CN117771325B - Application of composition in preparation of sleep improving medicine - Google Patents
Application of composition in preparation of sleep improving medicine Download PDFInfo
- Publication number
- CN117771325B CN117771325B CN202410199781.5A CN202410199781A CN117771325B CN 117771325 B CN117771325 B CN 117771325B CN 202410199781 A CN202410199781 A CN 202410199781A CN 117771325 B CN117771325 B CN 117771325B
- Authority
- CN
- China
- Prior art keywords
- parts
- polysaccharide
- saponin
- epimedin
- rhizoma polygonati
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 36
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 230000007958 sleep Effects 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 9
- 229930182490 saponin Natural products 0.000 claims description 37
- 150000007949 saponins Chemical class 0.000 claims description 37
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 36
- 150000004676 glycans Chemical class 0.000 claims description 35
- 229920001282 polysaccharide Polymers 0.000 claims description 35
- 239000005017 polysaccharide Substances 0.000 claims description 35
- VGGSULWDCMWZPO-ODEMIOGVSA-N spinosin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=2C(=O)C=C(OC=2C=C1OC)C=1C=CC(O)=CC=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VGGSULWDCMWZPO-ODEMIOGVSA-N 0.000 claims description 31
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 29
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 claims description 23
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 claims description 23
- 229930003944 flavone Natural products 0.000 claims description 23
- 235000011949 flavones Nutrition 0.000 claims description 23
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 claims description 23
- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 claims description 22
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 claims description 22
- 150000002212 flavone derivatives Chemical class 0.000 claims description 19
- -1 stilbene glucoside Chemical class 0.000 claims description 19
- OCZZCFAOOWZSRX-LRHLXKJSSA-N Epimedin B Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)CO2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 OCZZCFAOOWZSRX-LRHLXKJSSA-N 0.000 claims description 17
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 claims description 16
- 241001061264 Astragalus Species 0.000 claims description 16
- LKNITMBRWDCKMG-UHFFFAOYSA-N Epimedin B Natural products COc1ccc(cc1)C2=C(OC3OC(C)C(O)C(O)C3OC4OC(CO)C(O)C4O)C(=O)c5c(O)cc(OC6OC(CO)C(O)C(O)C6O)c(CC=C(C)C)c5O2 LKNITMBRWDCKMG-UHFFFAOYSA-N 0.000 claims description 16
- 235000006533 astragalus Nutrition 0.000 claims description 16
- 229960003237 betaine Drugs 0.000 claims description 16
- IZQSVPBOUDKVDZ-UHFFFAOYSA-N isorhamnetin Chemical compound C1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 IZQSVPBOUDKVDZ-UHFFFAOYSA-N 0.000 claims description 16
- 210000004233 talus Anatomy 0.000 claims description 16
- ULZLIYVOYYQJRO-JIYCBSMMSA-N Epimedin C Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 ULZLIYVOYYQJRO-JIYCBSMMSA-N 0.000 claims description 15
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 claims description 15
- OVSQVDMCBVZWGM-SJWGPRHPSA-N Hyperin Natural products O[C@H]1[C@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-SJWGPRHPSA-N 0.000 claims description 15
- FVQOMEDMFUMIMO-UHFFFAOYSA-N Hyperosid Natural products OC1C(O)C(O)C(CO)OC1OC1C(=O)C2=C(O)C=C(O)C=C2OC1C1=CC=C(O)C(O)=C1 FVQOMEDMFUMIMO-UHFFFAOYSA-N 0.000 claims description 15
- GQODBWLKUWYOFX-UHFFFAOYSA-N Isorhamnetin Natural products C1=C(O)C(C)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 GQODBWLKUWYOFX-UHFFFAOYSA-N 0.000 claims description 15
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 claims description 15
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 claims description 15
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims description 15
- YPFSXWUDSOVOGG-UHFFFAOYSA-N epimedin C Natural products COc1ccc(cc1)C2=C(OC3OC(C)C(O)C(OC(=O)C)C3OC4OC(CO)C(O)C(O)C4O)C(=O)c5c(O)cc(OC6OC(CO)C(O)C(O)C6O)c(CC=C(C)C)c5O2 YPFSXWUDSOVOGG-UHFFFAOYSA-N 0.000 claims description 15
- VGGSULWDCMWZPO-UHFFFAOYSA-N flavoayamenin Natural products COC1=CC=2OC(C=3C=CC(O)=CC=3)=CC(=O)C=2C(O)=C1C1OC(CO)C(O)C(O)C1OC1OC(CO)C(O)C(O)C1O VGGSULWDCMWZPO-UHFFFAOYSA-N 0.000 claims description 15
- 229930182470 glycoside Natural products 0.000 claims description 15
- 235000008800 isorhamnetin Nutrition 0.000 claims description 15
- 229940100243 oleanolic acid Drugs 0.000 claims description 15
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 claims description 15
- OVSQVDMCBVZWGM-DTGCRPNFSA-N quercetin 3-O-beta-D-galactopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-DTGCRPNFSA-N 0.000 claims description 15
- BBFYUPYFXSSMNV-UHFFFAOYSA-N quercetin-7-o-galactoside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=C2C(=O)C(O)=C(C=3C=C(O)C(O)=CC=3)OC2=C1 BBFYUPYFXSSMNV-UHFFFAOYSA-N 0.000 claims description 15
- 235000021286 stilbenes Nutrition 0.000 claims description 15
- QVYARBLCAHCSFJ-UHFFFAOYSA-N butane-1,1-diamine Chemical compound CCCC(N)N QVYARBLCAHCSFJ-UHFFFAOYSA-N 0.000 claims description 14
- 229930182478 glucoside Natural products 0.000 claims description 13
- 150000002338 glycosides Chemical class 0.000 claims description 13
- 241001092040 Crataegus Species 0.000 claims description 12
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims description 12
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims description 12
- 235000009685 Crataegus X maligna Nutrition 0.000 claims description 12
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims description 12
- 235000009486 Crataegus bullatus Nutrition 0.000 claims description 12
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims description 12
- 235000009682 Crataegus limnophila Nutrition 0.000 claims description 12
- 235000004423 Crataegus monogyna Nutrition 0.000 claims description 12
- 235000002313 Crataegus paludosa Nutrition 0.000 claims description 12
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 235000017784 Mespilus germanica Nutrition 0.000 claims description 11
- 235000000560 Mimusops elengi Nutrition 0.000 claims description 11
- 235000007837 Vangueria infausta Nutrition 0.000 claims description 11
- 240000008866 Ziziphus nummularia Species 0.000 claims description 11
- 241000830535 Ligustrum lucidum Species 0.000 claims description 8
- ILRCGYURZSFMEG-UHFFFAOYSA-N Salidroside Natural products OC1C(O)C(O)C(CO)OC1OCCC1=CC=C(O)C=C1 ILRCGYURZSFMEG-UHFFFAOYSA-N 0.000 claims description 8
- ILRCGYURZSFMEG-RQICVUQASA-N salidroside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1OCCC1=CC=C(O)C=C1 ILRCGYURZSFMEG-RQICVUQASA-N 0.000 claims description 8
- 244000241838 Lycium barbarum Species 0.000 claims description 6
- 235000015459 Lycium barbarum Nutrition 0.000 claims description 6
- 235000015468 Lycium chinense Nutrition 0.000 claims description 6
- 235000003713 Rhodiola rosea Nutrition 0.000 claims description 6
- 244000042430 Rhodiola rosea Species 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 210000000582 semen Anatomy 0.000 claims description 6
- ZOLPMMWNCLHKPX-UHFFFAOYSA-N ligustrin Natural products CC1=CCC2C1C3OC(=C)C(=O)C3C(O)CC2=C ZOLPMMWNCLHKPX-UHFFFAOYSA-N 0.000 claims description 5
- QJVXKWHHAMZTBY-GCPOEHJPSA-N syringin Chemical compound COC1=CC(\C=C\CO)=CC(OC)=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 QJVXKWHHAMZTBY-GCPOEHJPSA-N 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 239000009636 Huang Qi Substances 0.000 claims description 3
- 241000201320 Ligustrum japonicum Species 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- NQYPTLKGQJDGTI-FCVRJVSHSA-N hyperoside Natural products OC[C@H]1O[C@@H](OC2=C(Oc3cc(O)cc(O)c3[C@H]2O)c4ccc(O)c(O)c4)[C@H](O)[C@@H](O)[C@H]1O NQYPTLKGQJDGTI-FCVRJVSHSA-N 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims 5
- 244000182216 Mimusops elengi Species 0.000 claims 4
- 241001165494 Rhodiola Species 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 71
- 241000699670 Mus sp. Species 0.000 description 42
- 235000017709 saponins Nutrition 0.000 description 23
- 230000000694 effects Effects 0.000 description 21
- 210000005013 brain tissue Anatomy 0.000 description 18
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 16
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 10
- 206010022437 insomnia Diseases 0.000 description 10
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 9
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 8
- 239000009147 Kangxin Substances 0.000 description 8
- 240000002624 Mespilus germanica Species 0.000 description 7
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 230000004620 sleep latency Effects 0.000 description 6
- 230000002195 synergetic effect Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 5
- 230000004622 sleep time Effects 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 4
- 235000013399 edible fruits Nutrition 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000008518 lycium barbarum polysaccharide Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229960001412 pentobarbital Drugs 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000010171 animal model Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000037831 Polygonatum sibiricum Species 0.000 description 2
- 235000018167 Reynoutria japonica Nutrition 0.000 description 2
- 240000001341 Reynoutria japonica Species 0.000 description 2
- 240000007164 Salvia officinalis Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940107666 astragalus root Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000003777 experimental drug Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 2
- 229960003987 melatonin Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229940126680 traditional chinese medicines Drugs 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- GMQXOLRKJQWPNB-UHFFFAOYSA-N (8E)-ligstroside Natural products CC=C1C(CC(=O)OCCC=2C=CC(O)=CC=2)C(C(=O)OC)=COC1OC1OC(CO)C(O)C(O)C1O GMQXOLRKJQWPNB-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- SMRPGWBDLOQHOS-UHFFFAOYSA-N 5-[4,5-dihydroxy-6-(hydroxymethyl)-3-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxy-3,4-dihydroxy-6-[[9-hydroxy-4-(hydroxymethyl)-4,6a,6b,8a,11,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]oxane-2-carboxylic acid Chemical compound OC1C(O)C(O)C(C)OC1OC1C(OC2C(OC(C(O)C2O)C(O)=O)OC2C(C3C(C4C(C5(CCC6(C)C(O)CC(C)(C)CC6C5=CC4=O)C)(C)CC3)(C)CC2)(C)CO)OC(CO)C(O)C1O SMRPGWBDLOQHOS-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 235000011468 Albizia julibrissin Nutrition 0.000 description 1
- 240000007185 Albizia julibrissin Species 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 244000061520 Angelica archangelica Species 0.000 description 1
- 241000213006 Angelica dahurica Species 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 235000015221 Bupleurum rotundifolium Nutrition 0.000 description 1
- 244000236521 Bupleurum rotundifolium Species 0.000 description 1
- 235000007516 Chrysanthemum Nutrition 0.000 description 1
- 244000189548 Chrysanthemum x morifolium Species 0.000 description 1
- 235000017159 Crataegus pinnatifida Nutrition 0.000 description 1
- 241000657480 Crataegus pinnatifida Species 0.000 description 1
- 235000018109 Cyperus longus Nutrition 0.000 description 1
- 244000150195 Cyperus longus Species 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000893536 Epimedium Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241001289529 Fallopia multiflora Species 0.000 description 1
- 235000001287 Guettarda speciosa Nutrition 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 240000007049 Juglans regia Species 0.000 description 1
- 235000009496 Juglans regia Nutrition 0.000 description 1
- 241000212322 Levisticum officinale Species 0.000 description 1
- 241001521474 Liriope <hydrozoan> Species 0.000 description 1
- 206010024642 Listless Diseases 0.000 description 1
- 241000157491 Morinda Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 235000006484 Paeonia officinalis Nutrition 0.000 description 1
- 244000170916 Paeonia officinalis Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000972673 Phellodendron amurense Species 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 241000756042 Polygonatum Species 0.000 description 1
- 235000008599 Poria cocos Nutrition 0.000 description 1
- 244000197580 Poria cocos Species 0.000 description 1
- 244000179560 Prunella vulgaris Species 0.000 description 1
- 235000017276 Salvia Nutrition 0.000 description 1
- 235000005010 Scirpus paludosus Nutrition 0.000 description 1
- 244000058416 Scirpus paludosus Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 244000040738 Sesamum orientale Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 101100438470 Trichosurus vulpecula CSN2 gene Proteins 0.000 description 1
- 241000157352 Uncaria Species 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 241000724115 Ziziphus lotus Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 239000003282 amino acid receptor affecting agent Substances 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 235000005272 common selfheal Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229930183477 epimedin Natural products 0.000 description 1
- 235000018905 epimedium Nutrition 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000001645 levisticum officinale Substances 0.000 description 1
- GMQXOLRKJQWPNB-MVVLSVRYSA-N ligstroside Chemical compound O([C@@H]\1OC=C([C@H](C/1=C\C)CC(=O)OCCC=1C=CC(O)=CC=1)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GMQXOLRKJQWPNB-MVVLSVRYSA-N 0.000 description 1
- 208000017971 listlessness Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 235000017524 noni Nutrition 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000005412 red sage Nutrition 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- PPRSVUXPYPBULA-UHFFFAOYSA-N saponin A Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(OC6OC(CO)C(O)C(O)C6=O)C(C)(C)C5CCC34C)C2C1)C(=O)O PPRSVUXPYPBULA-UHFFFAOYSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 230000004617 sleep duration Effects 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 230000036578 sleeping time Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an application of a composition in preparing a medicine for improving sleep, and relates to the technical field of pharmaceutical compositions. The composition can be used for preparing medicines for treating and improving sleep, and the composition and the corresponding medicines are accurate in medication and can be used for improving sleep efficiently.
Description
Technical Field
The invention relates to the technical field of pharmaceutical compositions, in particular to application of a composition in preparation of a sleep improving medicine.
Background
Insomnia (Insomnia) refers to a sleep disorder in which a person is difficult to fall asleep and/or sleep is difficult to maintain, thereby affecting normal physiological life needs. Long-term insomnia can cause senile dementia, parkinson disease, hypertension, etc., and can promote malignant tumor and diabetes. Clinically applied hypnotics such as benzodiazepine drugs, zolpidem, doxepin and the like have the defects of drug resistance and great adverse reaction although the curative effect is definite. At present, research on sedative and sleep-promoting effects and related mechanisms of extracts and active ingredients of traditional Chinese medicines has become a hotspot. In recent years, research shows that the natural medicine has unique advantages in treating insomnia, has the characteristics of low addiction, low dependence, multiple components, multiple targets and multiple ways, and has outstanding curative effect. The natural drug sedative hypnotic mechanisms of action include regulation of neurotransmitters, such as regulating the amino acid neurotransmitters gamma-aminobutyric acid (AmiNObutyric acid, GABA), monoamine neurotransmitters 5-hydroxytryptamine (5-hydroxy tryptamine, 5-HT) and glutamic acid (Glutamic acid, glu), regulating inflammatory factors, regulating hypothalamic-pituitary-adrenocortical (HPA) axis secretion function, regulating melatonin (Melatonin, MT) secretion function, and the like.
In the prior art, a plurality of medicaments for treating insomnia are disclosed, for example, patent CN103860934A discloses a Chinese medicament for treating insomnia, which is prepared from the following raw materials in parts by weight, 13-18 parts of grassleaf sweelflag rhizome, 13-18 parts of medlar, 17-23 parts of nutgrass galingale rhizome, 17-23 parts of Chinese angelica, 12-16 parts of wild jujube seed, 3-7 parts of Chinese thorowax root, 3-7 parts of common selfheal fruit-spike, 18-25 parts of szechuan lovage rhizome, 13-17 parts of uncaria, 28-34 parts of white paeony root, 10-14 parts of morinda root, 14-16 parts of Indian bread with hostwood, 14-16 parts of dried orange peel, 8-11 parts of liquoric root, 10-13 parts of silktree albizia bark, 28-34 parts of common macrocarpium fruit, 8-12 parts of tuber fleeceflower stem, 8-12 parts of glossy privet fruit, 13-17 parts of bamboo shavings, 16-20 parts of amur corktree bark and 7-10 parts of astragalus root. Also as disclosed in patent CN107126485A, a traditional Chinese medicine composition for assisting in improving sleep, and a preparation method and application thereof, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: 15-65 parts of walnut kernel, 15-65 parts of wild jujube seed, 5-55 parts of red sage root, 5-35 parts of acanthopanax, 5-35 parts of tuber fleeceflower stem, 5-15 parts of astragalus root, 5-15 parts of lotus seed, 5-35 parts of jujube, 5-35 parts of medlar, 5-15 parts of sesame, 5-15 parts of grape skin, 5-15 parts of dark plum fruit and 5-15 parts of hawthorn, the medicament can assist in prolonging the sleeping time of the sodium pentobarbital and obviously shortening the sleeping latency of the sodium barobarbital of the mice, but has no effect of directly promoting the sleeping of animals, and the medicament can be a health care product for improving the sleeping.
In addition, the finished products of the commercially available medicines such as Kangxin oral liquid, a liriope capsule, a ling capsule and the like, wherein the Kangxin oral liquid consists of medlar, polygonum multiflorum, epimedium, glossy privet fruit, angelica, semen cuscutae, astragalus, rhizoma polygonati, red-rooted salvia root, hawthorn, spine date seed, chrysanthemum and cortex lycii radicis, has the effects of tonifying kidney and replenishing essence, strengthening spleen and replenishing qi, nourishing blood and activating blood, and is used for treating the symptoms such as listlessness, soreness of waist and knees, insomnia and amnesia, weakness after illness and the like caused by deficiency of spleen and kidney and deficiency of qi and blood. Book: wang Shunnian, wu Xinrong, jiang Linlan, etc., national guidelines for over-the-counter drug application [ M ]. Beijing: people's military medical press, 2007, page 95, book: guo Pengju, guan Desheng et al, chinese over-the-counter Manual [ M ], sichuan: the corresponding records are also available on page 247 of Shaanxi science and technology Press 2005.
At present, the traditional Chinese medicine composition or the finished medicine mentioned in the prior art is mainly prepared by mixing traditional Chinese medicines, and then is directly extracted, the dissolution effect of active ingredients is different, the medication accuracy is low, and then the treatment effect is poor or the treatment course is long, so that aiming at the problems in the prior art, it is necessary to find a composition which is accurate in medication and can improve sleep efficiently.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the application of the composition in preparing the sleep improving medicine by deeply researching the Kangxin oral liquid, and the composition is accurate in medicine application and can improve sleep efficiently.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
The invention provides a composition which can be used for preparing a sleep improving medicament, and comprises the following components: lycium barbarum polysaccharide, astragalus polysaccharide, stilbene glucoside, epimedin B, epimedin C, ligustrin G13, spina date seed saponin, rhizoma polygonati saponin, salidroside, hyperin, salvianolic acid B, oleanolic acid, isorhamnetin, hawkthorn flavone, caffeoyl butanediamine, betaine and spinosin.
Further, the composition comprises the following components in parts by weight: 0.1-10 parts of medlar polysaccharide, 20-60 parts of astragalus polysaccharide, 0.1-5 parts of stilbene glucoside, 0.1-6 parts of epimedin B, 0.1-3 parts of epimedin C, 0.1-1 part of ligustrin G, 0.1-1 part of wild jujube saponin, 5-20 parts of rhizoma polygonati saponin, 0.1-5 parts of rhodioside, 0.05-1 part of hyperin, 0.5-10 parts of salvianolic acid B, 0.1-2 parts of oleanolic acid, 0.05-1 part of isorhamnetin, 10-30 parts of hawkthorn flavone, 0.1-1.5 parts of caffeoyl butanediamine, 0.5-8 parts of betaine and 0.05-3 parts of spinosin.
Preferably, the composition comprises, by weight, 1-8 parts of wolfberry polysaccharide, 30-50 parts of astragalus polysaccharide, 0.5-4 parts of stilbene glucoside, 0.5-3 parts of epimedin B, 0.5-2 parts of epimedin C, 13.1-0.5 parts of ligustrin G, 0.1-0.5 part of wild jujube seed saponin, 6-15 parts of rhizoma polygonati saponin, 0.5-2 parts of rhodiola rosea glycoside, 0.05-0.5 part of hyperin, 2-8 parts of salvianolic acid B, 0.1-1 part of oleanolic acid, 0.08-0.15 part of isorhamnetin, 15-25 parts of crataegus pinnatifida flavone, 0.2-1 part of caffeoyl butanediamine, 1-5 parts of betaine and 0.05-1 part of spinosin.
Further preferably, the composition comprises, in parts by weight: 2-4 parts of medlar polysaccharide, 35-45 parts of astragalus polysaccharide, 1-3 parts of stilbene glucoside, 1-2 parts of epimedin B, 1-1.5 parts of epimedin C, 0.2-0.5 part of glossy privet glycoside G, 0.1-0.3 part of wild jujube saponin, 7-10 parts of rhizoma polygonati saponin, 0.8-1.2 parts of rhodiola rosea glycoside, 0.1-0.3 part of hyperin, 4-6 parts of salvianolic acid B, 0.4-0.6 part of oleanolic acid, 0.08-0.12 part of isorhamnetin, 16-20 parts of haw flavone, 0.2-0.4 part of caffeoyl butanediamine, 2-4 parts of betaine and 0.05-0.15 part of spinosin.
Still more preferably, the composition comprises, in parts by weight: 3 parts of medlar polysaccharide, 40 parts of astragalus polysaccharide, 2 parts of stilbene glucoside, 1.5 parts of epimedin B, 1.2 parts of epimedin C, 0.3 part of glossy privet glycoside G, 0.2 part of wild jujube seed saponin, 9 parts of rhizoma polygonati saponin, 1 part of rhodiola rosea glycoside, 0.2 part of hyperin, 5 parts of salvianolic acid B, 0.5 part of oleanolic acid, 0.1 part of isorhamnetin, 18 parts of hawthorn flavone, 0.3 part of caffeoyl butanediamine, 3 parts of betaine and 0.1 part of spinosin.
Further, the weight ratio of astragalus polysaccharide to rhizoma polygonati saponin to salvianolic acid B to haw flavone is (30-50), 5-20, 0.5-10 and 10-30. Preferably 40:9:5:18.
Further, the weight ratio of the wolfberry polysaccharide to the rhizoma polygonati saponin to the salvianolic acid B to the hawthorn flavone is (0.1-10), 5-20, 0.5-10 and 10-30. Preferably 3:9:5:18.
Further, the medicament also comprises pharmaceutically acceptable auxiliary materials.
Further, the dosage forms of the medicine comprise oral liquid, tablets, capsules, granules, paste, powder, injection, spray or pills.
Preferably, the medicament is in the form of oral liquid.
Further, the preparation method of the composition comprises the following steps: mixing fructus Lycii polysaccharide, radix astragali polysaccharide, stilbene glucoside, epimedin B, epimedin C, ligustrum japonicum G13, semen Ziziphi Spinosae saponin, rhizoma Polygonati saponin, salidroside, hyperoside, salvianolic acid B, oleanolic acid, isorhamnetin, fructus crataegi flavone, caffeoyl butanediamine, betaine and spinosin.
The invention has the technical effects that:
The composition is prepared from the direct raw materials of medlar polysaccharide, astragalus polysaccharide, stilbene glucoside, epimedin B, epimedin C, ligustrin G13, spine date seed saponin, rhizoma polygonati saponin, rhodiola rosea glycoside, hyperin, salvianolic acid B, oleanolic acid, isorhamnetin, hawkthorn flavone, caffeoyl butanediamine, betaine and spinosin on the basis of the Kangxin oral liquid, fully plays the synergistic effect of the raw materials, has more accurate administration, definite ingredients, small dosage and quick curative effect, and can effectively improve sleep.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It should be noted that the raw materials used in the present invention are all common commercial products, and therefore the sources thereof are not particularly limited, and CAS NO corresponding to the raw materials is shown as follows:
Lycium barbarum polysaccharide CAS NO:107-43-7
Stilbene glycoside CAS NO:82373-94-2
Epimedin BCAS NO:110623-73-9
Epimedin C CAS NO:110642-44-9
Ligustrum lucidum glycoside G13 CAS NO:60037-39-0
Oleanolic acid CAS NO:508-02-1
Isorhamnetin CAS NO:480-19-3
Astragalus polysaccharide CAS NO:89250-26-0
Hawthorn flavone CAS NO:36052-37-6
Semen Ziziphi Spinosae saponin A CAS NO:55466-04-1
Caffeoylbutanediamine CAS NO:29554-26-5
Betaine CAS NO:107-43-7
Rhizoma polygonati saponin: CAS NO:144126-58-1
Salidroside CAS NO:10338-51-9
Spinosin CAS NO:72063-39-9
Hyperin CAS NO:482-36-0
Salvianolic acid B CAS NO:121521-90-2.
Examples 1 to 5, comparative examples 1 to 3:
TABLE 1 formula (unit: parts by weight) of inventive examples 1-5 and comparative examples 1-3
| Raw materials | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| Lycium barbarum polysaccharide | 0.1 | 10 | 1 | 8 | 3 | 3 | 20 | 3 |
| Astragalus polysaccharides | 20 | 60 | 30 | 50 | 40 | 18 | 40 | 40 |
| Stilbene glycoside | 0.1 | 5 | 0.5 | 4 | 2 | 2 | 2 | 2 |
| Epimedin B | 0.1 | 6 | 0.5 | 3 | 1.5 | 1.5 | 1.5 | - |
| Epimedin C | 0.1 | 3 | 0.5 | 2 | 1.2 | 1.2 | 1.2 | 1.2 |
| Ligustroside G13 | 0.1 | 1 | 0.1 | 0.5 | 0.3 | 0.3 | 0.3 | 0.3 |
| Semen Ziziphi Spinosae saponin | 0.1 | 1 | 0.1 | 0.5 | 0.2 | 0.2 | 0.2 | 0.2 |
| Polygonatum sibiricum saponins | 5 | 20 | 6 | 15 | 9 | 3 | 24 | 9 |
| Salidroside | 0.1 | 5 | 0.5 | 2 | 1 | 1 | 1 | - |
| Hyperin | 0.05 | 1 | 0.05 | 0.5 | 0.2 | 0.2 | 0.2 | 0.2 |
| Salvianolic acid B | 0.5 | 10 | 2 | 8 | 5 | 11 | 0.1 | 5 |
| Oleanolic acid | 0.1 | 2 | 0.1 | 1 | 0.5 | 0.5 | 0.5 | 0.5 |
| Isorhamnetin | 0.05 | 1 | 0.08 | 0.15 | 0.1 | 0.1 | 0.1 | 0.1 |
| Hawthorn flavone | 10 | 30 | 15 | 25 | 18 | 40 | 5 | 18 |
| Caffeoyl butanediamine | 0.1 | 1.5 | 0.2 | 1 | 0.3 | 0.3 | 0.3 | 0.3 |
| Betaine (betaine) | 0.5 | 8 | 1 | 5 | 3 | 3 | 3 | 3 |
| Spinosin | 0.05 | 3 | 0.05 | 1 | 0.1 | 0.1 | 0.1 | 0.1 |
As can be seen from the above table, comparative example 1 differs from example 5 only in the amounts of astragalus polysaccharide, polygonatum saponin, salvianolic acid B and haw flavone; comparative example 2 differs from example 5 only in the amounts of Lycium barbarum polysaccharide, polygonatum sibiricum saponin, salvianolic acid B and Hawthorn flavone; comparative example 3 differs from example 5 only in that epimedin B and salidroside are not contained.
The preparation method of the compositions in examples 1-5 and comparative examples 1-2 comprises the following steps: mixing fructus Lycii polysaccharide, radix astragali polysaccharide, stilbene glucoside, epimedin B, epimedin C, ligustrum japonicum G13, semen Ziziphi Spinosae saponin, rhizoma Polygonati saponin, salidroside, hyperoside, salvianolic acid B, oleanolic acid, isorhamnetin, fructus crataegi flavone, caffeoyl butanediamine, betaine and spinosin. The preparation method of the composition in comparative example 3 is the same as in example 5, except that epimedin B and salidroside are not added in the preparation process.
1. Materials and methods
1. Experimental materials
1.1 Laboratory animals
SPF-class Balb/C mice were 110, healthy adults, male and female halves, and had a body weight of 18-22g. Animal production pass number purchased from vinca Yiss laboratory animal technology, inc.: SCXK (Ji) -2020-0002. The experimental period is entered after 7 days of adaptive feeding.
1.2 Experimental drugs
Test drug: the compositions of examples 1-5 and comparative examples 1-3 were mixed to prepare experimental drugs, respectively, for use.
Positive drug: kangxin oral liquid extract (extract in the production process of Kangxin oral liquid, which is produced by Jilin Huakang pharmaceutical industry Co., ltd., batch number 210101).
Blank control: physiological saline.
1.3 Materials and reagents
TABLE 2 materials and reagents used in the present invention
1.4 Instruments
TABLE 3 instruments used in the present invention
2. Experimental method
2.1 Grouping of laboratory animals
110 Mice with good health condition are selected after the adaptation period, and are divided into 11 groups according to a random digital table method, wherein 10 mice in each group are respectively a blank control group, a model control group, a positive control group, comparative examples 1-3 groups and examples 1-5 groups.
2.2 Administration method
Samples of each test group were formulated at 200mg/kg with 0.5% CMC-Na, stored at 4℃and mixed well before daily use. Each group of samples was stored at 4℃and mixed well before daily use.
For therapeutic administration, mice of each group were administered by intragastric administration 1 time per day, 1ml/100g, 20g crude drug/kg of Kangxin oral liquid extract, 200mg/kg of examples 1-5 and comparative examples 1-3, and once daily for 7 days. The model group and the blank group were administered with the same volume of physiological saline.
2.3 Construction of Insomnia model
After grouping the mice, first, prophylactic administration was performed. The administration is carried out by gastric lavage in the administration group at about 9 am every day, the volume of normal saline is 10ml/kg in the blank control group and the model group, and the administration is carried out continuously for 7 days.
Then, insomnia model construction is carried out. Each of the other groups was intraperitoneally injected with pCPA physiological saline solution (350 mg/kg) 1 time per day for 4 days except for the blank group, to establish an insomnia model. Compared with the blank control group, the mice have the advantages of dysphoria, excitation enhancement, aggression enhancement, continuous activity, disappearance of circadian rhythm, appetite reduction, increase of urine and feces, dark and scattered hair, weight reduction and the like, and can initially represent that the model is successful.
Finally, therapeutic administration is performed. After successful molding, the injection is administered at about 9 am every day, the administration group is used for gastric lavage, and the blank control group and the model group are used for gastric lavage with equal volumes of physiological saline, wherein the administration volume is 10ml/kg, and the continuous administration is carried out for 7 days.
3. Detection index
3.1 Effects on weight and voluntary Activity in mice
The mice were observed daily for behavioral changes, weighed and recorded, and the changes in weight of the mice at the different dosing stages were compared. On day 6 of dosing, 60min after dosing, each group of mice was placed in an autonomous activity recorder, first adapted for 10min, then recording was started, the number of autonomous activities (forelimb lifting times) within 5min of each group of mice was recorded, and at the end of each measurement, the shells were thoroughly washed with 75% alcohol to avoid affecting the next mouse activity.
3.2 Determination of the sleep Rate in mice by synergistic sub-threshold doses
The mice of each group were intraperitoneally injected with subliminal sodium pentobarbital (the maximum dose that keeps 90% to 100% of the mice from everting) at a dose of pentobarbital sodium after the last administration for 30min without water withdrawal after a fasting period of 8 hours before the last administration. The mice with the loss of the regular reflection of the turnover within 30min for more than 1min were regarded as sleep, and the number of the mice with sleep was recorded.
3.3 Determination of sleep latency and sleep time in mice with synergistic suprathreshold doses of sodium pentobarbital
The mice of each group were given an intraperitoneal injection of hypnotic doses (minimum dose to sleep for 100% of the mice) after 30min of the last administration, with no water being forbidden for 8 hours before the last administration. The sleep latency and sleep duration of the mice were observed and recorded with the period from intraperitoneal injection of sodium pentobarbital to disappearance of the eversion as the sleep latency and the time from disappearance of the eversion to recovery as the sleep time of the mice.
3.4 Effects on neurotransmitter 5-HT, GABA, glu, NE, SOD and MDA in mouse brain tissue
After the last administration for 60min, the mice of each group are sacrificed by decapitation, the brain hippocampus of the mice is immediately dissected and separated on an ice tray, water is absorbed after the mice are washed by precooled PBS buffer solution, the brain tissues with the same quality are weighed and cut up after weighing and recording, then the brain tissues are put into an ice-cooled tissue grinder, 9 times of precooled PBS buffer solution is added for grinding and homogenizing on ice, the low temperature centrifugation is carried out for 10min at 12000rpm, and the supernatant is collected, thus obtaining brain tissue homogenized samples.
The content of 5-HT, GABA, glu, NE, SOD and MDA in the brain tissue of the mice is strictly determined according to the instruction of ELISA kit.
4. Statistical analysis method
Data were statistically analyzed using graphpadprism9.0 software. Each set of data is expressed as mean ± standard deviation, and the differences between the sets are t-test.
2. Experimental results:
1. Weight of body
TABLE 4 weight status (unit: g) of mice in the blank group, model group and each group of examples 1 to 5 in the present invention
Table 5 weight status (unit: g) of mice of comparative examples 1 to 3 and positive control group in the present invention
2. Autonomous activities
TABLE 6 autonomous activity of mice of each group of the present invention
Note that:
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
3. Synergistic subthreshold dose sleep rate
TABLE 7 sleep rate of mice of each group of the present invention
4. Synergistic suprathreshold dose sleep latency
TABLE 8 sleep latency conditions for groups of mice according to the invention
Note that:
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
5. Synergistic suprathreshold dose sleep time
TABLE 9 sleep time for groups of mice according to the invention
Note that:
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
6. Content of 5-HT in brain tissue
TABLE 10 conditions of 5-HT levels in brain tissue of mice of each group of the invention
Note that:
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
7. GABA content in brain tissue
TABLE 11 GABA content in brain tissue of mice of each group of the present invention
Note that:
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
8. Glu content in brain tissue
TABLE 12 Glu content in brain tissue of mice of each group of the invention
Note that:
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
9. Content of NE in brain tissue
TABLE 13 conditions of NE content in brain tissue of mice of each group of the present invention
Note that:
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
10. SOD content in brain tissue
TABLE 14 SOD content in brain tissue of mice of each group of the present invention
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
11. MDA content in brain tissue
TABLE 15 MDA content in brain tissue of mice of each group of the present invention
Comparison of # with blank: p < 0.05, # compared to the blank: p is less than 0.01;
* Comparison to model set: p < 0.05, compare to model group: p is less than 0.01;
Comparison with comparative example 1: p < 0.05, ≡O compared with comparative example 1: p is less than 0.01;
● Comparison with comparative example 2: p < 0.05, +. +.comparison with comparative example 2: p is less than 0.01;
comparison with comparative example 3: p < 0.05, # compared to comparative example 3: p is less than 0.01.
The above test results show that the drugs of examples 1-5, comparative examples 1-3 and positive control group of the present invention can increase the body weight of mice compared to the blank control group and the model control group, but have no significant difference.
The composition of examples 1-5 of the present invention can reduce the number of autonomous activities of mice, improve the sleep rate of mice, reduce the sleep latency, and improve the sleep time, and at the same time, the composition of the present invention can improve the 5-HT content, GABA content, and SOD content in brain tissues of mice, and reduce Glu content, NE content, and MDA content. The example groups have significant differences compared with the comparative examples 1-3, and the positive control groups have no significant differences compared with the comparative examples 1-3, which shows that the composition of the invention has the effect of significantly improving sleep, and the effect is better than the positive medicine Kangxin oral liquid.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (9)
1. An application of a composition in preparing a medicament for improving sleep, which is characterized in that: the composition comprises the following components in parts by weight: 0.1-10 parts of medlar polysaccharide, 20-60 parts of astragalus polysaccharide, 0.1-5 parts of stilbene glucoside, 0.1-6 parts of epimedin B, 0.1-3 parts of epimedin C, 0.1-1 part of ligustrin G, 0.1-1 part of wild jujube saponin, 5-20 parts of rhizoma polygonati saponin, 0.1-5 parts of rhodioside, 0.05-1 part of hyperin, 0.5-10 parts of salvianolic acid B, 0.1-2 parts of oleanolic acid, 0.05-1 part of isorhamnetin, 10-30 parts of hawkthorn flavone, 0.1-1.5 parts of caffeoyl butanediamine, 0.5-8 parts of betaine and 0.05-3 parts of spinosin.
2. The use according to claim 1, characterized in that: the composition comprises the following components in parts by weight: 1-8 parts of medlar polysaccharide, 30-50 parts of astragalus polysaccharide, 0.5-4 parts of stilbene glucoside, 0.5-3 parts of epimedin B, 0.5-2 parts of epimedin C, 0.1-0.5 part of glossy privet glycoside G, 0.1-0.5 part of wild jujube saponin, 6-15 parts of rhizoma polygonati saponin, 0.5-2 parts of rhodiola root glycoside, 0.05-0.5 part of hyperin, 2-8 parts of salvianolic acid B, 0.1-1 part of oleanolic acid, 0.08-0.15 part of isorhamnetin, 15-25 parts of hawkthorn flavone, 0.2-1 part of caffeoyl butanediamine, 1-5 parts of betaine and 0.05-1 part of spinosin.
3. The use according to claim 2, characterized in that: the composition comprises the following components in parts by weight: 2-4 parts of medlar polysaccharide, 35-45 parts of astragalus polysaccharide, 1-3 parts of stilbene glucoside, 1-2 parts of epimedin B, 1-1.5 parts of epimedin C, 0.2-0.5 part of glossy privet glycoside G, 0.1-0.3 part of wild jujube saponin, 7-10 parts of rhizoma polygonati saponin, 0.8-1.2 parts of rhodiola rosea glycoside, 0.1-0.3 part of hyperin, 4-6 parts of salvianolic acid B, 0.4-0.6 part of oleanolic acid, 0.08-0.12 part of isorhamnetin, 16-20 parts of haw flavone, 0.2-0.4 part of caffeoyl butanediamine, 2-4 parts of betaine and 0.05-0.15 part of spinosin.
4. A use according to claim 3, characterized in that: the composition comprises the following components in parts by weight: 3 parts of medlar polysaccharide, 40 parts of astragalus polysaccharide, 2 parts of stilbene glucoside, 1.5 parts of epimedin B, 1.2 parts of epimedin C, 0.3 part of glossy privet glycoside G, 0.2 part of wild jujube seed saponin, 9 parts of rhizoma polygonati saponin, 1 part of rhodiola rosea glycoside, 0.2 part of hyperin, 5 parts of salvianolic acid B, 0.5 part of oleanolic acid, 0.1 part of isorhamnetin, 18 parts of hawthorn flavone, 0.3 part of caffeoyl butanediamine, 3 parts of betaine and 0.1 part of spinosin.
5. The use according to claim 1, characterized in that: the weight ratio of astragalus polysaccharide, rhizoma polygonati saponin, salvianolic acid B and hawthorn flavone is (30-50)/(5-20)/(0.5-10)/(10-30); the weight ratio of the wolfberry polysaccharide to the rhizoma polygonati saponin to the salvianolic acid B to the hawthorn flavone is (0.1-10), and the weight ratio of the wolfberry polysaccharide to the rhizoma polygonati saponin to the hawthorn flavone is (5-20), and the weight ratio of the wolfberry polysaccharide to the rhizoma polygonati saponin to the salvianolic acid B is (0.5-10) and the weight ratio of the wolfberry polysaccharide to the hawthorn flavone is (10-30).
6. The use according to claim 1, characterized in that: the medicament also comprises pharmaceutically acceptable auxiliary materials.
7. The use according to claim 1, characterized in that: the dosage forms of the medicine comprise oral liquid, tablets, capsules, granules, paste, powder, injection, spray or pills.
8. The use according to claim 7, characterized in that: the dosage form of the medicine is oral liquid.
9. The use according to claim 1, characterized in that: the preparation method of the composition comprises the following steps: mixing fructus Lycii polysaccharide, radix astragali polysaccharide, stilbene glucoside, epimedin B, epimedin C, ligustrum japonicum G13, semen Ziziphi Spinosae saponin, rhizoma Polygonati saponin, salidroside, hyperoside, salvianolic acid B, oleanolic acid, isorhamnetin, fructus crataegi flavone, caffeoyl butanediamine, betaine and spinosin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410199781.5A CN117771325B (en) | 2024-02-23 | 2024-02-23 | Application of composition in preparation of sleep improving medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410199781.5A CN117771325B (en) | 2024-02-23 | 2024-02-23 | Application of composition in preparation of sleep improving medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117771325A CN117771325A (en) | 2024-03-29 |
| CN117771325B true CN117771325B (en) | 2024-05-07 |
Family
ID=90389274
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410199781.5A Active CN117771325B (en) | 2024-02-23 | 2024-02-23 | Application of composition in preparation of sleep improving medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117771325B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012094832A1 (en) * | 2011-01-14 | 2012-07-19 | 广东药学院 | Compound chinese medicine extract used for preventing and treating arteriosclerosis and preparation method thereof |
| CN104056052A (en) * | 2014-07-08 | 2014-09-24 | 福建金山生物制药股份有限公司 | Preparation process of powerful anti-aging Chinese patent medicine with anti-aging effect |
| CN105726947A (en) * | 2016-02-02 | 2016-07-06 | 王知斌 | Acanthopanax senticosus leaf and polygonatum odoratum leaf extract for improving sleeping and reducing blood sugar and preparing method and application thereof |
| CN105748953A (en) * | 2016-03-09 | 2016-07-13 | 北京采瑞医药科技有限公司 | Traditional Chinese medicine composition with functions of treating insomnia, improving senile dementia, enhancing learning and memory abilities and resisting to depression and anxiety |
| CN115154481A (en) * | 2022-09-07 | 2022-10-11 | 吉林华康药业股份有限公司 | A Chinese medicinal composition for preventing and treating atherosclerosis and coronary heart disease |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444549B (en) * | 2008-09-05 | 2011-08-17 | 广东药学院 | Composition of plant extracts for preventing or curing metabolism disorder of blood lipid and application thereof |
-
2024
- 2024-02-23 CN CN202410199781.5A patent/CN117771325B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012094832A1 (en) * | 2011-01-14 | 2012-07-19 | 广东药学院 | Compound chinese medicine extract used for preventing and treating arteriosclerosis and preparation method thereof |
| CN104056052A (en) * | 2014-07-08 | 2014-09-24 | 福建金山生物制药股份有限公司 | Preparation process of powerful anti-aging Chinese patent medicine with anti-aging effect |
| CN105726947A (en) * | 2016-02-02 | 2016-07-06 | 王知斌 | Acanthopanax senticosus leaf and polygonatum odoratum leaf extract for improving sleeping and reducing blood sugar and preparing method and application thereof |
| CN105748953A (en) * | 2016-03-09 | 2016-07-13 | 北京采瑞医药科技有限公司 | Traditional Chinese medicine composition with functions of treating insomnia, improving senile dementia, enhancing learning and memory abilities and resisting to depression and anxiety |
| CN115154481A (en) * | 2022-09-07 | 2022-10-11 | 吉林华康药业股份有限公司 | A Chinese medicinal composition for preventing and treating atherosclerosis and coronary heart disease |
Non-Patent Citations (3)
| Title |
|---|
| 康欣口服液对老年小鼠肾线粒体ＤＮＡ缺失突变的影响;张小如;中国老年学杂志;20060531;第26卷(5);650-652 * |
| 康欣口服液抗脑衰老的实验研究;张小如;中国老年学杂志;20061231;第26卷(第12期);1681-1683 * |
| 康欣口服液质量标准的改进;叶静;时珍国医国药;20061231;第17卷(第10期);2008-2010 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117771325A (en) | 2024-03-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112972547B (en) | Traditional Chinese medicine composition for treating qi and blood deficiency syndrome and preparation method and application thereof | |
| CN112426503B (en) | Traditional Chinese medicine composition for treating depression | |
| CN113115940A (en) | Heart calming and sleep aiding composition as well as preparation method and application thereof | |
| CN111973721A (en) | Pharmaceutical composition for improving sleep and preparation method and application thereof | |
| CN103585479A (en) | Blood-replenishing pill and blood-replenishing capsule for treating iron-deficiency anemia | |
| CN113209166A (en) | Anti-aging traditional Chinese medicine composition containing nicotinamide mononucleotide and preparation method thereof | |
| CN117771325B (en) | Application of composition in preparation of sleep improving medicine | |
| CN109464505B (en) | Traditional Chinese medicine composition for treating diabetes | |
| CN110876772A (en) | Preparation method and application of traditional Chinese medicine preparation with liver protection function | |
| CN110772552A (en) | Ginseng tablet capable of improving immunity and preparation method thereof | |
| CN115487239A (en) | Pharmaceutical composition for treating insomnia with anxiety and depression and preparation method thereof | |
| CN109876127B (en) | Blood-nourishing angelica sinensis capsule and preparation method thereof | |
| CN109172608B (en) | A kind of Chinese medicine composition that can improve sleep quality | |
| CN112890173A (en) | Medicinal and edible composition with function of improving sleep quality and application thereof | |
| CN106581299B (en) | Traditional Chinese medicine composition for improving kidney qi deficiency of middle-aged and old people and application thereof | |
| CN113057994B (en) | Patrinia scabiosaefolia active component, preparation method and application thereof | |
| CN109010593B (en) | Nerve-soothing and deficiency-tonifying pharmaceutical composition and preparation method and application thereof | |
| CN104906339B (en) | It is a kind of that there is the health food granule for improving sleep function | |
| CN102579801B (en) | Traditional Chinese medicine preparation for treating diabetic syndrome and preparation method of same | |
| CN116870120B (en) | Traditional Chinese medicine composition for treating hyperplasia of mammary glands and preparation method and application thereof | |
| CN116920061B (en) | Traditional Chinese medicine composition for treating hyperglycemia and preparation method thereof | |
| CN113101330B (en) | Menstruation regulating composition and application thereof | |
| CN112168931B (en) | A pharmaceutical composition for treating oral ulcer, and its preparation method | |
| CN107050187A (en) | A kind of Chinese medicine composition for treating impotence, premature ejaculation and preparation method thereof | |
| CN108524731B (en) | Traditional Chinese medicine composition for treating myasthenia gravis and preparation thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |