 A CN103402524 A CN 103402524A
- Authority
- CN
- China
- Prior art keywords
- dementia
- dlpc
- popc
- disease
- cognitive function
- 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
- 230000003920 cognitive function Effects 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title abstract description 24
- 229940079593 drug Drugs 0.000 title abstract description 12
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims abstract description 72
- 235000013305 food Nutrition 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 17
- FVXDQWZBHIXIEJ-LNDKUQBDSA-N 1,2-di-[(9Z,12Z)-octadecadienoyl]-sn-glycero-3-phosphocholine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC FVXDQWZBHIXIEJ-LNDKUQBDSA-N 0.000 claims abstract description 3
- 206010012289 Dementia Diseases 0.000 claims description 68
- 208000010877 cognitive disease Diseases 0.000 claims description 56
- 201000010099 disease Diseases 0.000 claims description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 42
- 230000006872 improvement Effects 0.000 claims description 7
- 230000007087 memory ability Effects 0.000 claims description 5
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 230000000694 effects Effects 0.000 abstract description 18
- 230000015654 memory Effects 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 description 38
- 238000002360 preparation method Methods 0.000 description 23
- 238000012360 testing method Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 11
- 238000011068 loading method Methods 0.000 description 11
- 208000027061 mild cognitive impairment Diseases 0.000 description 11
- 239000000463 material Substances 0.000 description 9
- 239000004033 plastic Substances 0.000 description 7
- 229920003023 plastic Polymers 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 208000030451 Vascular dementia disease Diseases 0.000 description 5
- 235000012054 meals Nutrition 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 206010056467 Cerebral dysgenesis Diseases 0.000 description 4
- 201000009906 Meningitis Diseases 0.000 description 4
- 206010039966 Senile dementia Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 208000037132 Subdural Chronic Hematoma Diseases 0.000 description 4
- 208000002667 Subdural Hematoma Diseases 0.000 description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 4
- 229960004373 acetylcholine Drugs 0.000 description 4
- -1 antibacterial Substances 0.000 description 4
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 208000018389 neoplasm of cerebral hemisphere Diseases 0.000 description 4
- 201000003077 normal pressure hydrocephalus Diseases 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 241000699800 Cricetinae Species 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229960003135 donepezil hydrochloride Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000007427 paired t-test Methods 0.000 description 3
- 150000008105 phosphatidylcholines Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 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
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 235000012970 cakes Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 230000001925 catabolic effect Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 235000013376 functional food Nutrition 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- 239000008274 jelly Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N linoleic acid group Chemical group C(CCCCCCC\C=C/C\C=C/CCCCC)(=O)O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 2
- 230000007787 long-term memory Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 238000010010 raising Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 230000001228 trophic effect Effects 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- WTJKGGKOPKCXLL-VYOBOKEXSA-N 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC WTJKGGKOPKCXLL-VYOBOKEXSA-N 0.000 description 1
- FVXDQWZBHIXIEJ-ZPPAUJSGSA-N 2,3-bis[[(9z,12z)-octadeca-9,12-dienoyl]oxy]propyl 2-(trimethylazaniumyl)ethyl phosphate Chemical group CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC(COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC FVXDQWZBHIXIEJ-ZPPAUJSGSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940039856 aricept Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Natural products O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000013101 initial test Methods 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- BOZILQFLQYBIIY-INTXDZFKSA-N mevinic acid Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)CCC=C21 BOZILQFLQYBIIY-INTXDZFKSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229940086319 nattokinase Drugs 0.000 description 1
- 108010073682 nattokinase Proteins 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- SBNFWQZLDJGRLK-UHFFFAOYSA-N phenothrin Chemical compound CC1(C)C(C=C(C)C)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 SBNFWQZLDJGRLK-UHFFFAOYSA-N 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000007015 preclinical effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 235000011962 puddings Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229930009674 sesquiterpene lactone Natural products 0.000 description 1
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 238000011870 unpaired t-test Methods 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Mycology (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
本发明的目的在于提供具有改善认知功能作用的药物和/或食品,以及改善认知功能的方法。本发明涉及用于改善认知功能的组合剂,其含有1,2-二亚油酰基-sn-甘油-3-磷酸胆碱和1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱,还涉及该组合剂的用于提高学习和/或记忆的用途;以及包括施用该组合剂的改善认知功能的方法、提高学习能力和/或记忆能力的方法。
Description
技术领域
本发明涉及用于改善认知功能的组合剂,更具体为用于改善认知功能的2种磷脂酰胆碱的组合。
发明背景
近年,痴呆症成为世界性的医疗上的大问题。痴呆症为伴有以记忆障碍和判断力低下为中心的多种症状的疾病,症状及进展根据引发其的疾病而不同。但是,任何情况下都存在一个共同点,即显著损害了患者的生活品质。另外,鉴于以病人家属为首的照顾者都被迫提供大量劳动力这一事实,痴呆症可以说是社会层面上的非常严重的问题。寿命增加而使老龄人口增加,由于这与痴呆症患者的增加有关,预计在日本痴呆症患者的数量在今后将进一步增加。此外,还有很多人患有不属于痴呆症的某种的认知障碍。
到现在为止,可以列举多个作为痴呆症原因的疾病,最多的是脑血管性痴呆症与阿尔茨海默型痴呆症,两者及其复合型占病因的大部分。特别是阿尔茨海默型痴呆症,近年在日本一直增加。
痴呆症发病的详细机制尚不明确。然而,痴呆症患者中,已报道过各种生化病变。关于阿尔茨海默型痴呆症和路易体痴呆症,已报道的是脑内的乙酰胆碱浓度低下。基于这一事实,在痴呆症、特别是阿尔茨海默型痴呆症的治疗中,使用乙酰胆碱分解酶抑制剂是迄今为止最成功的方法。在日本,以已经上市销售的盐酸多奈哌齐(商品名Aricept)起始,迄今已经研发了多种乙酰胆碱分解酶抑制剂。但是,这样的药物并不从根本上治疗痴呆症,只是具有延迟症状进展的效果。另外,盐酸多奈哌齐还存在急性肾功能衰竭以及横纹肌溶解症等的发病风险等所报道的副作用的问题。由于这些原因,期望研发理想的更安全且高效的改善痴呆症的药物,这样的药物与抑制乙酰胆碱降解酶具有不同作用机制的可能性很高。
本发明人目前已经报道过:作为与盐酸多奈哌齐不同的药物,磷脂酰胆碱具有改善认知功能的作用(专利文献1)。然而,现在仍然需要用于改善认知功能的药物。
现有技术文献
专利文献
专利文献1:特开2009-7329号公报
发明概述
本发明要解决的问题
本发明的目的是提供用于改善认知功能的药物和改善认知功能的方法。
解决问题的方法
本发明人已经从以往的研究中发现,磷脂酰胆碱(phosphatidylcholine)具有改善认知功能的作用。因此,基于这样的发现,为获得能够更有效地改善认知功能的药物不断地进行了进一步深入的研究。结果发现,特定的2种磷脂酰胆碱组合使用对改善认知功能具有更好的效果,并进一步确认其在临床实践中发挥出充分的效果,进而完成了本发明。即,本发明如下所述:
(1)用于改善认知功能的组合剂,其含有1,2-二亚油酰基-sn-甘油-3-磷酸胆碱(1,2-dilinoleoyl-sn-glycero-3-phosphocholine)和1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)。
(2)根据上述(1)所述的组合剂,其中,所述认知功能的改善是对伴有认知障碍的疾病或病症的患者的认知功能的改善。
(3)根据上述(2)所述的组合剂,其中,所述伴有认知障碍的疾病或病症为选自痴呆症(老年痴呆症、阿尔茨海默型痴呆症、脑血管性痴呆症、外伤后痴呆症、脑肿瘤引起的痴呆症、慢性硬膜下血肿引起的痴呆症、正常压力脑积水引起的痴呆症、脑膜炎后痴呆症和帕金森氏痴呆症等各种疾病引起的痴呆症)、非痴呆性的认知障碍(轻度认知障碍(MCI))以及学习或记忆障碍(脑发育障碍相关的学习及记忆障碍)中的至少1种。
(4)根据上述(1)所述的组合剂,其中为了提高学习能力和/或记忆能力而使用。
(5)根据上述(4)所述的组合剂,其为食品。
(6)改善认知功能的方法,其包括对需要的对象(受试者)施用有效量的1,2-二亚油酰基-sn-甘油-3-磷酸胆碱(DLPC)及有效量的1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)。
(7)根据上述(6)所述方法,其中,所述认知功能的改善为对具有伴有认知障碍的疾病或病症的患者的认知功能的改善。
(8)根据上述(7)所述方法,其中,所述伴有认知障碍的疾病或病症为选自痴呆症(老年痴呆症、阿尔茨海默型痴呆症、脑血管性痴呆症、外伤后痴呆症、脑肿瘤引起的痴呆症、慢性硬膜下血肿引起的痴呆症、正常压力脑积水引起的痴呆症、脑膜炎后痴呆症及帕金森氏痴呆症等各种疾病引起的痴呆症)、非痴呆性的认知障碍(轻度认知障碍(MCI))以及学习或记忆障碍(脑发育障碍相关的学习及记忆障碍)中的至少1种。
发明的效果
本发明的组合剂具有改善认知功能的作用,能够用于,例如,包括痴呆症、非痴呆症性的认知障碍、以及学习或记忆障碍等各种疾病或病症的预防或治疗,或者提高学习能力和/或记忆能力。
附图说明书
图1为表示DLPC单独给药、POPC单独给药、以及DLPC和POPC组合给药对正常大鼠的获得潜伏期的效果的图形。各点表示连续2天的获得潜伏期的平均值(±SEM)。N=6
图2为表示认知障碍中POPC和DLPC组合给药的效果的图形。各值表示每个时间点的平均值(±SEM)MMSE评分。***P<0.0001,配对t检验(paired t-test).
图3为表示认知障碍中POPC单独、DLPC单独或POPC+DLPC组合给药的效果的图形。计算摄取前与摄取5个月后的MMSE评分的差(Δincrease in MMSE score)。各柱表示MMSE评分的差的平均值(±SEM)((±SEM)Δincrease in MMSE score)。P值,未配对t检验(unpaired t-test)。
发明的具体实施方式
以下对本发明进行详细说明。
本发明的特征在于组合使用2种特定的磷脂酰胆碱。
其中一个磷脂酰胆碱为下式表示的二亚油酰基磷脂酰胆碱(1,2-二亚油酰基-sn-甘油-3-磷酸胆碱;以下简称DLPC):
其中,-C(O)R1和-C(O)R2分别为亚油酸残基。
另一个磷脂酰胆碱是由下式表示的棕榈酰基油酰基磷脂酰胆碱(1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;以下简称POPC):
其中,-C(O)R3为棕榈酸残基,-C(O)R4为油酸残基。
DLPC和POPC可以从其活性、安全性方面进行衍生。可以例举,例如进行加氢、羟基化、烷基化、卤化等衍生化,但不限于此。
本发明所使用的DLPC和POPC没有特别限定,可以为从动物(卵黄等)、植物(大豆等)、真菌(酵母、霉菌)等进行分离纯化的物质,也可以为化学合成的物质。此外,就本发明所使用的DLPC和POPC而言,只要将其纯化到能够用作药物的程度,其使用并无特别限制。另外,也可以使用市售商品。
本发明中的“组合剂”意指将上述DLPC和POPC进行组合给药。
本发明的组合剂的给药形式并无特殊限制,在给药时,可以将DLPC与POPC组合起来使用即可。作为此类给药形式,可以例举,例如:
(1)将DLPC与POPC同时进行制剂,得到单一的制剂来给药,
(2)将DLPC与POPC分别进行制剂得到2种制剂,以同一给药途径同时给药,
(3)将DLPC与POPC分别进行制剂得到2种制剂,以同一给药途径错时给药,
(4)将DLPC与POPC分别进行制剂得到2种制剂,以不同给药途径同时给药,
(5)将DLPC与POPC分别进行制剂得到2种制剂,以不同给药途径错时给药等。
从简便性的观点来看,优选单一制剂给药,或2种制剂以同一给药途径同时给药。
在下文中,本发明中的“制剂”包括同时将DLPC和POPC进行制剂所得到的单一制剂,以及将DLPC和POPC分别进行制剂所得到的2种制剂中的每一个、任何一个都包含在内。
本发明的组合剂中的DLPC和POPC的量各自根据该组合剂的给药形式(上述)、病情的严重度、作为给药对象的动物种类、给药对象的药物耐受性、体重、年龄等而不同。通常,对成人每天给药50~500mg的DLPC、优选100~300mg的DLPC,和50~500mg的POPC、优选100~300mg的POPC。DLPC与POPC的摄取比例优选为1:1左右。DLPC和POPC在组合使用的情况下的给药量可以比各自单独使用的情况下减少。
本发明的组合剂中,除了作为有效成分的DLPC和POPC以外,可以含有任意添加物,例如医药上可接受的载体。作为医药上可接受的载体,可以列举赋形剂例如蔗糖、淀粉、甘露糖醇、山梨糖醇、乳糖、葡萄糖、纤维素、滑石、磷酸钙、碳酸钙等;粘合剂例如纤维素、甲基纤维素、羟丙基纤维素、聚丙基吡咯烷酮、明胶、阿拉伯胶、聚乙二醇、蔗糖、淀粉等;崩解剂例如淀粉、羧甲基纤维素、羟丙基淀粉、乙二醇淀粉钠、碳酸氢钠、磷酸钙、柠檬酸钙等;润滑剂例如硬脂酸镁、气相二氧化硅(エアロジル)、滑石、月桂基硫酸钠等;芳香剂例如柠檬酸、薄荷醇、glycyllysin(グリシルリシン)·铵盐、甘氨酸、橙粉等;防腐剂例如苯甲酸钠、亚硫酸氢钠、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等;稳定剂例如柠檬酸、柠檬酸钠、乙酸等;悬浮剂例如甲基纤维素、聚乙烯吡咯烷酮、硬脂酸铝等;分散剂例如表面活性剂等;稀释剂例如水、生理盐水、橙汁等;基蜡例如可可脂、聚乙二醇、白矿油等,但不限于此。
在一个实施方案中,可以得到本发明的组合剂被配制成适宜用于口服给药的制剂的配方。适宜用于口服给药的制剂可以为:用水、生理盐水类稀释液将有效量的物质进行溶解所得到的液体制剂;含有作为固体、颗粒的有效量的物质的胶囊、颗粒剂、散剂或片剂;将有效量的物质用适当的分散介质进行混悬的悬浮液;将溶解了有效量的物质的溶液用适当的分散介质分散并进行乳化所得到的乳化剂等。
在另一个实施方案中,可以得到本发明的组合剂配制成适宜用于非口服给药的制剂的配方。作为适宜用于非口服给药(例如静脉注射、皮下注射、肌肉注射、局部注射等)的制剂包括水性和非水性等渗无菌注射溶液,其中可以含有抗氧化剂、缓冲剂、抑菌剂、等渗剂等。另外,可列举水性和非水性的无菌悬浮液,其中可以含有助悬剂、增溶剂、增稠剂、稳定剂、防腐剂等。此类制剂可以用小瓶和安瓿之类的容器封装单位剂量或多个剂量。此外,可以以下状态保存:将有效成分和医药上可接受的载体进行冷冻干燥,只需要在即将使用前用合适的无菌载体进行溶解或悬浮即可。
本发明的组合剂中,含有作为有效成分的DLPC和POPC,其对哺乳动物(例如,小鼠、大鼠、仓鼠、兔子、猫、狗、牛、羊、猴、人等)具有改善认知功能的作用,因此,含有DLPC和POPC的本发明的组合剂作为用于伴有认知障碍的疾病或病症的预防或治疗是有用的,可以作为医药品提供。作为伴有认知障碍的疾病或病症,具体而言,可以列举包括痴呆症(例如老年痴呆症、阿尔茨海默型痴呆症、脑血管性痴呆症、外伤后痴呆症、脑肿瘤引起的痴呆症、慢性硬膜下血肿引起的痴呆症、正常压力脑积水引起的痴呆症、脑膜炎后痴呆症和帕金森氏型痴呆症等各种疾病所引起的痴呆症)、非痴呆性的认知障碍(例如轻度认知障碍(MCI))、学习或记忆障碍(例如脑发育障碍相关的学习和记忆障碍)等各种疾病或病症。并且,本发明的组合剂可以为了提高学习、记忆(例如短期记忆、长期记忆)而使用。
当用在本说明书中时,“预防”的意思是指对于未表现出认知障碍、学习、记忆障碍等的对象(受试者),预防该症状的明显化,“治疗”的意思是指对于表现了认知功能障碍、学习、记忆障碍等受试者,使该症状减轻或者防止该症状恶化或使其发展延迟。“改善”的意思是指对于未表现出认知障碍、学习、记忆障碍等的对象,使他们的认知能力、学习、记忆能力提高,对于表现了认知障碍、学习、记忆障碍等受试者,优选使该症状缓和至在日常生活中没有问题的程度。
本发明的组合剂可以作为食品提供。含有作为有效成分含有DLPC和POPC的本发明的组合剂,对哺乳动物(例如,小鼠、大鼠、仓鼠、兔子、猫、狗、牛、羊、猴、人等)具有改善认知功能的作用,因此,含有作为有效成分的DLPC和POPC的本发明的组合剂,对于伴有认知障碍的疾病或病症的预防或调节是有效的。特别是可以作为对伴有认知障碍的疾病或病症的预防或调节有效功能性食品,以及对学习、记忆的提高有效的功能性食品来提供。
本发明中的“食品”的意思是指所有药物和准药物以外的食品和饮料。例如包括特定保健用食品,营养功能食品,和所谓的补充剂,但不限于此。
本发明的组合剂作为食品来使用的情况下,作为食品包括例如一般食品(例如,面包、乳制品(例如牛奶、酸奶)、糕点、糖果、糖、巧克力、蛋糕、布丁、果冻、饮料、面条)、健康食品、膳食补充剂,还有日本厚生劳动省的保健功能食品制度中所规定的特定保健用食品和营养功能食品。上述食品可以为液体(水溶性、不溶性)、粉末、颗粒、片剂、胶囊等固体、果冻状等半固体等任意形态。本发明的组合剂可以用水或指定水溶液溶解后使用。在这种情况下,本发明的组合剂可以含有辅助溶解的物质(例如,亚油酸)和稳定剂。
当本发明的组合剂被用作食品的情况下,根据使用形式(例如,液体、固体、半固体)、DLPC和POPC的含有浓度、还有是否含有DLPC和POPC以外的成分、其种类和含量等,其摄取量不同,不能一概而论,通常在食品中含有的DLPC和POPC的总含量优选30%以上的比例,更加优选90%以上的比例。作为食品中除DLPC和POPC以外的成分,可以例举上述任意添加物。
本发明的组合剂可以为如下形式:所述组合剂的单位摄取量或其分装量被单独包装或填充,或者包括多个单位摄取量或其分装量的包装或填充。
当本发明的组合剂作为单独制剂提供时,所述组合剂的单位摄取量或其分装量为DLPC和POPC两者,即磷脂酰胆碱全体的单位摄取量或其分装量。当本发明的组合剂作为2种制剂的组合使用提供时,所述组合剂的单位摄取量或其分装量为DLPC的单位摄取量或分装量与POPC的单位摄取量或分装量的组合。
作为单位摄取量或其分装量被单独包装或填充的药物或食品,可以例举,例如单位摄取量或其分装量分别被包装或填充到普通包装物(例如PTP(press through packing)泡罩包装片材、纸制容器、膜(例如塑料膜)容器、玻璃容器、塑料容器)中。上述独立包装或填充的药物或食品可以进一步组合起来,一起包装或填充到1个容器(例如,纸制容器、膜(例如塑料膜)容器、玻璃容器、塑料容器)中。作为包括多个单位摄取量或其分装量的包装或填充的药物或食品,可以例举例如将多个片剂或胶囊不进行区分包装或填充到1个容器(例如,纸制容器、薄膜(例如塑料薄膜)容器、玻璃容器、塑料容器)中。本发明的药物或食品,可包括对于长期摄入足够数量的单位摄取量或其分装量,例如在食品的情况下,可包括对于3天以上,优选7天、10天、14天、或21天以上,或1个月、2个月、3个月以上足够的量。
本发明的组合剂中,作为必须的有效成分DLPC和POPC之外,还可以含有1种以上可以预防或治疗神经退行性疾病的化合物。
其它用于预防或治疗神经退行性疾病化合物的例子可以例举,多酚、辅酶Q10、β-谷甾醇、异黄酮、麦文酸、维生素C、维生素E、黄酮类、萜类、叶酸、维生素B6、维生素B12、倍半萜内酯、尿激酶、纳豆激酶、二亚油酰基磷脂酰乙醇胺、丙基硫醚、苹果果胶、乙酸、EPA和DHA。
在本发明中,通过DLPC和POPC的组合给药,可以对哺乳动物(例如,小鼠、大鼠、仓鼠、兔子、猫、狗、牛、羊、猴、人等)改善认知功能。因此,通过DLPC和POPC的组合给药,可预防或治疗伴有认知障碍的疾病或病症。作为伴有认知障碍的疾病或病症,具体而言,可以列举痴呆症(例如,老年痴呆症、阿尔茨海默型痴呆症、脑血管性痴呆症、外伤后痴呆症、脑肿瘤引起的痴呆症、慢性硬膜下血肿引起的痴呆症、正常压力脑积水引起的痴呆症、脑膜炎后痴呆症和帕金森氏型痴呆症等各种疾病引起的痴呆症)、非痴呆性的认知障碍(例如轻度认知障碍(MCI))、学习或记忆障碍(例如脑发育障碍相关的学习和记忆障碍)等各种疾病或病症。并且通过本发明的DLPC和POPC的组合给药,可以期待提高学习或记忆(例如短期记忆、长期记忆)。本发明方法中DLPC和POPC的给药量、给药形式与上述本发明的组合剂中所述情况相同。
在本说明书中例举的包括专利和专利申请的所有出版物中公开的内容,通过引用将其全部公开内容并入本说明书。
下面例举实施例来对本发明进行进一步详细说明,但本发明并不限于下述实施例。
实施例
(实验方法和材料)
1.水迷宫试验
用雄性Wistar大鼠(7周)进行水迷宫试验。使用圆形的塑料水槽(直径180厘米,深45厘米)。水槽的内部完全被涂上黑色,从底部到25厘米处装满用墨汁浑浊的水(22℃)。在水中放置涂上黑色的平台(直径11厘米),没入水面下1厘米。水箱置于试验室,设计几个大鼠从水槽中可以看到的标记。在试验进行期间不改变标记的位置。平台置于水箱的中央与两端相等距离的某个位置,即四分之一圆的中心。在随机选择的5个地点之一处,面向水箱壁放下大鼠,测定其到逃避到站台上的时间(获得潜伏期(acquisitionlatency))。如果大鼠顺利逃避,就让其在站台上停滞10秒钟。从水迷宫试验的7天前到试验期间,每天对大鼠口服给药溶解于聚乙二醇(PEG)的单独DLPC(5mg/kg)、单独DLPC(10mg/kg)、单独POPC(5mg/kg)、单独POPC(10mg/kg)、或DLPC(5mg/kg)和POPC(5mg/kg)、或者单独PEG。每天进行2次水迷宫试验,第2次试验于最初试验的2分钟后开始。连续进行8天,计算连续2天内的到达站台上的获得潜伏期的平均值。(±SEM)。
2.简易精神状态检查(Mini Mental State Examination(MMSE))测试
对具有认知障碍的59岁~95岁(平均76±1.1岁)的患者310人(男性135人、女性175人)进行MMSE测试。对214人的患者口服给药POPC(90mg/天),对21人口服给药DLPC(100mg/天),对75人口服给药DLPC(50mg/天)与POPC(45mg/天),分别在早饭后给药1次。在MMSE测试中,满分为30,未满20的情况下判断为轻度认知障碍和痴呆症。
(结果)
实施例1.DLPC单独给药、POPC单独给药、以及DLPC与POPC的组合给药对大鼠的获得潜伏期的影响。
在试验7天前到水迷宫试验期间,每天对大鼠口服给药PEG、DLPC(5mg/kg)、DLPC(10mg/kg)、POPC(5mg/kg)、POPC(10mg/kg)或、DLPC(5mg/kg)与POPC(5mg/kg)。
在DLPC(5mg/kg)和POPC(5mg/kg)组合使用的情况下,大鼠的获得潜伏期显著缩短。另一方面,在DLPC(5mg/kg、10mg/kg)单独给药或者POPC(5mg/kg、10mg/kg)单独给药的情况下,没有观察到显著的效果(图1)。
这表明,DLPC和POPC的组合使用可以增强学习及记忆能力。
实验例2.认知功能障碍中POPC和DLPC组合给药的效果
通过MMSE测试检查了认知障碍中POPC和DLPC组合给药的效果。
对75人患者,在早饭后口服摄取1次POPC(50mg/天)和DLPC(45mg/天),之后,每月进行一次MMSE测试。结果如图2所示。
另外,以同样的方式,对口服摄取单独POPC(90mg/天,每天早饭后1次)的214人患者、口服摄取单独DLPC(100mg/天,每天早饭后1次)的21人患者,也每月进行一次MMSE测试。计算摄取前与摄取5个月后的MMSE评分的差(Δincrease in MMSE score)。结果如图3所示。
本试验中测试的患者(310人)中,约65%患有轻度认知障碍和痴呆症。关于摄取POPC与DLPC两者的75人患者,摄取前的平均MMSE评分为14.7±0.7(图2),每天早饭后组合摄取DLPC(50mg/天)与POPC(45mg/天)1次,MMSE评分显著上升,平均评分超过20。即,患者在摄取后5个月恢复到了正常的认知功能(图2)。
与单独摄取POPC(90mg/天)的患者、或者单独摄取DLPC(100mg/天)的患者相比,组合摄取DLPC(50mg/天)与POPC(45mg/天)5个月的患者中有更为显著的MMSE评分上升(图3)。
这些结果表明,与POPC或DLPC的单独治疗相比,DLPC和POPC的组合使用治疗更有效地改善轻度认知障碍及痴呆症
工业实用性
本发明的组合剂具有改善认知功能的作用,可用于例如包括痴呆症、非痴呆性的认知障碍、以及学习或记忆障碍等多种疾病或病症的预防或治疗、或者学习能力和/或记忆能力的提高。
本申请基于在日本申请的专利申请第2010-294487号(申请日期:平成22年12月29日),本文包括其全部内容。
Claims (8)
1.用于改善认知功能的组合剂,其含有1,2-二亚油酰基-sn-甘油-3-磷酸胆碱和1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
2.根据权利要求1所述的组合剂,其中,所述认知功能的改善是对伴有认知障碍的疾病或病症的患者的认知功能的改善。
3.根据权利要求2所述的组合剂,其中,所述伴有认知障碍的疾病或病症为选自痴呆症、非痴呆性的认知障碍、以及学习或记忆障碍中的至少1种。
4.根据权利要求1所述的组合剂,其是为了提高学习能力和/或记忆能力而使用。
5.根据权利要求4所述的组合剂,其为食品。
6.改善认知功能的方法,其包括对需要的对象施用有效量的1,2-二亚油酰基-sn-甘油-3-磷酸胆碱(DLPC)和有效量的1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)。
7.根据权利要求6所述的方法,其中,所述认知功能的改善为对具有伴有认知障碍的疾病或病症的患者的认知功能的改善。
8.根据权利要求7所述的方法,其中,所述伴有认知障碍的疾病或病症为选自痴呆症、非痴呆性的认知障碍、以及学习或记忆障碍中的至少1种。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010-294487 | 2010-12-29 | ||
JP2010294487 | 2010-12-29 | ||
PCT/JP2011/078989 WO2012090713A1 (ja) | 2010-12-29 | 2011-12-15 | 認知機能改善用併用剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103402524A true CN103402524A (zh) | 2013-11-20 |
CN103402524B CN103402524B (zh) | 2015-09-02 |
Family
ID=46382826
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201180068708.5A Active CN103402524B (zh) | 2010-12-29 | 2011-12-15 | 用于改善认知功能的组合剂 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20130274228A1 (zh) |
EP (1) | EP2659892B1 (zh) |
JP (1) | JP5896474B2 (zh) |
KR (1) | KR101522123B1 (zh) |
CN (1) | CN103402524B (zh) |
WO (1) | WO2012090713A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113509474A (zh) * | 2021-08-31 | 2021-10-19 | 广东工业大学 | β-谷甾醇在制备用于抗神经炎症药物中的应用 |
CN115944656A (zh) * | 2020-06-18 | 2023-04-11 | 森永乳业株式会社 | 认知功能改善剂、认知功能维持剂、海马体功能改善剂和海马体功能维持剂 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9655911B2 (en) * | 2013-10-15 | 2017-05-23 | Nishizaki Bioinformation Research Institute | Antidepressant combination drug |
CN105682481A (zh) * | 2013-10-21 | 2016-06-15 | 酶学技术有限公司 | 包含胆碱及其衍生物的组合物、其用途以及其制备方法 |
CA3145418A1 (en) * | 2019-06-26 | 2020-12-30 | Kannalife Sciences, Inc. | Use of certain phosphatidylcholines containing long chain polyunsaturated fatty acids as neuroprotective agents |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1084880A (ja) * | 1996-09-13 | 1998-04-07 | Takeda Shokuhin Kogyo Kk | 脂質代謝促進作用を有するリン脂質含有組成物 |
JP2009007329A (ja) * | 2007-05-31 | 2009-01-15 | Tomoyuki Nishizaki | 認知障害を伴う疾患又は状態の予防又は治療用の組成物 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL84840A0 (en) | 1987-12-16 | 1988-06-30 | Rapaport Erich | Dietary supplement |
JP3073224B2 (ja) | 1990-08-08 | 2000-08-07 | キユーピー株式会社 | 脳機能改善用食品又は医薬品組成物並びにその製造方法 |
WO2005027933A1 (en) * | 2003-09-23 | 2005-03-31 | The Corporation Of The Trustees Of The Order Of The Sisters Of Mercy In Queensland | Unsaturated phosphatidylcholines and uses thereof |
US20060008517A1 (en) * | 2004-07-09 | 2006-01-12 | Lynch Marina A | Treatment of age-related memory impairment |
-
2011
- 2011-12-15 US US13/977,190 patent/US20130274228A1/en not_active Abandoned
- 2011-12-15 EP EP11853728.1A patent/EP2659892B1/en not_active Not-in-force
- 2011-12-15 JP JP2012550820A patent/JP5896474B2/ja active Active
- 2011-12-15 WO PCT/JP2011/078989 patent/WO2012090713A1/ja active Application Filing
- 2011-12-15 CN CN201180068708.5A patent/CN103402524B/zh active Active
- 2011-12-15 KR KR1020137017972A patent/KR101522123B1/ko active IP Right Grant
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1084880A (ja) * | 1996-09-13 | 1998-04-07 | Takeda Shokuhin Kogyo Kk | 脂質代謝促進作用を有するリン脂質含有組成物 |
JP2009007329A (ja) * | 2007-05-31 | 2009-01-15 | Tomoyuki Nishizaki | 認知障害を伴う疾患又は状態の予防又は治療用の組成物 |
Non-Patent Citations (2)
Title |
---|
TAKAHIRO YAGUCHI, ET AL.: "1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine improves cognitive decline by enhancing long-term depression", 《BEHAVIOURAL BRAIN RESEARCH》, vol. 204, no. 1, 31 December 2009 (2009-12-31), pages 129 * |
TAKAHIRO YAGUCHI, ET AL.: "Dilinoleoylphosphatidylcholine ameliorates scopolamine-induced impairment of spatial learning and memory by targeting α7 nicotinic ACh receptors", 《LIFE SCIENCES》, vol. 84, no. 910, 27 February 2009 (2009-02-27), pages 263 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115944656A (zh) * | 2020-06-18 | 2023-04-11 | 森永乳业株式会社 | 认知功能改善剂、认知功能维持剂、海马体功能改善剂和海马体功能维持剂 |
CN113509474A (zh) * | 2021-08-31 | 2021-10-19 | 广东工业大学 | β-谷甾醇在制备用于抗神经炎症药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
KR20130102633A (ko) | 2013-09-17 |
EP2659892A1 (en) | 2013-11-06 |
EP2659892A4 (en) | 2015-04-29 |
CN103402524B (zh) | 2015-09-02 |
JPWO2012090713A1 (ja) | 2014-06-05 |
KR101522123B1 (ko) | 2015-05-20 |
WO2012090713A1 (ja) | 2012-07-05 |
US20130274228A1 (en) | 2013-10-17 |
JP5896474B2 (ja) | 2016-03-30 |
EP2659892B1 (en) | 2018-05-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2741560T3 (es) | Composiciones de ésteres de ácidos grasos omega-3 | |
ES2769583T3 (es) | Composiciones de magnesio y usos de las mismas | |
CN103402524B (zh) | 用于改善认知功能的组合剂 | |
US11738037B2 (en) | Agent for preventing or improving decline in brain function | |
ES2736183T3 (es) | Composición de absorción oro-bucal para neuro-protector | |
KR20130041902A (ko) | 성인 폴리글루코산체병(apbd)의 치료를 위한 트리헵타노인 식이 | |
EP2077111B1 (en) | Antidepressant agent | |
JP7298593B2 (ja) | 認知機能の改善用組成物および不安様症状の改善用組成物、ならびに脳萎縮の抑制用組成物 | |
US8557236B2 (en) | Cardiovascular support supplement and compositions and methods thereof | |
WO2003082339A1 (en) | Multivitamin and mineral nutritional supplement | |
US10986857B2 (en) | Dietary supplementation with mixed alkali salts | |
JP4891522B2 (ja) | 血清got、gpt改善剤 | |
NZ545751A (en) | A water drink with supplements to alleviate the effects of ageing | |
KR20120068006A (ko) | 혈액 중의 요산치를 저하시키기 위한 조성물 | |
US20220023283A1 (en) | Pharmaceutical composition for treatment of dementia and cerebrovascular disorders | |
WO2019022149A1 (ja) | ケトン体生成促進剤 | |
JP2005015417A (ja) | 抗疲労組成物 | |
EP2143433A1 (en) | Preparation for the prevention of joint disease | |
JP2005053844A (ja) | インスリン誘発低血糖に起因する脳障害を予防、改善するための薬剤および食品 | |
AU2005203518A1 (en) | Pharmaceutical and nutritional compositions containing essential fatty acids and homocysteine-lowering agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1189493 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1189493 Country of ref document: HK |