WO2008013215A1 - Sleep-inducing oral preparation, and oral preparation for amelioration of stress-induced insomnia - Google Patents
Sleep-inducing oral preparation, and oral preparation for amelioration of stress-induced insomnia Download PDFInfo
- Publication number
- WO2008013215A1 WO2008013215A1 PCT/JP2007/064641 JP2007064641W WO2008013215A1 WO 2008013215 A1 WO2008013215 A1 WO 2008013215A1 JP 2007064641 W JP2007064641 W JP 2007064641W WO 2008013215 A1 WO2008013215 A1 WO 2008013215A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- serine
- sleep
- oral
- oral preparation
- stress
- Prior art date
Links
- 230000007958 sleep Effects 0.000 title claims abstract description 77
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 title claims abstract description 54
- 206010022437 insomnia Diseases 0.000 title claims abstract description 54
- 230000001939 inductive effect Effects 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 128
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 claims abstract description 29
- ZPDQFUYPBVXUKS-YADHBBJMSA-N 1-stearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@H](N)C(O)=O ZPDQFUYPBVXUKS-YADHBBJMSA-N 0.000 claims abstract description 25
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims abstract description 24
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims abstract description 23
- BZQFBWGGLXLEPQ-UHFFFAOYSA-N O-phosphoryl-L-serine Natural products OC(=O)C(N)COP(O)(O)=O BZQFBWGGLXLEPQ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229950006137 dexfosfoserine Drugs 0.000 claims abstract description 22
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 235000018417 cysteine Nutrition 0.000 claims abstract description 19
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 31
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- -1 acetylylserine Chemical compound 0.000 claims description 13
- 230000006872 improvement Effects 0.000 claims description 13
- 230000006698 induction Effects 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 8
- 230000007065 protein hydrolysis Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 238000000855 fermentation Methods 0.000 claims description 5
- 230000004151 fermentation Effects 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 230000002255 enzymatic effect Effects 0.000 claims description 3
- 238000010494 dissociation reaction Methods 0.000 claims description 2
- 230000005593 dissociations Effects 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000006186 oral dosage form Substances 0.000 claims 1
- JJIHLJJYMXLCOY-BYPYZUCNSA-N N-acetyl-L-serine Chemical compound CC(=O)N[C@@H](CO)C(O)=O JJIHLJJYMXLCOY-BYPYZUCNSA-N 0.000 abstract description 5
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 abstract 1
- 229960001153 serine Drugs 0.000 description 85
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 38
- 241001465754 Metazoa Species 0.000 description 32
- 238000012360 testing method Methods 0.000 description 32
- 230000000694 effects Effects 0.000 description 28
- 230000006399 behavior Effects 0.000 description 19
- 239000004471 Glycine Substances 0.000 description 17
- 241000287828 Gallus gallus Species 0.000 description 13
- 235000013330 chicken meat Nutrition 0.000 description 13
- 239000000126 substance Substances 0.000 description 11
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 8
- 241000196324 Embryophyta Species 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229940068196 placebo Drugs 0.000 description 7
- 239000000902 placebo Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 6
- 229930195711 D-Serine Natural products 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000006911 enzymatic reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000004201 L-cysteine Substances 0.000 description 5
- 235000013878 L-cysteine Nutrition 0.000 description 5
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 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 description 5
- VZXPDPZARILFQX-BYPYZUCNSA-N O-acetyl-L-serine Chemical compound CC(=O)OC[C@H]([NH3+])C([O-])=O VZXPDPZARILFQX-BYPYZUCNSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000411 inducer Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- 102100027992 Casein kinase II subunit beta Human genes 0.000 description 3
- 101710158100 Casein kinase II subunit beta Proteins 0.000 description 3
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 235000010469 Glycine max Nutrition 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229960003067 cystine Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 208000019116 sleep disease Diseases 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- 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
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 235000013345 egg yolk Nutrition 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 229960003699 evans blue Drugs 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- 235000013402 health food Nutrition 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000001095 phosphatidyl group Chemical group 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 2
- 235000014102 seafood Nutrition 0.000 description 2
- 230000004622 sleep time Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- 238000006276 transfer reaction Methods 0.000 description 2
- 229940074410 trehalose Drugs 0.000 description 2
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 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
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 235000014036 Castanea Nutrition 0.000 description 1
- 241001070941 Castanea Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 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
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 239000007983 Tris buffer Substances 0.000 description 1
- LXNHXLLTXMVWPM-UHFFFAOYSA-N Vitamin B6 Natural products CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 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
- 239000011230 binding agent Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000004289 cerebral ventricle Anatomy 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(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-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008918 emotional behaviour Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 235000013376 functional food Nutrition 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
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 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
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 230000010365 information processing Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 150000002632 lipids Chemical group 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 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
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 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
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045999 vitamin b 12 Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 230000021542 voluntary musculoskeletal movement Effects 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
- A61P25/20—Hypnotics; Sedatives
Definitions
- Oral agent for inducing sleep oral agent for improving stress insomnia
- the present invention relates to a sleep inducer and a stress insomnia improving agent.
- insomnia is a state in which the amount of sleep time necessary to maintain a person's health is insufficient in terms of quantity or quality, which hinders social life and is also concerned consciously.
- temporary insomnia for a few days
- short-term insomnia for 1-3 weeks
- long-term insomnia for more than a month.
- the causes of insomnia vary, but often they are associated with some form of stress, and the longer this stress is, the more likely the symptoms of insomnia become.
- the use of sleeping pills, tranquilizers, stress relievers, etc. is commonly used.
- the effect of improving insomnia is greatly influenced by the psychological state of the subject and the surrounding environment, and is limited by the characteristics of the action point of the drug used, side effects and drug dependence. There are many things. Therefore, it is necessary to develop new medicines and functional foods in order to improve the drawbacks of these sleeping pills, tranquilizers and stress relievers.
- the present inventors found an anxiolytic effect on a compound having a serine unit such as serine phosphatidylserine, or glycine, phosphatidic acid, etc., and filed a patent application (Japanese Patent Application No. 2005-029114). . This time, as an extension of the study, we discovered that administration of L-serine and the like showed a remarkable sleep-inducing effect under stress loading conditions, and found that effect.
- the present invention provides a new sleep inducer and stress insomnia improving agent.
- the present inventors have found that serine, phosphoserine, Each of phosphatidylserine, lysophosphatidylserine, acetylserine, or cysteine is L-type, and these compounds are found to have sleep-inducing or stress-induced insomnia-improving effects, and are effective and effective by oral prescription. It was confirmed. That is, the present invention is based on the following means.
- Each of serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is L-type, and one or more selected from these compounds
- An oral agent for inducing sleep characterized by containing two or more.
- Each of serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is L-type, and one or more selected from these compounds
- Serine is produced by any of the following methods: protein hydrolysis, chemical synthesis, enzymatic method, fermentation method, extraction from natural raw materials and purification (1) (2) An oral preparation for inducing sleep or an oral preparation for improving stress insomnia.
- the lysophosphatidylserine product extracted from a natural raw material, or produced by enzymatic base conversion reaction or phosphatidylserine fatty acid dissociation, (1) or (2) An oral preparation for sleep induction or an oral preparation for improving stress insomnia.
- the phosphoserine, cysteine, and acetylylserine are produced by any one of a protein hydrolysis method, a chemical synthesis method, an enzymatic method, a fermentation method, or a natural raw material extraction / purification method.
- Item 3. An oral preparation for inducing sleep or an oral preparation for improving stress insomnia according to item 1 or 2.
- the content of one or more selected from serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is 5% by mass or more.
- a sleep-inducing or stress-induced insomnia characterized by containing the oral agent for inducing sleep or the oral agent for improving stress-induced insomnia as described in! / Of any one of (1) to (7) Oral medicine for symptom improvement.
- FIG. 1 is a diagram showing sleep behavior in L-serine (L-Ser) concentration-based administration groups in Example 1.
- FIG. 2 Sleep behavior of L-serine (L-Ser) and D-serine (D_Ser) administration groups in Example 2
- L-Ser L-serine
- D_Ser D-serine
- FIG. 3 Diagram showing sleep behavior of L-serine (L-Ser), O-phospho-L-serine (Phos_S), O-acetyl-L-serine (Ace-S), and L-cysteine (L-Cys) administration groups in Example 3. .
- FIG. 4 is a view showing sleep behavior in a group administered with L-serine (L-Ser), glycine (Gly), and La lysophosphatidylserine (Lyso-PS) in Example 4.
- L-Ser L-serine
- Gly glycine
- Lyso-PS La lysophosphatidylserine
- FIG. 5 is a view showing sleep behavior of a group administered with L-a-phosphatidylserine (PS), L-a phosphatidylethanolamine (PE), and L a phosphatidylcholine (PC) in Example 5.
- PS L-a-phosphatidylserine
- PE L-a phosphatidylethanolamine
- PC L a phosphatidylcholine
- FIG. 6 is a diagram showing the L_Serine structure.
- FIG. 7 is a view showing a 0-phospho-L-Serine structure.
- FIG. 8 shows a structure of L-a-phosphatidylserine (L-a-Phosphatidy® Serine).
- FIG. 9 Diagram showing the structure of L—a lysophosphatidylserine (L-a-Lyso-Phosphatidy ⁇ Serine).
- FIG. 10 Diagram showing the structure of O-acetyl-L-Serine (O-Acety-L-Serine).
- FIG. 11 is a diagram showing an L-Cysteine structure.
- FIG. 12 shows a structure of L—a phosphatidylcholine (L-a-Phosphatidy® Choline).
- FIG. 13 is a diagram showing the structure of L—a phosphatidylethanolamine (L-a-Phosphatidy ⁇ Ethanolamin).
- FIG. 14 is a diagram showing a D_serine structure.
- FIG. 15 is a graph showing the effect of improving sleep maintenance by serine intake in Example 6.
- FIG. 16 is a graph showing the sleep improvement effect of serine intake in Example 6.
- FIG. 17 is a graph showing the sleep improvement effect of serine intake by a person who feels stress in Example 6.
- a compound having a serine unit having an L-type structure and a cysteine having an L-type structure could be confirmed.
- the effective serine unit and cysteine of the present invention shown below are compounds having an L-type structure.
- the compound having a serine unit is a compound having a serine unit represented by the following general formula 1.
- stronger activity can be obtained in the case of an R-based phosphate group connected to this serine unit.
- Cysteine (Cys) is represented by the chemical formula “H—S—CH (NH 2) COOH”.
- Serine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, enzymatic method, and fermentation method.
- serine is a structural component of tissues, even those with low yields can be extracted and purified from natural raw materials such as animals and plants.
- it can also be produced from components derived from animals, plants, etc. by producing, extracting and purifying by chemical treatment such as phosphoserine and phosvitin.
- the selenium according to the present invention is not intended to limit the manufacturing method.
- the phosphoserine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods.
- Phosphoserine is known as a precursor of serine biosynthesis. Since it is a protein component containing phosphoric acid, it can be produced by extracting and purifying even low yields from animals and plants. Examples of proteins rich in phosphoserine include casein and phosvitin. Furthermore, it can also be produced from components derived from animals, plants, etc., for example, casein, phosvitin, etc. by chemical treatment, extraction, and purification.
- the production method of phosphoserine according to the present invention is not particularly limited.
- the phosphatidylserine related to the present invention is a natural product such as soybean, cottonseed and other plant species. It can be produced by extraction from offspring, egg yolk, seafood, poultry and meat. Alternatively, a phosphatidylserine-rich phospholipid raw material can be produced by carrying out a phosphatidyl group transfer reaction using these produced lecithins.
- the production method of phosphatidylserine according to the present invention is not particularly limited.
- the lysophosphatidylserine according to the present invention can be produced by extraction from natural plant seeds such as soybeans and cottonseed, egg yolk, seafood, and animal meat.
- a lysophosphatidylserine-rich phospholipid raw material can be produced by carrying out a phosphatidyl group transfer reaction using lysolecithin produced therefrom. Since lysophosphatidylserine is obtained by dissociating the fatty acid moiety of phosphatidylserine, it can be produced, extracted, and purified from phosphatidylserine by enzyme or chemical treatment.
- the production method of lysophosphatidylserine according to the present invention is not particularly limited.
- Acetylserine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. Acetylserine is known as an intermediate of cysteine biosynthesis in microorganisms. Acetylserine according to the present invention does not particularly limit the production method.
- the cystine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods.
- cysteine is a structural component of tissues, those with low yields can be extracted and purified from animals and plants.
- cysteine is one in which the hydroxyl group oxygen atom of serine is substituted with a sulfur atom, it can be produced from serine by chemical treatment, extraction and purification.
- the cystine according to the present invention does not particularly limit the production method.
- Serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine which is a compound having a serine unit, is a natural type or an L type produced by any of the methods described above. Is available.
- Fig. 6 shows L-serine
- Fig. 7 shows O-Phospho-L-Serine
- Fig. 8 shows L-a-phosphatidylserine
- Fig. 9 Is L-a-lysophosphatidylserine (L-a-Lyso-Phosphatidyl-Serine)
- Figure 10 shows O-acetylyl-L —Serine (O-Acety to L-Serine)
- Fig. 11 is L-Cysteine
- Fig. 12 is L- ⁇ -phosphatidinorecholine (L-a-Phosphatidy ⁇ Choline)
- Fig. 13 is L-a-phosphatidinorethanolamine (L-Phosphatidyl-Ethanolamin is shown.
- serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, and cysteine produced by the above method are used as active ingredients.
- commercially available serine, phosphine, phosphatidylserine, lysophosphatidylserine, facetylserine, cystine as active ingredients and can be formulated in combination with known non-toxic pharmaceutical carriers according to conventional methods. Good! /
- the oral agent for inducing sleep and the oral agent for improving stress insomnia according to the present invention can be orally administered in various dosage forms.
- the oral agent include tablets, granules, powders, Examples include solid agents such as pushells and soft capsules, solutions such as solutions, suspensions and emulsions, and freeze-dried preparations.
- parenteral administration agents in addition to injections, suppositories, sprays, and transdermal absorption agents are possible, but oral intake is preferable for convenience of users.
- non-toxic carrier for pharmaceutical use examples include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, and albumin. , Water, physiological saline and the like. If necessary, conventional additives such as stabilizers, lubricants, wetting agents, emulsifiers, binders and the like can be appropriately added.
- the oral agent for inducing sleep and the oral agent for improving stress insomnia which are compounds having a serine unit
- the dosage is appropriately selected and determined according to the patient's age, weight, symptoms, degree of disease, administration schedule, formulation, etc.
- the dose is about 0.01 to 10 g / kg body weight per day. It may be administered once to several times a day.
- Test condition 1 applies to Examples;! In each example, the experiment was conducted at different times and compounds.
- Test animals Egg breeder male chickens (Julia, 5 or 6 days old) were used for the test. Prior to sample application, the test animals were grouped according to their body weights, with 6 to 10 birds in pairs.
- Test sample The following reagents were prepared by dissolving in 0.85% saline containing 0.1% Evans blue (additional 5% DMSO when necessary).
- Test method Ten reagents were administered to the ventricles of chicken chicks using a microsyringe. Also In the Control group, 101 ventricle was injected with 0.85% saline containing 0.1% Evans blue.
- Noturn 1 Make a voluntary movement and use it as an index of anxiety.
- Pattern 2 It may sound like it stands in the middle state, but it is not an index.
- Pattern 3 Sleeping behavior can be used as an indicator of sleeping behavior by closing eyes or sitting and dropping head.
- Test condition 2 applies to Example 5.
- Test animals Egg breeder male chickens (Julia, 4 or 5 days old) were used for the test. Prior to sample application, the test animals were grouped according to their body weights, with 6 to 10 birds in pairs. Breeding conditions: Under the condition of 29 ⁇ 1 ° C, commercial feed (Toyohashi Feed Co., Ltd., AX) and water were freely fed.
- Test sample The following reagents were prepared by suspending each in Tris-HC1 Buffer containing 0.1% Evans Blue.
- L-a-phosphatidinoreserin 98%, derived from bovine brain
- Test method Ten reagents were administered to the ventricles of chicken chicks using a microsyringe.
- the Control group received 10 ⁇ l ventricle of Tris HC1 Buffer containing 0.1% Evans Blue.
- Example 1 the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 1. Figure 1 shows the sleep behavior.
- the L-serine 0.82 mol administration group showed clear sleep-inducing effects and stress-induced insomnia improvement effects compared to the control group.
- Example 2 the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 2. Figure 2 shows sleep behavior.
- the L-serine administration group showed significantly the same sleep induction effect and stress insomnia improvement effect as Example 1 compared to the control group.
- Example 3 the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 3. Figure 3 shows sleep behavior.
- L-acetylserine which has a serine unit, showed a tendency to induce sleep and improve stress insomnia compared to the control group.
- the O phospho-L-serine administration group in which the R group connected to the serine unit is a phosphate group showed a stronger remarkable sleep-inducing effect or stress-induced insomnia-improving effect.
- the sleep-inducing effect is significantly increased in the same manner as the compound having the serine unit, Stress insomnia improved.
- Example 4 the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 4. Figure 4 shows sleep behavior.
- the glycine administration group and the La-lysophosphatidylserine (Lyso-PS) administration group have sleep-inducing effects and stress-induced insomnia-improving effects as compared to the control group. Showed a trend.
- Example 5 the following compounds were used as test samples.
- Figure 5 shows the sleep behavior of chickens.
- PS, Lyso-PS, PE and PC are phospholipids with a structure common to the lipid part.
- PS and Lyso-PS show sleep-inducing effects and stress-induced insomnia improvement effects, while PE and PC The fact that such an effect was not shown confirmed that the serine unit has a sleep-inducing effect and an effect of improving stress insomnia.
- the inner volume was filled with a soft capsule filling machine to 250 mg.
- a soft capsule filling machine For the coating, a commonly used gelatin and glycerin mixture was used. After drying, as a result of conducting a standard test on grains that have passed liquid leakage inspection, shape selection inspection, and visual inspection, capsule long diameter, force capsule short diameter, capsule total weight, capsule film weight, capsule contents weight, film moisture content It was confirmed that the drug product satisfies various standards such as quantity, disintegration time, acid value, peroxide value, general viable cell count, coliform bacteria, etc.
- Example 6 serine was used as an evaluation product, and a double-blind cross-over test was performed by the following method and content for comparison with a placebo product and a non-essential amino acid glycine.
- Test samples trehalose (manufactured by Hayashibara Shoji Co., Ltd .; placebo product), glycine (manufactured by Kyowa Hakko Kogyo Co., Ltd .; comparative product), L-serine (manufactured by Kyowa Hakko Kogyo Co., Ltd .; test product).
- Study period Ingestion period is 4 consecutive days, washout is 10 days or more as raw shellfish IJ, and this is repeated three times (each placebo, glycine, and serine) (see Table 6 Test schedule)
- Non-patent literature Mitsugu Oguri et al., Psychiatry, Vol.27 (7), 791-799, 1985
- Example:! ⁇ 5 is a test administered directly to the chick cerebral ventricles
- This Example 6 is a test taken orally by humans. This study confirmed that oral administration provided a mechanism of action for humans and that oral ingestion was effective.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The object is to develop a sleep-inducing agent and an ameliorating agent for stress-induced insomnia. Disclosed is a sleep-inducing oral preparation comprising one or more members selected from serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylserine (which are compounds having a serine unit) and cysteine each in an L-form.
Description
明 細 書 Specification
睡眠誘導用経口剤、ストレス性不眠症改善用経口剤 Oral agent for inducing sleep, oral agent for improving stress insomnia
技術分野 Technical field
[0001] 本発明は睡眠誘導剤、ストレス性不眠症改善剤に関するものである。 The present invention relates to a sleep inducer and a stress insomnia improving agent.
背景技術 Background art
[0002] 睡眠は脳を発達させた動物たちの重要な生理機能であり，生存のために欠くことの できない行動である。睡眠力 まくとれないと，大脳の情報処理能力に悪影響が出る 。従って，発達した大脳をもつ高等動物ほど睡眠の役割は大きい。質のよい睡眠が あってはじめて，脳は高次の情報処理能力を発揮できる。 [0002] Sleep is an important physiological function of animals whose brains have developed, and is an indispensable behavior for survival. If you don't get enough sleep, your brain's ability to process information will be adversely affected. Therefore, higher animals with a developed cerebrum have a greater role for sleep. Only when there is good quality sleep, the brain can demonstrate high-level information processing capabilities.
近年、かってないほど，睡眠に対する関心が高くなつている。その大きな理由は 2 つある。一つは，脳科学の進歩によって，睡眠の重要性がしだいに認識されてきたこ とである。もう一つは，現代社会が睡眠を慢性的に犠牲にする活動様式になり，さま ざまな悪影響を生じたことである。 In recent years, there has been a greater interest in sleep than ever before. There are two main reasons. One is that the importance of sleep has gradually been recognized due to advances in brain science. Another is that modern society has become a mode of activity that chronically sacrifices sleep and has had various adverse effects.
[0003] 深刻な睡眠障害が世界的に増加しつつある。不眠に代表される睡眠障害の対策 はこれからますます比重を高めて!/、くことになる。 [0003] Serious sleep disorders are increasing worldwide. Measures for sleep disorders such as insomnia will increase the specific gravity from now on!
不眠症は人の健康を維持するために必要な睡眠時間が量的にあるいは質的に不 足し、そのために社会生活に支障をきたし、 自覚的にも悩んでいる状態である。不眠 症状がどのくらい続いているかによって、数日の場合には「一過性不眠」、 1〜3週間 の場合には「短期不眠」、 1ヶ月以上続く場合には「長期不眠」と呼ぶ。不眠の原因は さまざまであるが、多くの場合、何等かのストレスと関わること、そしてこのストレスは長 引くほど、不眠の症状が重くなる傾向がある。不眠に対しては睡眠薬、精神安定剤、 ストレス緩和剤などの投与が一般的な治療法として用いられている。 Insomnia is a state in which the amount of sleep time necessary to maintain a person's health is insufficient in terms of quantity or quality, which hinders social life and is also worried consciously. Depending on how long the symptoms of insomnia last, it is called “temporary insomnia” for a few days, “short-term insomnia” for 1-3 weeks, and “long-term insomnia” for more than a month. The causes of insomnia vary, but often they are associated with some form of stress, and the longer this stress is, the more likely the symptoms of insomnia become. For insomnia, the use of sleeping pills, tranquilizers, stress relievers, etc. is commonly used.
しかしながら、不眠症改善効果は対象者の心神的な状態や周囲の環境に大きく左 右されることと共に、使用した薬剤の作用点の特徴のほか、副作用や薬物依存性な どの理由で制限されることも多い。従って、これら睡眠薬、精神安定剤、ストレス緩和 剤の欠点を改善するために新たな医薬品及び機能性食品などの開発が必要とされ
[0004] 本発明者らは以前の試験において、セリンゃホスファチジルセリンなどセリンュニッ トを有する化合物、あるいはグリシン、ホスファチジン酸などに抗不安効果を見出し、 特許出願を行った（特願 2005-029114号)。今回、その試験の延長として、 Lーセリン などの投与によりストレス負荷条件下で顕著に睡眠誘導効果が現れることを発見し、 その効果を見出した。 However, the effect of improving insomnia is greatly influenced by the psychological state of the subject and the surrounding environment, and is limited by the characteristics of the action point of the drug used, side effects and drug dependence. There are many things. Therefore, it is necessary to develop new medicines and functional foods in order to improve the drawbacks of these sleeping pills, tranquilizers and stress relievers. [0004] In the previous test, the present inventors found an anxiolytic effect on a compound having a serine unit such as serine phosphatidylserine, or glycine, phosphatidic acid, etc., and filed a patent application (Japanese Patent Application No. 2005-029114). . This time, as an extension of the study, we discovered that administration of L-serine and the like showed a remarkable sleep-inducing effect under stress loading conditions, and found that effect.
発明の開示 Disclosure of the invention
発明が解決しょうとする課題 Problems to be solved by the invention
[0005] 本発明は新たな睡眠誘導剤、ストレス性不眠症改善剤を提供するものである。 [0005] The present invention provides a new sleep inducer and stress insomnia improving agent.
課題を解決するための手段 Means for solving the problem
[0006] 本発明者は、睡眠誘導剤、ストレス性不眠症改善剤など不眠症状を対応する医薬 品を開発するために鋭意検討を重ねた結果、セリンユニットを有する化合物であるセ リン、ホスホセリン、ホスファチジルセリン、リゾホスファチジルセリン、ァセチルセリン、 又はシスティンのそれぞれは L—型であって、これらの化合物に睡眠誘導又はストレ ス性不眠症改善効果があることを見出し、経口処方により作用、効果を発揮すること を確認した。すなわち、本発明は、次のような手段による。 [0006] As a result of intensive investigations to develop a pharmaceutical product that responds to insomnia such as a sleep inducer and a stress insomnia ameliorating agent, the present inventors have found that serine, phosphoserine, Each of phosphatidylserine, lysophosphatidylserine, acetylserine, or cysteine is L-type, and these compounds are found to have sleep-inducing or stress-induced insomnia-improving effects, and are effective and effective by oral prescription. It was confirmed. That is, the present invention is based on the following means.
[0007] (1)セリンユニット（Serine Unit)を有する化合物であるセリン、ホスホセリン、ホスファ チジルセリン、リゾホスファチジルセリン、ァセチルセリン、又はシスティンのそれぞれ は L 型であり、これらの化合物から選択される 1種又は 2種以上を含有することを特 徴とする睡眠誘導用経口剤。 [0007] (1) Each of serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is L-type, and one or more selected from these compounds An oral agent for inducing sleep, characterized by containing two or more.
(2)セリンユニット（Serine Unit)を有する化合物であるセリン、ホスホセリン、ホスファ チジルセリン、リゾホスファチジルセリン、ァセチルセリン、又はシスティンのそれぞれ は L 型であり、これらの化合物から選択される 1種又は 2種以上を含有することを特 徴とするストレス性不眠症改善用経口剤。 (2) Each of serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is L-type, and one or more selected from these compounds An oral preparation for ameliorating stress insomnia characterized by comprising
(3)セリンが、蛋白質加水分解法、化学合成法、酵素法、発酵法、又は天然原料か ら抽出 '精製のいずれかの方法によって製造されたものであることを特徴とする（1)又 は（2)記載の睡眠誘導用経口剤又はストレス性不眠症改善用経口剤。 (3) Serine is produced by any of the following methods: protein hydrolysis, chemical synthesis, enzymatic method, fermentation method, extraction from natural raw materials and purification (1) (2) An oral preparation for inducing sleep or an oral preparation for improving stress insomnia.
(4)ホスファチジルセリンカ、天然原料から抽出されたもの、或いは酵素による塩基転 換反応によって製造されたものであることを特徴とする（1 )又は（2)記載の睡眠誘導
用経口剤又はストレス性不眠症改善用経口剤。 (4) Sleep induction according to (1) or (2), characterized in that it is extracted from a phosphatidylserine product, a natural raw material, or produced by an enzymatic base conversion reaction. Oral preparation for oral use or for improving stress insomnia.
(5)リゾホスファチジルセリンカ、天然原料から抽出されたもの、或いは酵素による塩 基転換反応又はホスファチジルセリンの脂肪酸解離によって製造されたものであるこ とを特徴とする（1)又は（2)記載の睡眠誘導用経口剤又はストレス性不眠症改善用 経口剤。 (5) The lysophosphatidylserine product, extracted from a natural raw material, or produced by enzymatic base conversion reaction or phosphatidylserine fatty acid dissociation, (1) or (2) An oral preparation for sleep induction or an oral preparation for improving stress insomnia.
(6)ホスホセリン、システィン、ァセチルセリンが、蛋白質加水分解法、化学合成法、 酵素法、発酵法、又は天然原料力 抽出'精製のいずれかの方法によって製造され たものであることを特徴とする請求項 1又は 2記載の睡眠誘導用経口剤又はストレス 性不眠症改善用経口剤。 (6) The phosphoserine, cysteine, and acetylylserine are produced by any one of a protein hydrolysis method, a chemical synthesis method, an enzymatic method, a fermentation method, or a natural raw material extraction / purification method. Item 3. An oral preparation for inducing sleep or an oral preparation for improving stress insomnia according to item 1 or 2.
(7)セリンユニットを有する化合物であるセリン、ホスホセリン、ホスファチジルセリン、 リゾホスファチジルセリン、ァセチルセリン、又はシスティンから選択される 1種又は 2 種以上の含有量が、 5質量％以上であることを特徴とする（1)〜（6)の!/、ずれかに記 載の睡眠誘導用経口剤又はストレス性不眠症改善用経口剤。 (7) The content of one or more selected from serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is 5% by mass or more. (1) to (6)! /, An oral preparation for sleep induction or an oral preparation for ameliorating stress insomnia according to any one of the above.
(8) (1 )〜（7)の!/、ずれかに記載された睡眠誘導用経口剤又はストレス性不眠症改 善用経口剤を含有することを特徴とする睡眠誘導用又はストレス性不眠症改善用経 口医薬品。 (8) A sleep-inducing or stress-induced insomnia characterized by containing the oral agent for inducing sleep or the oral agent for improving stress-induced insomnia as described in! / Of any one of (1) to (7) Oral medicine for symptom improvement.
発明の効果 The invention's effect
[0008] 1.セリンユニット（Serine Unit)を有する化合物であるセリン、ホスホセリン、ホスファチ は睡眠誘導、ストレス性不眠症改善効果があることが確認できた。 [0008] 1. It has been confirmed that serine, phosphoserine, and phosphati, which are compounds having a serine unit, have an effect of improving sleep induction and stress insomnia.
2.本発明により副作用を起こさず安全な睡眠誘導剤、ストレス性不眠改善剤を経口 摂取斉 IJとして提供すること力 Sできる。 2. According to the present invention, it is possible to provide a safe sleep inducer and stress insomnia-improving agent that cause no side effects as an orally ingested IJ.
3. L 型構造を有するセリンユニットを有する化合物であるセリン、ホスホセリン、ホス ファチジルセリン、リゾホスファチジルセリン、ァセチルセリン、又はシスティンを用いた 睡眠誘導用経口剤、ストレス性不眠改善用経口剤を提供する。 3. To provide an oral agent for inducing sleep and an agent for improving stress insomnia using serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which are compounds having a serine unit having an L-type structure. .
図面の簡単な説明 Brief Description of Drawings
[0009] [図 1]実施例 1における Lーセリン (L-Ser)濃度別投与群の睡眠行動を示す図。 FIG. 1 is a diagram showing sleep behavior in L-serine (L-Ser) concentration-based administration groups in Example 1.
[図 2]実施例 2における Lーセリン (L-Ser)と D セリン (D_Ser)投与群の睡眠行動を
示す図。 [Fig. 2] Sleep behavior of L-serine (L-Ser) and D-serine (D_Ser) administration groups in Example 2 FIG.
[図 3]実施例 3における Lーセリン（L-Ser)、 O ホスホー Lーセリン（Phos_S)、 O ァ セチルー Lーセリン (Ace-S)、 L システィン (L-Cys)投与群の睡眠行動を示す図。 [Fig. 3] Diagram showing sleep behavior of L-serine (L-Ser), O-phospho-L-serine (Phos_S), O-acetyl-L-serine (Ace-S), and L-cysteine (L-Cys) administration groups in Example 3. .
[図 4]実施例 4における Lーセリン（L-Ser)、グリシン（Gly)、 L a リゾホスファチジ ルセリン (Lyso-PS)投与群の睡眠行動を示す図。 FIG. 4 is a view showing sleep behavior in a group administered with L-serine (L-Ser), glycine (Gly), and La lysophosphatidylserine (Lyso-PS) in Example 4.
[図 5]実施例 5における L— aーホスファチジルセリン（PS)、 L- a ホスファチジル エタノールァミン（PE)、 L a ホスファチジルコリン（PC)投与群の睡眠行動を示す 図。 FIG. 5 is a view showing sleep behavior of a group administered with L-a-phosphatidylserine (PS), L-a phosphatidylethanolamine (PE), and L a phosphatidylcholine (PC) in Example 5.
[図 6]L_セリン (L-Serine)構造を示す図。 FIG. 6 is a diagram showing the L_Serine structure.
[図 7]0—ホスホ Lーセリン（O-Phospho-L-Serine)構造を示す図。 FIG. 7 is a view showing a 0-phospho-L-Serine structure.
[図 8]L— aーホスファチジルセリン（L- a -Phosphatidy卜 Serine)構造を示す図。 FIG. 8 shows a structure of L-a-phosphatidylserine (L-a-Phosphatidy® Serine).
[図 9]L— a リゾホスファチジルセリン（L- a -Lyso-Phosphatidy卜 Serine)構造を示 す図。 [Fig. 9] Diagram showing the structure of L—a lysophosphatidylserine (L-a-Lyso-Phosphatidy 卜 Serine).
[図 10]O ァセチルー Lーセリン（O-Acetyト L-Serine)構造を示す図。 [Fig. 10] Diagram showing the structure of O-acetyl-L-Serine (O-Acety-L-Serine).
[図 11]L—システィン（L-Cysteine)構造を示す図。 FIG. 11 is a diagram showing an L-Cysteine structure.
[図 12]L— a ホスファチジルコリン（L- a -Phosphatidy卜 Choline)構造を示す図。 FIG. 12 shows a structure of L—a phosphatidylcholine (L-a-Phosphatidy® Choline).
[図 13]L— a ホスファチジルエタノールァミン（L- a -Phosphatidy卜 Ethanolamin)構 造を示す図。 FIG. 13 is a diagram showing the structure of L—a phosphatidylethanolamine (L-a-Phosphatidy 卜 Ethanolamin).
[図 14]D_セリン (D-Serine)構造を示す図。 FIG. 14 is a diagram showing a D_serine structure.
[図 15]実施例 6におけるセリン摂取による睡眠維持の改善効果を示すグラフ。 FIG. 15 is a graph showing the effect of improving sleep maintenance by serine intake in Example 6.
[図 16]実施例 6におけるセリン摂取による寝つき改善効果を示すグラフ。 FIG. 16 is a graph showing the sleep improvement effect of serine intake in Example 6.
[図 17]実施例 6におけるストレスを感じる人のセリン摂取による寝つき改善効果を示す グラフ。 FIG. 17 is a graph showing the sleep improvement effect of serine intake by a person who feels stress in Example 6.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
本発明に関する睡眠誘導、ストレス性不眠症改善効果に有効な化合物は、 L 型 構造を有するセリンユニット（Serine Unit)を有する化合物、 L 型構造を有するシス ティンを確認することができた。以下に示す本願発明の有効なセリンユニット（Serine Unit)及びシスティンは L 型構造を有する化合物である。
セリンユニット（Serine Unit)を有する化合物としては、特に次の一般式 1に示される セリンユニットを有する化合物である。 As a compound effective for the sleep induction and stress insomnia improvement effects according to the present invention, a compound having a serine unit having an L-type structure and a cysteine having an L-type structure could be confirmed. The effective serine unit and cysteine of the present invention shown below are compounds having an L-type structure. The compound having a serine unit is a compound having a serine unit represented by the following general formula 1.
セリン [Serine (Ser) ]、ホスホセリン [Phospho-Serine (Phos-S) ]、ホスファチジルセリン [Pnosphatidyl-Senne (PS) ]、リゾホスファチンノレセリン [Lyso— Phosphatidy卜 5enne (Lys o_PS) ]、ァセチルセリン [Acetyト Serine (Ace-S) ]を挙げることができる。また、このセリ ンユニット（Serine Unit)に接続する R基力 リン酸基である場合は、より強い活性が得 られる。 Serine [Serine (Ser)], phosphoserine [Phospho-Serine (Phos-S)], phosphatidylserine [Pnosphatidyl-Senne (PS)], lysophosphatin noreserin [Lyso- Phosphatidy 卜 5enne (Lys o_PS)], acetylylserine [Acety to Serine (Ace-S)]. In addition, stronger activity can be obtained in the case of an R-based phosphate group connected to this serine unit.
[0011] [化 1]
[0011] [Chemical 1]
(一般式 1 ) (General formula 1)
[0012] システィン [Cysteine (Cys) ]は、化学式「H— S— CH (NH ) COOH」で示される。 [0012] Cysteine (Cys) is represented by the chemical formula “H—S—CH (NH 2) COOH”.
2 2
セリンユニットの「一 O—」が属性の近!/、「一 S—」に置換されて、その活性が維持され ている。 The activity of the serine unit is maintained by substituting the “one O—” for the attribute!
[0013] 本発明に関わるセリンは蛋白質加水分解法、化学合成法、酵素法、発酵法の何れ かの方法によって製造することができる。また、セリンは組織の構成成分であることか ら、収率は低いものも動物、植物などの天然原料から抽出 ·精製して製造することも できる。さらに、動物、植物など由来成分から、例えばホスホセリンやホスビチンなど 力、ら化学処理により生成 ·抽出 ·精製して製造することもできる。本発明に関わるセリ ンは特に製造方法を限定するものではなレ、。 [0013] Serine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, enzymatic method, and fermentation method. In addition, since serine is a structural component of tissues, even those with low yields can be extracted and purified from natural raw materials such as animals and plants. Furthermore, it can also be produced from components derived from animals, plants, etc. by producing, extracting and purifying by chemical treatment such as phosphoserine and phosvitin. The selenium according to the present invention is not intended to limit the manufacturing method.
[0014] 本発明に関わるホスホセリンは蛋白質加水分解法、化学合成法、酵素法の何れか の方法によって製造することができる。ホスホセリンはセリンの生合成の先駆体として 知られる。リン酸が含まれる蛋白質の構成成分であることから、収率は低いものも動 物、植物などから抽出 ·精製して製造することもできる。ホスホセリンを多く含む蛋白 質として、カゼイン、ホスビチンなどがある。さらに、動物、植物など由来成分から、例 えばカゼインやホスビチンなどから化学処理により生成 ·抽出'精製して製造すること もできる。本発明に関わるホスホセリンは特に製造方法を限定するものではない。 [0014] The phosphoserine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. Phosphoserine is known as a precursor of serine biosynthesis. Since it is a protein component containing phosphoric acid, it can be produced by extracting and purifying even low yields from animals and plants. Examples of proteins rich in phosphoserine include casein and phosvitin. Furthermore, it can also be produced from components derived from animals, plants, etc., for example, casein, phosvitin, etc. by chemical treatment, extraction, and purification. The production method of phosphoserine according to the present invention is not particularly limited.
[0015] 本発明に関わるホスファチジルセリンは、天然物である、大豆、綿実などの植物種
子や卵黄、魚介類、鳥獣肉類などから抽出により製造することができる。又は、これら 力 製造されたレシチンを用いてホスファチジル基転移反応を行うことにより、ホスフ ァチジルセリン高含有リン脂質原料が製造できる。本発明に関わるホスファチジルセ リンは特に製造方法を限定するものではない。 [0015] The phosphatidylserine related to the present invention is a natural product such as soybean, cottonseed and other plant species. It can be produced by extraction from offspring, egg yolk, seafood, poultry and meat. Alternatively, a phosphatidylserine-rich phospholipid raw material can be produced by carrying out a phosphatidyl group transfer reaction using these produced lecithins. The production method of phosphatidylserine according to the present invention is not particularly limited.
本発明に関わるリゾホスファチジルセリンは、天然物である、大豆、綿実などの植物 種子や卵黄、魚介類、鳥獣肉類などから抽出により製造することができる。又は、これ らから製造されたリゾレシチンを用いてホスファチジル基転移反応を行うことにより、リ ゾホスファチジルセリン高含有リン脂質原料が製造できる。リゾホスファチジルセリン はホスファチジルセリンの脂肪酸部分が解離されたものであるから、ホスファチジルセ リンから酵素や化学的処理により生成 ·抽出 ·精製して製造することもできる。本発明 に関わるリゾホスファチジルセリンは特に製造方法を限定するものではない。 The lysophosphatidylserine according to the present invention can be produced by extraction from natural plant seeds such as soybeans and cottonseed, egg yolk, seafood, and animal meat. Alternatively, a lysophosphatidylserine-rich phospholipid raw material can be produced by carrying out a phosphatidyl group transfer reaction using lysolecithin produced therefrom. Since lysophosphatidylserine is obtained by dissociating the fatty acid moiety of phosphatidylserine, it can be produced, extracted, and purified from phosphatidylserine by enzyme or chemical treatment. The production method of lysophosphatidylserine according to the present invention is not particularly limited.
[0016] 本発明に関わるァセチルセリンは蛋白質加水分解法、化学合成法、酵素法の何れ かの方法によって製造することができる。ァセチルセリンは微生物におけるシスティン の生合成の中間体として知られる。本発明に関わるァセチルセリンは特に製造方法 を限定するものではない。 [0016] Acetylserine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. Acetylserine is known as an intermediate of cysteine biosynthesis in microorganisms. Acetylserine according to the present invention does not particularly limit the production method.
[0017] 本発明に関わるシスティンは蛋白質加水分解法、化学合成法、酵素法の何れかの 方法によって製造することができる。また、システィンは組織の構成成分であることか ら、収率は低いものも動物、植物などから抽出 ·精製して製造することもできる。さらに 、システィンはセリンのヒドロキシル基酸素原子を硫原子に置換されるものであるので 、セリンから化学処理により生成 ·抽出 ·精製して製造することもできる。本発明に関わ るシスティンは特に製造方法を限定するものではない。 [0017] The cystine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. In addition, since cysteine is a structural component of tissues, those with low yields can be extracted and purified from animals and plants. Furthermore, since cysteine is one in which the hydroxyl group oxygen atom of serine is substituted with a sulfur atom, it can be produced from serine by chemical treatment, extraction and purification. The cystine according to the present invention does not particularly limit the production method.
[0018] セリンユニット（Serine Unit)を有する化合物であるセリン、ホスホセリン、ホスファチ ジルセリン、リゾホスファチジルセリン、ァセチルセリン、又はシスティンが天然型或い は上述のいずれに記載の方法によって製造された L 型のものが利用できる。 [0018] Serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is a natural type or an L type produced by any of the methods described above. Is available.
[0019] 各化合物の構造の例を図 6〜； 1 1に記載する。 [0019] Examples of the structure of each compound are shown in FIGS.
図 6は L セリン（L-Serine)、図 7は O ホスホ一 L セリン（O-Phospho-L-Serine) 、図 8は L— a—ホスファチジルセリン（L- a - Phosphatidyト Serine)、図 9は L— a—リ ゾホスファチジルセリン（L- a -Lyso-Phosphatidyl-Serine)、図 10は O ァセチルー L
—セリン（O- Acetyト L-Serine)、図 1 1は L—システィン（L- Cysteine)、図 12は L— α —ホスファチジノレコリン（L- a - Phosphatidy卜 Choline)、図 13は L— a—ホスファチジ ノレエタノーノレアミン (L- -Phosphatidyl-Ethanolamin を示す。 Fig. 6 shows L-serine, Fig. 7 shows O-Phospho-L-Serine, Fig. 8 shows L-a-phosphatidylserine, Fig. 9 Is L-a-lysophosphatidylserine (L-a-Lyso-Phosphatidyl-Serine), Figure 10 shows O-acetylyl-L —Serine (O-Acety to L-Serine), Fig. 11 is L-Cysteine, Fig. 12 is L-α-phosphatidinorecholine (L-a-Phosphatidy 卜 Choline), Fig. 13 is L-a-phosphatidinorethanolamine (L-Phosphatidyl-Ethanolamin is shown.
[0020] 本発明に関わる睡眠誘導用経口剤、ストレス性不眠症改善用経口剤を製造するに は、上記の方法で製造したセリン、ホスホセリン、ホスファチジルセリン、リゾホスファチ ジルセリン、ァセチルセリン、システィンを有効成分とするもの又は市販のセリン、ホス ホセリン、ホスファチジルセリン、リゾホスファチジルセリン、ァセチルセリン、システィン を有効成分とするものを原料として用いることができ、常法に従って公知の医薬用無 毒性担体と組み合わせて製剤化すればよ!/、。 [0020] In order to produce an oral preparation for sleep induction and an oral preparation for improving stress insomnia according to the present invention, serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, and cysteine produced by the above method are used as active ingredients. Or commercially available serine, phosphine, phosphatidylserine, lysophosphatidylserine, facetylserine, cystine as active ingredients, and can be formulated in combination with known non-toxic pharmaceutical carriers according to conventional methods. Good! /
[0021] 本発明に関わる睡眠誘導用経口剤、ストレス性不眠症改善用経口剤は、種々の剤 型での経口投与が可能であり、例えば、経口投与剤としては錠剤、顆粒剤、散剤、力 プセル剤、ソフトカプセル剤等の固形剤、溶液剤、懸濁剤、乳剤等の液剤、凍結乾 燥製剤等が挙げられる。非経口投与剤としては、注射剤のほか、坐剤、噴霧剤、経 皮吸収剤も可能であるが、利用者の利便性から経口摂取が好ましい。上記の医薬用 無毒性担体としては、例えば、グルコース、乳糖、ショ糖、澱粉、マンニトール、デキス トリン、脂肪酸グリセリド、ポリエチレングリコール、ヒドロキシェチルデンプン、エチレン グリコール、ポリオキシエチレンソルビタン脂肪酸エステル、アミノ酸、アルブミン、水、 生理食塩水等が挙げられる。また、必要に応じて、安定化剤、滑剤、湿潤剤、乳化剤 、結合剤等の慣用の添加剤を適宜添加することができる。 [0021] The oral agent for inducing sleep and the oral agent for improving stress insomnia according to the present invention can be orally administered in various dosage forms. Examples of the oral agent include tablets, granules, powders, Examples include solid agents such as pushells and soft capsules, solutions such as solutions, suspensions and emulsions, and freeze-dried preparations. As parenteral administration agents, in addition to injections, suppositories, sprays, and transdermal absorption agents are possible, but oral intake is preferable for convenience of users. Examples of the non-toxic carrier for pharmaceutical use include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, and albumin. , Water, physiological saline and the like. If necessary, conventional additives such as stabilizers, lubricants, wetting agents, emulsifiers, binders and the like can be appropriately added.
[0022] 本発明に関わる睡眠誘導用経口剤、ストレス性不眠症改善用経口剤において、セ リンユニット（Serine Unit)を有する化合物であるセリン、ホスホセリン、ホスファチジル セリン、リゾホスファチジルセリン、ァセチルセリン、又はシスティンの投与量は、患者 の年齢、体重、症状、疾患の程度、投与スケジュール、製剤形態等により、適宜選択 •決定される力 例えば、 1日あたり 0. 01〜10g/kg体重程度とされ、 1日 1〜数回 に分けて投与してもよい。 [0022] In the oral agent for inducing sleep and the oral agent for improving stress insomnia according to the present invention, serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which are compounds having a serine unit The dosage is appropriately selected and determined according to the patient's age, weight, symptoms, degree of disease, administration schedule, formulation, etc. For example, the dose is about 0.01 to 10 g / kg body weight per day. It may be administered once to several times a day.
[0023] セリンユニット（Serine Unit)を有する化合物、システィンを有効成分とする組成物の 睡眠誘導、ストレス性不眠症改善機能を検証することに当たって、本発明者はまず新 生ニヮトリヒナの脳室内に直接 L—セリン [L-Serine (L-Ser) ]、 D—セリン [D-Serine (D
- Ser]、 O ホスホ— L セリン [O- Phospho- L- Serine(Phos- S)]、 O ァセチル— L— セリン [0_Acetyト L-Serine (Ace-S) ]、 L システィン [L_Cysteine (Cys) ]、グリシン [Gl ycine(Gly)]、 L— a—ホスファテンノレセリン [L— a— Phosphatidy卜 Serine (PS)]、 L— a —リゾホスファチンノレセリン [L— a— Lyso— Phosphatidyト Serine (Lyso— PS)]、 L— a—ホ スファチジルコリン [L-a-Phosphatidy卜 (¾01 6(? ]及びしー a ホスファチジルェ タノールァミン [L- a - Phosphatidyト Ethanolamin(PE)]を投与し、その後ニヮトリヒナの 行動を観察した。 [0023] In verifying the sleep induction and stress insomnia ameliorating function of a composition having a serine unit (serine unit) and a composition containing cysteine as an active ingredient, the present inventor first directly enters the ventricle of a new chicken chick. L-Serine [L-Serine (L-Ser)], D-Serine [D-Serine (D -Ser], O phospho- L-serine [O- Phospho- L- Serine (Phos- S)], O-acetyl-L-serine [0_Acety-to-L-Serine (Ace-S)], L-cysteine [L_Cysteine (Cys) ], Glycine [Glycine (Gly)], L—a—Phosphatenoloserine [L—a—Phosphatidy 卜 Serine (PS)], L—a—Lysophosphatin noreserin [L—a—Lyso— Administration of Phosphatidy Serine (Lyso-PS)], L-a-phosphatidylcholine [La-Phosphatidy 卜 (¾01 6 (? Then, we observed the behavior of chickens.
以下に実施例を挙げて本発明を具体的に説明するが、本発明はこれらに限定され るものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
[0024] 〔試験条件 1〕 [Test condition 1]
試験条件 1は、実施例；!〜 4に適用する。各実施例は、時期と化合物を変えて実験 を fiつた。 Test condition 1 applies to Examples;! In each example, the experiment was conducted at different times and compounds.
試験動物：卵用種雄ニヮトリヒナ (Julia、 5又は 6日齢)を試験に使用した。試料を投 与する前に、試験動物は体重を応じて群分けを行い、 6〜； 10羽を一組にした。 Test animals: Egg breeder male chickens (Julia, 5 or 6 days old) were used for the test. Prior to sample application, the test animals were grouped according to their body weights, with 6 to 10 birds in pairs.
飼育条件： 30 ±1°Cの条件下で、市販飼料 (豊橋飼料社製、 AX)と水を自由摂食さ せた。 Breeding conditions: Under the condition of 30 ± 1 ° C, commercial feed (Toyohashi Feed Co., Ltd., AX) and water were freely fed.
試験試料：次の試薬はそれぞれ 0.1%のエバンスブルーを含む 0.85%の生理食塩水に 溶かし（必要時にさらに 5%の DMSOにより助溶する）、調製した。 Test sample: The following reagents were prepared by dissolving in 0.85% saline containing 0.1% Evans blue (additional 5% DMSO when necessary).
[0025] 実施例に用いる試薬： [0025] Reagents used in the examples:
(1) Lーセリン (和光純薬工業社製、 99%)、 (1) L-serine (Wako Pure Chemical Industries, 99%),
(2) D セリン (和光純薬工業社製、 99%)、 (2) D-serine (Wako Pure Chemical Industries, 99%),
(3) 0—ホスホー Lーセリン（SIGMA社製、 98%)、 (3) 0-phospho L-serine (SIGMA, 98%),
(4) 0—ァセチルー Lーセリン (和光純薬工業社製、 99%)、 (4) 0-acetyl-L-serine (Wako Pure Chemical Industries, 99%),
(5) L システィン (和光純薬工業社製、 99%)、 (5) L Sistine (Wako Pure Chemical Industries, 99%),
(6)グリシン (和光純薬工業社製、 99%)、 (6) Glycine (99% manufactured by Wako Pure Chemical Industries, Ltd.)
(7) L- a—リゾホスファチジルセリン（MP Biomedicals社製、 98%、牛脳由来） (7) L-a-lysophosphatidylserine (MP Biomedicals, 98%, derived from bovine brain)
[0026] 試験方法：マイクロシリンジを用いてニヮトリヒナの脳室に試薬を 10 投与した。また
、 Control群には 0.1%のエバンスブルーを含む 0.85%の生理食塩水を 10 1脳室投 与した。 [0026] Test method: Ten reagents were administered to the ventricles of chicken chicks using a microsyringe. Also In the Control group, 101 ventricle was injected with 0.85% saline containing 0.1% Evans blue.
行動観察：投与から 10分後、各ニヮトリヒナを群飼育ケージから行動観察用分離飼 育ケージに移した脳室投与の直後に単離ストレス状況下で 10分間の行動を 3つの角 度からビデオカメラで記録した。 Behavioral observation: 10 minutes after administration, each chicken chick was transferred from the group cage to a separate cage for behavioral observation Immediately after the ventricular administration, the behavior was observed for 10 minutes under isolated stress conditions. Recorded in.
[0027] 結果解析：記録したビデオからニヮトリヒナの情緒的な行動を観察し、以下の 3パター ンに分類し、 1羽当たりの平均値 (秒数）として表とグラフに示した。 [0027] Analysis of results: Emotional behaviors of chickens were observed from the recorded videos, classified into the following three patterns, and shown in the table and graph as the average value per second (seconds).
ノ ターン 1 :自発運動一鳴いたり、動いたりにして不安の指標とする。 Noturn 1: Make a voluntary movement and use it as an index of anxiety.
パターン 2 :中間状態一立ちままで、鳴く場合もあるが、特に指標としない。 Pattern 2: It may sound like it stands in the middle state, but it is not an index.
パターン 3：睡眠行動一立ち状態で目を閉じたり、坐って頭を下がったりにし て睡眠行為の指標とする。 Pattern 3: Sleeping behavior can be used as an indicator of sleeping behavior by closing eyes or sitting and dropping head.
[0028] 〔試験条件 2〕 [0028] [Test condition 2]
試験条件 2は、実施例 5に適用する。 Test condition 2 applies to Example 5.
試験動物：卵用種雄ニヮトリヒナ (Julia、 4又は 5日齢)を試験に使用した。試料を投 与する前に、試験動物は体重を応じて群分けを行い、 6〜； 10羽を一組にした。 飼育条件：29 ± 1°Cの条件下で、市販飼料 (豊橋飼料社製、 AX)と水を自由摂食さ せた。 Test animals: Egg breeder male chickens (Julia, 4 or 5 days old) were used for the test. Prior to sample application, the test animals were grouped according to their body weights, with 6 to 10 birds in pairs. Breeding conditions: Under the condition of 29 ± 1 ° C, commercial feed (Toyohashi Feed Co., Ltd., AX) and water were freely fed.
試験試料：次の試薬はそれぞれ 0.1%のエバンスブルーを含む Tris— HC1 Buffer中 に懸濁させ、調製した。 Test sample: The following reagents were prepared by suspending each in Tris-HC1 Buffer containing 0.1% Evans Blue.
[0029] 実施例に用いる試薬： [0029] Reagents used in the examples:
( 1 ) L - a—ホスファチジノレセリン (SIGMA、 98 %、牛脳由来）、 (1) L-a-phosphatidinoreserin (SIGMA, 98%, derived from bovine brain),
(2) L - a ホスファチジルコリン（SIGMA、 99%、大豆由来）、 (2) L-a phosphatidylcholine (SIGMA, 99%, derived from soybeans),
(3) L - a ホスファチジルエタノールァミン（SIGMA、 98 %、牛脳由来） (3) L-a phosphatidylethanolamine (SIGMA, 98%, derived from bovine brain)
[0030] 試験方法：マイクロシリンジを用いてニヮトリヒナの脳室に試薬を 10 投与した。ま た、 Control群には 0.1%のエバンスブルーを含む Tris HC1 Bufferを 10 μ 1脳室 投与した。 [0030] Test method: Ten reagents were administered to the ventricles of chicken chicks using a microsyringe. The Control group received 10 μl ventricle of Tris HC1 Buffer containing 0.1% Evans Blue.
行動観察:試験条件 1と同じ。 Behavioral observation: Same as test condition 1.
結果解析:試験条件 1と同じ。
実施例 1 Results analysis: Same as test condition 1. Example 1
[0031] 実施例 1は次の化合物を試験試料として用いた。ニヮトリヒナの行動をパターン分類 した。測定結果 (秒数)を表 1に示した。また、睡眠行動を図 1に示した。 [0031] In Example 1, the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 1. Figure 1 shows the sleep behavior.
(1) Control群（10匹）、 (1) Control group (10 animals),
(2) L—セリン [L-Serine (L-Ser) ] 0.21 ^ mol投与群（8匹）、 (2) L-Serine [L-Serine (L-Ser)] 0.21 ^ mol administration group (8 animals),
(3) L—セリン [L-Serine (L-Ser) ] 0.42 μ mol投与群（7匹）、 (3) L-Serine [L-Serine (L-Ser)] 0.42 μmol administration group (7 animals),
(4) Lーセリン [L-Serine (L-Ser) ] 0.82 μ mol投与群（7匹）。 (4) L-Serine [L-Serine (L-Ser)] 0.82 μmol administration group (7 animals).
表 1、図 1に示したように、 L-セリン 0.82 mol投与群において、コントロール群に比 ベて明らかな睡眠誘導効果、ストレス性不眠症改善効果を示した。 As shown in Table 1 and Fig. 1, the L-serine 0.82 mol administration group showed clear sleep-inducing effects and stress-induced insomnia improvement effects compared to the control group.
[0032] [表 1] [0032] [Table 1]
[0033] 実施例 2は次の化合物を試験試料として用いた。ニヮトリヒナの行動をパターン分類 した。測定結果 (秒数)を表 2に示した。また、睡眠行動を図 2に示した。 [0033] In Example 2, the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 2. Figure 2 shows sleep behavior.
(1) Control群（7匹）、 (1) Control group (7 animals),
(2) L—セリン [L-Serine (L-Ser) ] 0.82 μ mol投与群（7匹）、 (2) L-Serine [L-Serine (L-Ser)] 0.82 μmol administration group (7 animals),
(3) D—セリン [L-Serine (D-Ser) ] 0.82 μ mol投与群（7匹）。 (3) D-serine [L-Serine (D-Ser)] 0.82 μmol administration group (7 animals).
[0034] 表 2、図 2に示したように、コントロール群に比べて L-セリン投与群は実施例 1とほぼ 同じ有意に睡眠誘導効果、ストレス性不眠症改善効果を示した。 [0034] As shown in Table 2 and FIG. 2, the L-serine administration group showed significantly the same sleep induction effect and stress insomnia improvement effect as Example 1 compared to the control group.
さらに、 Lーセリンの構造ユニット（Serine Unit)を持つ他の化合物の睡眠誘導効果 、ストレス性不眠症改善効果を確認するために、次の実施例を行った。 Furthermore, in order to confirm the sleep-inducing effect and stress-induced insomnia improving effect of other compounds having a L-serine structural unit (Serine Unit), the following examples were carried out.
[0035] [表 2]
¾ 2 ： L -セリン (L-Ser) と D—セリン O-Ser) 投与 の行 U¾ ^計^栗
[0035] [Table 2] ¾ 2: Line of L-serine (L-Ser) and D-serine O-Ser administration U¾ ^ Total ^ Chestnut
Pく 0.05 (単位：秒) 実施例 3 P 0.05 (unit: seconds) Example 3
[0036] 実施例 3は次の化合物を試験試料として用いた。ニヮトリヒナの行動をパターン分類 した。測定結果 (秒数）は表 3に示した。また、睡眠行動を図 3に示した。 [0036] In Example 3, the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 3. Figure 3 shows sleep behavior.
(1) Control群（7匹）、 (1) Control group (7 animals),
(2) L セリン [L-Serine (L-Ser) ] 0.84 μ mol投与群（7匹）、 (2) L serine [L-Serine (L-Ser)] 0.84 μmol administration group (7 animals),
(3) O ホスホ L—セリン [O-Phospho- L- Serine (Phos- S) ] 0.84 ^ mol 投与群（6匹）、 (3) O-phospho L-serine [O-Phospho- L- Serine (Phos-S)] 0.84 ^ mol administration group (6 animals),
(4) O ァセチル— L セリン [O- Acetyト L-Serine (Ace_S) ] 0.82 μ mol 投与群（7匹）、 (4) O-acetyl-L-serine [O-Acety-to-L-Serine (Ace_S)] 0.82 μmol administration group (7 animals),
(5) L システィン [L-Cysteine (Cys) ] 0.82 μ mol投与群（6匹）。 (5) L-cysteine [L-Cysteine (Cys)] 0.82 μmol administration group (6 animals).
[0037] [表 3] 表 3 : ： L セリン (L-Ser) 、 O ホスホ—: L _セリン （Plios-S) 、 〇—ァセチル—： L
[0037] [Table 3] Table 3: L-serine (L-Ser), O-phospho: L_serine (Plios-S), O-acetyl-: L
*)P< 0.05 (単位：秒) *) P <0.05 (unit: seconds)
[0038] 表 3、図 3に示したように、コントロール群に比べてセリンユニット（Serine Unit)を有 する L ァセチルセリンに睡眠誘導効果、ストレス性不眠症改善効果の傾向を示した 。また、このセリンユニット（Serine Unit)に接続する R基がリン酸基である O ホスホー Lーセリン投与群はより強い顕著な睡眠誘導効果又はストレス性不眠改善効果を示 した。さらに、セリンユニット（Serine Unit)の「一 O 」が属性の近い「一 S―」に置換さ れている L-システィン投与群でもセリンユニットを有する化合物と同じように有意に睡 眠誘導効果、ストレス性不眠症改善効果を表れた。
実施例 4 [0038] As shown in Table 3 and Fig. 3, L-acetylserine, which has a serine unit, showed a tendency to induce sleep and improve stress insomnia compared to the control group. In addition, the O phospho-L-serine administration group in which the R group connected to the serine unit is a phosphate group showed a stronger remarkable sleep-inducing effect or stress-induced insomnia-improving effect. Furthermore, in the L-cysteine-administered group in which “one O” of the serine unit is replaced with “one S-” having a similar attribute, the sleep-inducing effect is significantly increased in the same manner as the compound having the serine unit, Stress insomnia improved. Example 4
[0039] 実施例 4は次の化合物を試験試料として用いた。ニヮトリヒナの行動をパターン分類 した。測定結果 (秒数）は表 4に示した。また、睡眠行動を図 4に示した。 [0039] In Example 4, the following compounds were used as test samples. The behavior of chickens was classified into patterns. The measurement results (seconds) are shown in Table 4. Figure 4 shows sleep behavior.
(1) Control群（7匹）、 (1) Control group (7 animals),
(2) L セリン [L-Serine (Ser) ] 0.84 μ mol投与群（7匹）、 (2) L-serine [L-Serine (Ser)] 0.84 μmol administration group (7 animals),
(3)グリシン [Glycine (Gly) ] 0.84 μ mol投与群（7匹）、 (3) Glycine [Glycine (Gly)] 0.84 μmol administration group (7 animals),
4)L— a—リゾホスファテンノレセリン [L— α— lysophosphatidylsenne 4) L— a— Lysophosphatene noreserin [L— α— lysophosphatidylsenne
(Lyso-PS)] 0.82 0101投与群（6匹）。 (Lyso-PS)] 0.82 01 0 1 administration group (6 animals).
[0040] [表 4] 表 4： L -セリン (L-£er) 、 グリシン (Gly) 、 ； L— iiーリゾホスフ ヂジルセリン [0040] [Table 4] Table 4: L-serine (L- £ er), glycine (Gly), L-ii-lysophosphididylserine
(単位： (Unit:
[0041] 表 4、図 4に示したように、コントロール群に比べてグリシン投与群と L aーリゾホス ファチジルセリン (Lyso-PS)投与群は睡眠誘導効果、ストレス性不眠症改善効果を有 する傾向を示した。 [0041] As shown in Table 4 and FIG. 4, the glycine administration group and the La-lysophosphatidylserine (Lyso-PS) administration group have sleep-inducing effects and stress-induced insomnia-improving effects as compared to the control group. Showed a trend.
実施例 5 Example 5
[0042] 実施例 5は次の化合物を試験試料として用いた。ニヮトリヒナの睡眠行動を図 5に示 した。 [0042] In Example 5, the following compounds were used as test samples. Figure 5 shows the sleep behavior of chickens.
(1) Control群（10匹）、 (1) Control group (10 animals),
(2) L- aーホスファチジルセリン[し-« 1103 11&«(^-56 6(?5)] 0.21 mol投与群（9匹）、 (2) L-a-phosphatidylserine [Shi- «1103 11 &« (^-56 6 (? 5)] 0.21 mol administration group (9 animals),
(3) L- a ホスファチジルエタノールァミン (3) L- a phosphatidylethanolamine
[L- a -Phosphatidyl-Ethanolamin (PE) ] 0.21 μ mol投与群（7匹）、 [L-a-Phosphatidyl-Ethanolamin (PE)] 0.21 μmol administration group (7 animals),
(4) L- aーホスファチジルコリン[し_« 1103 11&11(^-(¾01^16(? ]0.21 mol投与群（5匹） (4) L-a-phosphatidylcholine [__ 1103 11 & 11 (^-(¾01 ^ 16 (?] 0.21 mol administration group (5 animals)
[0043] 図 5に示したように、コントロール群に比べて L aーホスファチジルセリン（PS)投
与群は有意に睡眠誘導効果、ストレス性不眠症改善効果を表れた。一方、 L α— ホスファチジルエタノールァミン（ΡΕ)投与群と L a ホスファチジルコリン（PC)投 与群にはこの様な効果がなかった。 [0043] As shown in FIG. 5, compared to the control group, La-phosphatidylserine (PS) was administered. The given group showed significant effects of inducing sleep and improving stress insomnia. On the other hand, there was no such effect in the L α-phosphatidylethanolamine (ΡΕ) administration group and the La phosphatidylcholine (PC) administration group.
PS、 Lyso-PS、 PEと PCは脂質部分に共通な構造を持つリン脂質であり、 PSと Lyso-P Sに睡眠誘導効果、ストレス性不眠症改善効果を示し、一方、 PEと PCにこの様な効果 を示していないことは、セリンユニット（Serine Unit)が睡眠誘導効果、ストレス性不眠 症改善効果を有することを裏づけた。 PS, Lyso-PS, PE and PC are phospholipids with a structure common to the lipid part. PS and Lyso-PS show sleep-inducing effects and stress-induced insomnia improvement effects, while PE and PC The fact that such an effect was not shown confirmed that the serine unit has a sleep-inducing effect and an effect of improving stress insomnia.
[0044] 〔参考処方例 1〕 [0044] [Reference Formulation Example 1]
睡眠誘導効果又はストレス性不眠症改善効果を持つセリンとホスファチジルセリン を含有することを特徴とする健康食品用ソフトカプセル剤の製造 セリン、ホスファチ ジルセリン 25%含有液体大豆レシチン、ホスファチジン酸、システン、グリシン、ホス ホセリン、ビタミン Eオイル、ビタミン B 1 (チアミン硝酸塩）、ビタミン B6 (ピリドキシン塩酸 塩）、ビタミン B 12 (シァノコバラミン）、ミツロウとパーム油は表 6に示した配合量となる ように混合し、 30分間撹拌した。 80メッシュで篩過した後、真空撹拌機で脱泡処理を 行った。ソフトカプセル充填機により内容量が 250mgとなるように充填した。皮膜は 通常用いられるゼラチン、グリセリン混合物を用いた。乾燥後、液漏れ検査、形状選 別検査、 目視検査を合格した粒について規格試験を行った結果、カプセル長径、力 プセル短径、カプセル総重量、カプセル皮膜重量、カプセル内容物重量、皮膜水分 含有量、崩壊時間、酸価、過酸化物価、一般生菌数、大腸菌群等の諸規格を満た す製剤であることが確認された。 Manufacture of soft capsules for health foods characterized by containing serine and phosphatidylserine with sleep-inducing effect or stress insomnia-improving effect Liquid soy lecithin, phosphatidic acid, cystene, glycine, phosphine containing 25% serine and phosphatidylserine Joselin, Vitamin E oil, Vitamin B 1 (thiamine nitrate), Vitamin B6 (pyridoxine hydrochloride), Vitamin B 12 (Shyanokobalamin), beeswax and palm oil are mixed so that the blending amounts shown in Table 6 are obtained. Stir for 30 minutes. After sieving with 80 mesh, defoaming was performed with a vacuum stirrer. The inner volume was filled with a soft capsule filling machine to 250 mg. For the coating, a commonly used gelatin and glycerin mixture was used. After drying, as a result of conducting a standard test on grains that have passed liquid leakage inspection, shape selection inspection, and visual inspection, capsule long diameter, force capsule short diameter, capsule total weight, capsule film weight, capsule contents weight, film moisture content It was confirmed that the drug product satisfies various standards such as quantity, disintegration time, acid value, peroxide value, general viable cell count, coliform bacteria, etc.
[0045] 〔参考処方例 2〕 [0045] [Reference Formulation Example 2]
睡眠誘導効果又はストレス性不眠症改善効果を持つセリンを含有することを特徴と する健康食品用飲料の製造。セリン、グリシン、クェン酸、マルチトール、エリスリトー ル、トレハロース、オレンジ果汁、ラカン力エキス、香料は表 6に示した様な配合量で 配合し、最後に水を 50mlになるように加え、原料を水に混合 ·溶解させ、容器に充填 を行い、 85°C 10分の殺菌を行った。殺菌後冷却し、本飲料を完成させた。 Production of a health food beverage characterized by containing serine having a sleep-inducing effect or a stress-induced insomnia-improving effect. Serine, glycine, citrate, maltitol, erythritol, trehalose, orange juice, lacan extract, and fragrance are blended in the amounts shown in Table 6. Finally, add 50 ml of water and add the ingredients. Mixed and dissolved in water, filled into containers, and sterilized at 85 ° C for 10 minutes. After sterilization and cooling, the beverage was completed.
処方例 1及び 2を表 6に示す。 Formulation Examples 1 and 2 are shown in Table 6.
[0046] [表 5]
表 5 ：参考処方 1と 2 [0046] [Table 5] Table 5: Reference prescriptions 1 and 2
実施例 6はセリンを評価品として、以下の方法と内容でプラセボ品および非必須ァ ミノ酸のグリシンと比較する二重盲検交差試験を行った。 In Example 6, serine was used as an evaluation product, and a double-blind cross-over test was performed by the following method and content for comparison with a placebo product and a non-essential amino acid glycine.
試験方法 Test method
. 試験サンプル：トレハロース（林原商事社製;プラセボ品とする）、グリシン (協和発 酵工業社製；比較品とする）、 L-セリン (協和発酵工業社製；被験品とする)。 Test samples: trehalose (manufactured by Hayashibara Shoji Co., Ltd .; placebo product), glycine (manufactured by Kyowa Hakko Kogyo Co., Ltd .; comparative product), L-serine (manufactured by Kyowa Hakko Kogyo Co., Ltd .; test product).
• デザイン:プラセボボを対照とする二重盲検交差試験。 • Design: Double-blind crossover study with placebo controls.
• 被験者数: 45例。 • Number of subjects: 45.
• 試験期間:摂取期間は 4日間連続で、ゥォッシュアゥトは原貝 IJとして 10日間以上と し、これを 3回（各プラセボボ、グリシン、セリン)繰り返す（表 6 試験スケジュール 参 • Study period: Ingestion period is 4 consecutive days, washout is 10 days or more as raw shellfish IJ, and this is repeated three times (each placebo, glycine, and serine) (see Table 6 Test schedule)
"昭、、） J〇
• 摂取方法：就寝 30分前にそれぞれ 3gを水とともに摂取する。 "Akira,) J〇 • Ingestion method: Take 3g each with water 30 minutes before going to bed.
注)試験は次の非特許引用文献の方法に従い行った。 Note) The test was conducted according to the method of the following non-patent citation.
非特許引用文献:小栗 貢ら、精神医学、 Vol.27 (7)、 791-799, 1985 Non-patent literature: Mitsugu Oguri et al., Psychiatry, Vol.27 (7), 791-799, 1985
[0048] 試験対象： [0048] Test subjects:
• 選択基準：（a)年齢 20歳以上 65歳未満の男女。 • Selection criteria: (a) Men and women aged between 20 and 65 years.
(b)睡眠に不満を感じる者。 (b) Those who are unhappy with sleep.
• 除外基準：（a)背景調査の結果、睡眠に問題がないと判断された者。 • Exclusion criteria: (a) Those who are determined to have no sleep problems as a result of background surveys.
(b)妊娠、妊娠していると思われる婦人、授乳中の婦人。 (b) Pregnancy, a woman who seems to be pregnant, or a lactating woman.
(c)重度花粉症、胃腸疾患、肝疾患、腎疾患、心疾患を有する者。 (c) Those with severe hay fever, gastrointestinal disease, liver disease, kidney disease, heart disease.
(d)睡眠に影響を及ぼす薬 (風邪薬、抗アレルギー薬などを含む）、サ プリメントを試験期間に中断できない者。 (d) Those who cannot stop taking drugs that affect sleep (including cold medicines and antiallergic drugs) and supplements during the study period.
[0049] 調査項目： [0049] Survey items:
• 背景調査:年齢、性別、生活習慣、既往歴、睡眠状態を観察期間に記載させる。 • 生活調査:体調、身体活動の程度、被験品、コーヒーなどの摂取状態を摂取期間 中毎日、就寝前に記載させる。 • Background survey: Age, sex, lifestyle, medical history, and sleep status should be recorded in the observation period. • Life Survey: Physical condition, degree of physical activity, test article, coffee consumption, etc. should be recorded every day during the intake period, before going to bed.
• 睡眠調査： OSA (起床直後の主観的睡眠感)睡眠調査票 (精神医学、 27巻、 7号 1985年 7月 79；!〜 799ページ参照）、睡眠日記を用いて、睡眠時間、質、 目覚めの 爽快感などを摂取期間中に毎日、起床から 30分以内に記載させる。 • Sleep Survey: OSA (Subjective Sleep Sensation) Sleep Survey Form (Psychiatry, Vol. 27, No. 7, July 1985, July 79;! To 799 pages), sleep diary, sleep time, quality, Have a refreshing feeling of waking up written within 30 minutes of getting up every day during the intake period.
[0050] 試験結果： [0050] Test results:
図 15と 16に示したように、睡眠維持因子と寝つき因子において、セリン摂取はブラ セボ摂取及びグリシン摂取に比べて、顕著な睡眠改善効果を示した。さらに、ストレス を感じている試験対象をピックアップ（計 27名）して統計した結果においても、セリン 摂取はプラセボ摂取及びグリシン摂取に比べて、顕著な寝つき改善効果を示した（ 表 7、図 17)。 As shown in Figs. 15 and 16, serine intake showed a significant sleep improvement effect compared to intake of placebo and glycine in sleep maintenance factors and sleep factors. In addition, the results of picking up test subjects who felt stress (a total of 27 people) showed that serine intake significantly improved sleep improvement compared to placebo intake and glycine intake (Table 7, Figure 17). ).
実施例;!〜 5は、ニヮトリのヒナの脳室に直接投与した試験である力 本実施例 6は 、人間が経口摂取した試験である。この試験によって、経口投与によって人間に対し て作用機序が得られ、経口摂取が有効であることが確認できた。 Example:! ~ 5 is a test administered directly to the chick cerebral ventricles This Example 6 is a test taken orally by humans. This study confirmed that oral administration provided a mechanism of action for humans and that oral ingestion was effective.
[0051] [表 6]
試験スケジュール [0051] [Table 6] Exam schedule
Table 1 Study schedule Table 1 Study schedule
表 7] 睡眠維持 寝つき 寝つき (ストレス感じる）Table 7] Sleep maintenance Sleeping Sleeping (feeling stress)
Ave MeaniSE Ave MeaniSE Ave MeaniSEAve MeaniSE Ave MeaniSE Ave MeaniSE
Placebo 22.8 0.57 24.7 0.67 24.5 0.75Placebo 22.8 0.57 24.7 0.67 24.5 0.75
Glycine 23.5 0.79 25. 1 0.94 23.9 1. 1Glycine 23.5 0.79 25. 1 0.94 23.9 1. 1
Serine 24.9 0.76 26.9 0.72 26.7 0.84
Serine 24.9 0.76 26.9 0.72 26.7 0.84
Claims
[1] セリンユニット（Serine Unit)を有する化合物であるセリン、ホスホセリン、ホスファチジ 型であり、これらの化合物から選択される 1種又は 2種以上を含有することを特徴と する睡眠誘導用経口剤。 [1] An oral agent for inducing sleep, which is a serine, phosphoserine, or phosphatide type compound having a serine unit and contains one or more selected from these compounds.
[2] セリンユニット（Serine Unit)を有する化合物であるセリン、ホスホセリン、ホスファチジ 型であり、これらの化合物から選択される 1種又は 2種以上を含有することを特徴と するストレス性不眠症改善用経口剤。 [2] Serine, phosphoserine, phosphatide type compounds that have a serine unit (Serine Unit), and contain one or more selected from these compounds, for the improvement of stress insomnia Oral.
[3] セリンが、蛋白質加水分解法、化学合成法、酵素法、発酵法、又は天然原料から抽 出 ·精製のいずれかの方法によって製造されたものであることを特徴とする請求項 1 又は 2記載の睡眠誘導用経口剤又はストレス性不眠症改善用経口剤。 [3] The serine is produced by any one of a protein hydrolysis method, a chemical synthesis method, an enzyme method, a fermentation method, or extraction / purification from a natural raw material. 2. An oral preparation for sleep induction or an oral preparation for improving stress insomnia according to 2.
[4] ホスファチジルセリンが、天然原料から抽出されたもの、或いは酵素による塩基転換 反応によって製造されたものであることを特徴とする請求項 1又は 2記載の睡眠誘導 用経口剤又はストレス性不眠症改善用経口剤。 [4] The oral agent for sleep induction or stress insomnia according to claim 1 or 2, wherein the phosphatidylserine is extracted from a natural raw material or produced by an enzyme base conversion reaction. Oral for improvement.
[5] リゾホスファチジルセリンカ、天然原料から抽出されたもの、或いは酵素による塩基転 換反応又はホスファチジルセリンの脂肪酸解離によって製造されたものであることを 特徴とする請求項 1又は 2記載の睡眠誘導用経口剤又はストレス性不眠症改善用経 口剤。 [5] The sleep induction according to claim 1 or 2, characterized in that it is produced by lysophosphatidylserine, extracted from a natural raw material, or produced by enzymatic base conversion or fatty acid dissociation of phosphatidylserine. Oral preparation for oral use or oral preparation for improving stress insomnia.
[6] ホスホセリン、システィン、ァセチルセリンが、蛋白質加水分解法、化学合成法、酵素 法、発酵法、又は天然原料力 抽出'精製のいずれかの方法によって製造されたも のであることを特徴とする請求項 1又は 2記載の睡眠誘導用経口剤又はストレス性不 眠症改善用経口剤。 [6] The phosphoserine, cysteine, and acetylylserine are produced by any one of a protein hydrolysis method, a chemical synthesis method, an enzyme method, a fermentation method, or a natural raw material extraction / purification method. Item 3. An oral preparation for inducing sleep or an oral preparation for ameliorating stress insomnia.
[7] セリンユニットを有する化合物であるセリン、ホスホセリン、ホスファチジルセリン、リゾ ホスファチジルセリン、ァセチルセリン、又はシスティンから選択される 1種又は 2種以 上の含有量が、 5質量％以上であることを特徴とする請求項;!〜 6のいずれかに記載 の睡眠誘導用経口剤又はストレス性不眠症改善用経口剤。 [7] The content of one or more selected from serine, phosphoserine, phosphatidylserine, lysophosphatidylserine, acetylylserine, or cysteine, which is a compound having a serine unit, is 5% by mass or more. The oral preparation for sleep induction or the oral preparation for improving stress insomnia according to any one of claims 6 to 6.
[8] 請求項 1〜7のいずれかに記載された睡眠誘導用経口剤又はストレス性不眠症改善
用経口剤を含有することを特徴とする睡眠誘導用又はストレス性不眠症改善用経口 医薬品。
[8] The oral agent for inducing sleep or the improvement of stress insomnia according to any one of claims 1 to 7 An oral medicine for sleep induction or for improvement of stress insomnia, characterized by containing an oral dosage form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006206140A JP3999249B2 (en) | 2005-08-08 | 2006-07-28 | Sleep inducer, stress insomnia improving agent |
| JP2006-206140 | 2006-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008013215A1 true WO2008013215A1 (en) | 2008-01-31 |
Family
ID=38981526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2007/064641 WO2008013215A1 (en) | 2006-07-28 | 2007-07-26 | Sleep-inducing oral preparation, and oral preparation for amelioration of stress-induced insomnia |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR20090034302A (en) |
| CN (1) | CN101437507A (en) |
| TW (1) | TW200816988A (en) |
| WO (1) | WO2008013215A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010035026A1 (en) * | 2008-09-23 | 2010-04-01 | Merck Sharp & Dohme Ltd | Use of nmda activity enhancers to treat hypersomnia, reduced wakefulness or reduced vigilance |
| JP2010235490A (en) * | 2009-03-31 | 2010-10-21 | Fancl Corp | Phosphatidylserine-containing capsule and phosphatidylserine composition for capsule filling |
| WO2012043481A1 (en) * | 2010-09-30 | 2012-04-05 | 国立大学法人東京海洋大学 | Composition containing 2-acyl-lysophosphatidylserine and method for producing same |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015146844A1 (en) * | 2014-03-25 | 2015-10-01 | 株式会社ヤクルト本社 | Sleep quality improver |
| KR101998821B1 (en) * | 2017-12-28 | 2019-07-10 | 제주파나텍 (주) | Composition for Improving Sleep Disorders containing Fermentated Dendropanax morbifera and L-Serine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005247841A (en) * | 2004-02-04 | 2005-09-15 | Fancl Corp | Anxiolytic |
-
2007
- 2007-07-26 WO PCT/JP2007/064641 patent/WO2008013215A1/en active Application Filing
- 2007-07-26 KR KR1020087026580A patent/KR20090034302A/en not_active Application Discontinuation
- 2007-07-26 CN CNA2007800166791A patent/CN101437507A/en active Pending
- 2007-07-27 TW TW096127468A patent/TW200816988A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005247841A (en) * | 2004-02-04 | 2005-09-15 | Fancl Corp | Anxiolytic |
Non-Patent Citations (3)
| Title |
|---|
| ASECHI M. ET AL.: "Intracerebroventricular injection of L-serine analogs and derivatives induces sedative and hypnotic effects under an acute stressful condition in neonatal chicks", BEHAV. BRAIN RES., vol. 170, no. 1, 3 June 2006 (2006-06-03), pages 71 - 77, XP005408399 * |
| ASECHI M. ET AL.: "L-Serine no Noshitsu Toyo ni yoru Niwatori Hina no Stress Kodo wa Keigen Sareru", 2005 NENDO (HEISEI 17 NEN) THE JAPANESE SOCIETY FOR ANIMAL SCIENCES DAI 105 KAI TAIKAI KOEN YOSHISHU, 25 August 2005 (2005-08-25), pages 7, XP003020697 * |
| KOUTOKU T. ET AL.: "Central administration of phosphatidylserine attenuates isolation stress-induced behavior in chicks", NEUROCHEM. INT., vol. 47, no. 3, August 2005 (2005-08-01), pages 183 - 189, XP004953073 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010035026A1 (en) * | 2008-09-23 | 2010-04-01 | Merck Sharp & Dohme Ltd | Use of nmda activity enhancers to treat hypersomnia, reduced wakefulness or reduced vigilance |
| JP2010235490A (en) * | 2009-03-31 | 2010-10-21 | Fancl Corp | Phosphatidylserine-containing capsule and phosphatidylserine composition for capsule filling |
| WO2012043481A1 (en) * | 2010-09-30 | 2012-04-05 | 国立大学法人東京海洋大学 | Composition containing 2-acyl-lysophosphatidylserine and method for producing same |
| US9290781B2 (en) | 2010-09-30 | 2016-03-22 | National University Corporation Tokyo University Of Marine Science And Technology | Composition containing 2-acyl-lysophosphatidylserine and method for producing the same |
| JP6025143B2 (en) * | 2010-09-30 | 2016-11-16 | 国立大学法人東京海洋大学 | 2-Acyl-lysophosphatidylserine-containing composition and method for producing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101437507A (en) | 2009-05-20 |
| KR20090034302A (en) | 2009-04-07 |
| TW200816988A (en) | 2008-04-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6016363B2 (en) | Cranial nerve cell neoplasia | |
| US20130172293A1 (en) | Drug against central nervous system inflammation | |
| JP3999249B2 (en) | Sleep inducer, stress insomnia improving agent | |
| JP2007509066A (en) | Food and other compositions, compounds and methods for reducing body fat, suppressing appetite and regulating fatty acid metabolism | |
| JP4878436B2 (en) | Anxiolytic | |
| WO2008013215A1 (en) | Sleep-inducing oral preparation, and oral preparation for amelioration of stress-induced insomnia | |
| JP2016210696A (en) | Learning and memory capacity enhancer | |
| JPS6284028A (en) | Lipid mixture for membrane fluidization | |
| US7951844B2 (en) | Tranquilizer and functional food | |
| WO2007119588A1 (en) | Brain function-improving agent, and functional food containing the improving agent | |
| CN108714208A (en) | Composition, preparation method, using and relieve stress, improve sleep product | |
| JP7633238B2 (en) | Nicotinamide adenine dinucleotide (NAD) concentration increaser | |
| US5001117A (en) | Use of lecithin to restore olfaction and taste | |
| JP2007230954A (en) | Sleep inducer and stress insomnia-improving agent | |
| JP2008056628A (en) | Sleep inducer, stress insomnia improving agent | |
| CN112494471A (en) | Application of cholesterol ester synthetase ACAT1 inhibitor in preparing medicine for preventing/treating non-alcoholic fatty liver disease | |
| WO2005044176A2 (en) | Compositions containing phosphatidic acid, methods of use thereof, methods of manufacture thereof, and articles of manufacture containing same | |
| CN116322370A (en) | Composition for anti-fatigue and composition for improving, reducing, suppressing or maintaining energy production | |
| JP5351930B2 (en) | Anxiolytic | |
| JP2021078397A (en) | Lipid decrease promoter | |
| CN114599358A (en) | Sleep-improving composition containing ergothioneine or its salt | |
| JP2008189573A (en) | Sleep inducer, stress insomnia improving agent | |
| WO2022210856A1 (en) | Composition for improving quality of sleep | |
| TWI745609B (en) | Composition for promoting antioxidative activity | |
| JP2008031154A (en) | Hypoglycemic agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07791341 Country of ref document: EP Kind code of ref document: A1 |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1020087026580 Country of ref document: KR |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 200780016679.1 Country of ref document: CN |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| NENP | Non-entry into the national phase |
Ref country code: RU |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 07791341 Country of ref document: EP Kind code of ref document: A1 |